Evidence review for escalation of lipid-lowering treatment for secondary prevention of CVD

Evidence review for escalation of lipid-lowering treatment for secondary prevention of CVD

Cardiovascular disease: risk assessment and reduction, including lipid modification

Evidence review D

NICE Guideline, No. 238

London: National Institute for Health and Care Excellence (NICE); 2023 Dec.

ISBN-13: 978-1-4731-5638-8

1. Escalation of lipid-lowering treatment for secondary prevention of CVD

1.1. Review question

In adults with CVD requiring escalation of therapy beyond statins, what is the effectiveness of lipid-lowering therapy?

1.1.1. Introduction

Recommendations in NICE guideline CG181, to date, have included advice on follow-up for people started on statin treatment; recommending a percentage reduction of non-HDL cholesterol levels to aim for at 3 months follow-up and guidance on factors to consider if this is not achieved, such as adherence and dose of statin therapy. However, the recommendations do not address when to escalate treatment beyond statin therapy.

Recent evidence suggests that many people are not being prescribed lipid lowering medicines beyond high intensity statins, even after a CVD event. This partial update of CG181 intends to address this gap, specifically for secondary prevention of CVD where risk of further CVD events is greatest. An evidence review and economic analysis will be undertaken to inform escalation of lipid lowering therapy beyond statins, including consideration of a treatment target for secondary prevention.

1.1.2. Summary of the protocol

For full details see the review protocol in Appendix A.

Table 1

PICO characteristics of review question.

1.1.3. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in Appendix A and the methods document. The clinical review was conducted mainly to provide inputs for the model and neither the pairwise nor network meta-analysis estimates directly inform the recommendations, as they cannot give any information about a cholesterol target. Therefore, setting specific clinical importance thresholds was not prioritised, but the size of the effects in relation to risks and benefits for people with CVD was discussed.

Where studies reported lipid levels as mg/dl, these were converted to mmol/litre using a conversion factor of 0.02586.

An original network meta-analysis was conducted by the NICE Technical Support Unit for the outcomes of percentage and absolute change in both LDL cholesterol and non-HDL cholesterol. Details of this analysis are provided in a separate NMA results document.

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

1.1.4. Effectiveness evidence

Included studies

Thirty four RCT studies reported in 51 papers were included in the review;^{1–27, 29–42, 44–53} these are summarised in Table 2 below. Evidence from these studies is summarised in the clinical evidence summaries below (Table 3 to Table 7).

See also the study selection flow chart in B.2, study evidence tables in Appendix D, forest plots in Appendix E and GRADE tables in Appendix G.

All included studies reported having at least 80% of participants with cardiovascular disease (CVD) at baseline. However, there were differences between the studies regarding statin treatment before randomisation and statin intensity during the trial, as well as in the dosing regimens of the PCSK9 monoclonal antibodies. Furthermore, not all of the trials were placebo controlled, with some using an active comparator or usual care with no blinding. These details are summarised in Table 2.

Of the 34 included trials:

15 (reported in 19 papers)^{3–5, 7, 15–17, 21, 23–25, 35, 39, 46–48, 50–52} compared ezetimibe plus statin with statin alone. Of these:
- 2 were placebo-controlled.^{5, 16}
- At randomisation 4 used medium-intensity statins,^{3, 5, 25, 52} 8 used high-intensity^{16, 17, 23, 24, 35, 39, 49, 50} and 2 used mixed or unclear statin intensities.^{46, 48}
- IMPROVE-IT was the largest trial, and it should be noted that 27% of participants in the statin arm were escalated from simvastatin 40 mg to simvastatin 80 mg.⁵
- Only 1 trial exclusively included patients who had prior statin treatment;⁴⁹ 1 had 57% with statin pre-treatment,³ 6 reported <50% with prior statin,^{5, 25, 39, 46, 48, 52} and 2 included only statin-naïve patients.^{16, 35}
- Follow-up ranged from 12 weeks to 6 years.
14 (reported in 26 papers)^{1, 2, 8, 9, 11, 12, 18–20, 26, 27, 29–34, 36, 38, 40–42, 44, 45, 49, 53} compared PCSK9 inhibitors (PCSK9i) with placebo or usual care in populations amongst whom the majority were taking background statin treatment. Of these:
- The control group was usual care in 4 trials.^{2, 11, 36, 38}
- All except one³⁴ enrolled those with statin pre-treatment, which continued during trial.
- Statin intensity definitions did not match those used in this guideline, but most participants were on maximum tolerated dose, which included high and medium intensity statins in varying proportions.
- The largest trials were FOURIER⁴² (N=27563) and ODYSSEY OUTCOMES⁴⁵ (N=18924).
- The specific PCSK9 monoclonal antibody used was alirocumab in 9 trails reported in 8 papers^{2, 11, 18, 19, 26, 34, 36, 45} and evolocumab in 4 trials,^{12, 29, 31, 42} with 1 trial including both.³⁸
- Follow-up ranged from 12 weeks to >2 years.
- The results for ODYSSEY LONG TERM,²⁶ ODYSSEY DM-DYSLIPIDEMIA³⁶ and ODYSSEY DM-INSULIN³⁶ do not represent the full trial cohort, which included <80% with CVD. Therefore, the CVD subgroup from individual participant data (IPD) meta-analysis has been reported in this review.
2 trials^{6, 13} compared PCSK9i with ezetimibe in populations amongst whom the majority were taking background statin treatment.
1 trial¹⁴ compared PCSK9i plus ezetimibe with ezetimibe in populations amongst whom the majority were taking background statin treatment.
2 trials (reported in 1 paper)³⁷ compared inclisiran with placebo (ORION 10 and 11) in populations amongst whom the majority were taking background statin treatment.

Cochrane reviews

Two Cochrane reviews^{43, 54} were identified that partially matched the protocol and were included and used in the following ways:

All included studies were cross-checked for inclusion in this review.
Relevant outcome data for studies included in this review was cross-checked with the data extracted for this analysis as an additional measure of quality assurance.
Risk of bias assessments for studies included in this review were used as a basis for critical appraisal considerations but were re-assessed per outcome and in line with NICE guideline methodology.

Evidence tables for the individual systematic reviews have not been included in the present review but the relevant information from them has been used to inform the analyses and cross-check data included in the evidence tables for the relevant studies.

Earlier versions of these reviews and their review protocols have not been included. See the excluded studies list in Appendix K.

1.1.5. Summary of studies included in the effectiveness evidence

Details of the included studies are summarised in Table 2.

Table 2

Summary of studies included in the evidence review.

See Appendix D for full evidence tables.

1.1.6. Summary of the effectiveness evidence

Primary analyses

Table 3

Clinical evidence summary: ezetimibe plus statin versus statin.

Table 4

Clinical evidence summary: PCSK9i versus placebo or usual care.

Table 5

Clinical evidence summary: PCSK9i versus ezetimibe.

Table 6

Clinical evidence summary: PCSK9i plus ezetimibe versus ezetimibe.

Table 7

Clinical evidence summary: inclisiran versus placebo.

See Appendix G for full GRADE tables.

Sensitivity analyses

Forest plots showing the data stratified according to the prespecified subgroups (baseline LDL cholesterol, and non-HDL cholesterol and statin intensity) are provided in Appendix F where sufficient data were available.

These were discussed at the guideline committee meeting and the committee agreed that, while there was often insufficient outcome data to test robustly, the sensitivity analyses results did not show a consistent signal of any difference in LDL cholesterol, non-HDL cholesterol or MACE reductions achieved by any of the interventions according to baseline LDL cholesterol or non-HDL cholesterol or by statin intensity. Thus, decision making was based on the primary analysis using the total population and GRADE tables are not presented for the sensitivity analyses.

1.1.7. Economic evidence

The purpose of this review question was to identify key inputs for an economic model comparing the cost effectiveness of different cholesterol targets – see separate economic analysis report. Economic evaluations of lipid modification therapy were not systematically reviewed.

1.1.8. Evidence statements

Effectiveness/Qualitative

Not applicable.

Economic

Not applicable.

1.1.9. The committee's discussion and interpretation of the evidence

The outcomes that matter most

The committee agreed that LDL cholesterol, non-HDL cholesterol, combined major adverse cardiovascular events (CVD death, non-fatal MI, non-fatal ischemic stroke), quality of life and specific treatment-related adverse events (myopathy/rhabdomyolysis, new-onset diabetes, increased liver transaminases, cancer, gall-bladder related diseases, injection-site reactions, nausea and influenza) were all required for this evidence review. For the purposes of decision making, all outcomes were considered equally important and were therefore rated as critical.

The quality of the evidence

There were 34 RCTs included in the clinical evidence. The quality of the evidence varied across comparisons ranging from very low to high for different outcomes.

Pairwise analyses

Ezetimibe plus statin versus statin alone

There were 15 RCTs comparing ezetimibe plus statin versus statin alone, 10 of which were open-label unblinded studies. The majority of the outcomes available for this comparison were rated as moderate quality, including percentage change in LDL cholesterol from baseline, MACE outcomes and raised liver transaminases and gallbladder-related adverse events. These were downgraded for either imprecision where the confidence interval around the effect estimated crossed an MID, or for concerns over intervention indirectness due to imbalance in statin dose between intervention and comparator groups. Evidence for cancer was rated as high quality. Evidence for LDL cholesterol and non-HDL cholesterol reported as final values or absolute changes and percentage change in non-HDL cholesterol was of very low quality because of imprecision and further downgrading for risk of bias (such as high rates of missing data, imbalance in age between groups, insufficient information about randomisation procedures and potential deviation from randomised intervention in unblinded studies). Evidence for myopathy/rhabdomyolysis was also of very low quality, downgraded for imprecision and the aforementioned concerns over indirectness related to the intervention received, which was particularly important for this outcome because simvastatin 80 mg is known to be associated with an increased incidence of muscle adverse events.

The committee discussed the characteristics of the trial participants, including statin use before and during the study period. For this comparison only 1 trial exclusively included people who had prior statin treatment, 1 had 57% with statin pre-treatment, 6 reported <50% with prior statin, 3 included only statin naïve participants, while the remaining 4 did not provide information on prior statin use. Regarding the starting dose of statin at randomisation, 4 used medium intensity statins, 9 used high intensity and 2 were mixed or unclear. Statin dose titration was permitted if targets were not met in at least 3 trials that did not start participants on high-intensity statins. This included the IMPROVE-IT trial, in which 27% in the statin alone arm were escalated to simvastatin 80 mg compared to 6% in the ezetimibe arm. The committee noted that this is likely to dilute the relative benefit of adding ezetimibe to statin but agreed that this does not limit the usefulness of the data as it reflects real-world practice. Other studies did not specify if dose escalation was permitted.

PCSK9i (alirocumab or evolocumab) versus placebo or usual care

Evidence for PCSK9i (alirocumab and evolocumab) compared to placebo or usual care was available from 14 RCTs. The quality of the evidence for the majority of outcomes including LDL cholesterol and non-HDL cholesterol and nausea was low due to imprecision around the effect estimates and inconsistency due to heterogeneity in the results of the studies contributing to the lipid outcomes that was unexplained by subgroup analysis. The quality of the evidence for MACE was moderate, only downgraded due to imprecision. The quality of the evidence for the adverse events of new-onset diabetes, increased liver transaminases and injection-site reactions was high, with no concerns lowering confidence in the evidence.

All except 1 trial enrolled people who were already receiving statins, which they continued alongside the randomised interventions. In most cases statins were administered at the maximally tolerated dose, which included high and medium intensity in varying proportions. A small proportion of participants (ranging from 1 to 14%) were also receiving ezetimibe as part of lipid-lowering therapy in 9 trials. The committee agreed that this was similar to current UK practice for those receiving PCSK9 inhibitors.

PCSK9i versus ezetimibe

The quality of the evidence for PCSK9i vs ezetimibe, available from 2 RCTs, was mostly of very low or low quality as it was downgraded for imprecision around the effect estimates and in some cases indirectness related to the outcome reporting (time-point being shorter than 12 months for MACE in one of the two contributing studies). For influenza, there was also risk of bias as it was unclear whether the outcome was consistently reported. The quality of the evidence for lipid outcomes was higher. Specifically, evidence was considered high quality for LDL cholesterol and moderate for percentage change in non-HDL cholesterol from baseline, the latter being downgraded for concerns over inconsistency due to heterogeneity in the results of the two studies contributing to the pooled estimate. Participants were receiving stable maximally tolerated statin therapy, which continued alongside the randomised interventions, which is directly applicable.

PCSK9i plus ezetimibe versus ezetimibe alone

Evidence for PCSK9i plus ezetimibe compared to ezetimibe alone, available from one RCT, was of low quality, downgraded for risk of bias due to the recruitment and randomisation methods not being specified (leading to potential selection bias), and treatment being adjusted according to lipid control during follow-up in combination with lack of blinding.

Inclisiran versus placebo

Evidence for inclisiran versus placebo, available from 2 studies was of moderate quality for LDL cholesterol and MACE and of low quality for injection site reactions and very low quality for increased liver transaminases. The quality of the evidence was mostly downgraded for imprecision and for inconsistency in the cases of LDL cholesterol and injection-site reactions due to heterogeneity in the results reported between the studies contributing to the pooled estimates for those outcomes. Increased liver transaminases and injection-site reactions were further downgraded for risk of bias due to the event rate being lower than the number lost to follow-up meaning that if any events had occurred in those who were not available for the analysis the effect estimate may have changed significantly.

Summary

Overall, the committee were confident that the evidence for LDL and non-HDL cholesterol were of sufficient quality to reliably inform the network meta-analyses and health economic model.

Network meta-analyses

For absolute and percentage change in LDL cholesterol and non-HDL cholesterol, the risk of bias and indirectness was as described for the pairwise analyses because the same studies were included.

The credible intervals around the effect estimates for each intervention relative to placebo varied. For absolute and percentage change in LDL cholesterol, there was little uncertainty for most of the estimates for active treatments compared to placebo. However, there was moderate uncertainty for percentage change in LDL cholesterol for inclisiran compared to placebo, with credible intervals spanning around 20% and for evolocumab plus ezetimibe there was considerable uncertainty for absolute change in LDL cholesterol with credible intervals spanning 0.8 mmol/litre.

For percentage change in non-HDL cholesterol there was considerable uncertainty for ezetimibe and inclisiran, with the credible intervals spanning an interval of more than 20% and moderate uncertainty for PCSK9i with the credible interval spanning around 15%. For absolute change in non-HDL cholesterol, which was not available for inclisiran, the credible intervals spanned more than 1.0 mmol/litre for ezetimibe and more than 0.8 mmol/litre for PCSK9i, again showing considerable uncertainty.

Inconsistency was minimal for all of the modelled datasets, and there was good agreement between the direct and indirect treatment effect estimates.

The committee were confident that these results were a good reflection of the true effects and could therefore be used to inform the economic model.

Benefits and harms

Pairwise analyses

Ezetimibe plus statin versus statin alone

Absolute LDL cholesterol change from baseline or final score was more commonly reported than other lipid outcomes. The committee noted variability between studies in the change and final scores. Overall, adding ezetimibe had a clear benefit for additional lipid lowering compared with statin alone. There was limited evidence to demonstrate whether this benefit translated into a reduction in MACE and the absolute risk difference was modest. However, the committee discussed that the majority of studies had a follow-up of 1 year or less, and that in the largest study with the longest follow-up the benefit of ezetimibe was likely to have been diluted by the simvastatin dose being increased in a larger proportion of the control group than the experimental group. Therefore, they agreed that the evidence was likely to be an underestimate of the true benefit of ezetimibe for this outcome.

The occurrence of protocol-reported adverse events (including myopathy/rhabdomyolysis, liver transaminases, cancer or gallbladder-related adverse events) was rare overall making the estimates imprecise, but the committee agreed that there were no clinically important differences for any reported adverse events. This was in line with the committee’s opinion that the adverse events of ezetimibe were minimal and did not outweigh the benefits.

PCSK9i (alirocumab or evolocumab) versus placebo or usual care

The committee noted that LDL cholesterol was more commonly reported than non-HDL cholesterol, and that there was some inconsistency between studies in the lipid outcomes. However, adding alirocumab or evolocumab to statin, with or without ezetimibe, resulted in additional lipid lowering compared with placebo or usual care and the size of the effects, showing a large benefit of PCSK9i compared with control, were as the committee would expect based on their clinical experience.

As for ezetimibe, there was limited evidence to demonstrate whether this benefit translated into a reduction in MACE. The committee noted that despite there being a greater lowering of LDL cholesterol with PCSK9i than with ezetimibe, the MACE benefit in terms of the absolute effect was similar. They discussed that this could be due to the PCSK9i trials being shorter due to insufficient funding for longer durations, which could mean that the maximal benefit for this outcome was not observed during the trials.

There were no clinically important differences in terms of adverse events including myopathy/rhabdomyolysis, new onset diabetes, increased liver transaminases, injection-site reactions or nausea. The committee noted that although the effect was not clinically important compared to control, a small proportion of people receiving PCSK9i experienced injection-site reactions. They agreed that this reflected a low number of events and that injection-site reactions are not likely to be significant or long-lasting.

PCSK9i versus ezetimibe

Amongst participants receiving stable maximally tolerated statin therapy PCSK9i achieved greater reductions in LDL cholesterol and non-HDL cholesterol compared to ezetimibe. There were no clinically important differences in terms of MACE, new onset of diabetes or increased liver transaminases. The committee agreed evidence for this comparison was limited considering the number of participants included and the relatively short duration of follow-up. They agreed evidence contributed to the NMA results but was of limited usefulness in its own right.

PCSK9i plus ezetimibe versus ezetimibe alone

The committee noted that evidence for this comparison was very limited as it was only available from one study with a total of 129 participants and the short duration of follow-up limiting the extent to which conclusions could be drawn.

Inclisiran versus placebo

Participants were receiving stable maximally tolerated statin therapy, with 6–10% also receiving ezetimibe, which continued alongside the randomised interventions. Evidence showed a large clinical benefit of inclisiran compared to placebo in terms of LDL cholesterol reduction, which the committee agreed reflected their experience. There was no clinically important difference between inclisiran and placebo in terms of MACE (definition including non-adjudicated events: CV death, cardiac arrest, non-fatal myocardial infarction and nonfatal stroke), but the committee agreed that the size of the absolute benefit of inclisiran was encouraging considering that the MACE outcome was exploratory and so the trials were not powered to detect a difference. They agreed that this exploratory endpoint gives indicative evidence that supports the likely translation of decreased cholesterol levels to reduced cardiovascular events, and they had confidence in the findings as being sufficient to inform the economic model.

The committee noted that inclisiran did result in more injection site reactions compared to placebo. However, they noted that the trials reported most of these to be mild (discomfort noticed, but no disruption to daily activity) and some moderate (discomfort sufficient to reduce or affect normal daily activity), but none were severe or persistent. The committee agreed that the effect was not clinically important particularly as injection frequency of inclisiran is low (every 6 months).

Sensitivity analyses (all comparisons)

It was noted that some studies conducted sensitivity analyses exploring the effect of different baseline LDL cholesterol and non-HDL cholesterol levels and of different statin intensities used by study participants upon lipid and MACE outcomes. Forest plots of those analyses were presented to the committee and it was agreed that while there was often insufficient outcome data to test robustly, there was no consistent signal of any difference in LDL cholesterol, non-HDL cholesterol or MACE reductions achieved by any of the interventions according to baseline LDL cholesterol or non-HDL cholesterol or by statin intensity. Thus, decision making was based on the primary analysis using the total population.

Summary

The pairwise evidence showed a benefit of all reviewed lipid lowering therapies for additional reduction of LDL cholesterol beyond that achieved by statins alone, without any clinically important increase in adverse events. Although there was some imprecision and heterogeneity, the findings for efficacy and adverse events were consistent with the committee’s clinical experience and expectations. Therefore, they agreed that the evidence was reliable to help inform the network meta-analysis and economic model.

Network meta-analyses

The committee discussed the effect estimates that draw on all available clinical evidence to provide consistent effect sizes compared to a control group (labelled placebo, but which included statin treatment) across all treatments in the network. They agreed that the findings for LDL cholesterol and non-HDL cholesterol broadly aligned with their expectations and experience, showing a large benefit of PCSK9i compared to control, with a similar but slightly lower benefit for inclisiran and a benefit for ezetimibe that was considerably less than that for PCSK9 or inclisiran.

The committee noted that they would expect to see a greater relative benefit for LDL cholesterol than for non-HDL cholesterol, but that this was not the case for the ezetimibe effect estimates from the NMA. The committee discussed that the greater benefit for non-HDL cholesterol in the ezetimibe data could be due to the fact that only 1 small study reported non-HDL cholesterol percentage change for ezetimibe versus statin alone, and showed a larger benefit for serum cholesterol than some other studies. The committee also discussed the possibility that ezetimibe can lead to 2–5% increase in HDL cholesterol and therefore this may also contribute to the NMA findings. Therefore, the NMA estimate for ezetimibe versus control was informed more by the indirect effect of alirocumab compared to ezetimibe, which may have caused the discrepancy from expectations.

The NMA effect estimates for inclisiran and PCSK9i were broadly consistent with those from the pairwise meta-analysis for all 4 outcomes assessed. However, for ezetimibe the NMA estimate for percentage change in LDL cholesterol and non-HDL cholesterol were higher than the results from the pairwise analyses. For non-HDL cholesterol this was likely to be due to the limited evidence available for percentage change in the direct comparison of ezetimibe versus control, meaning the NMA estimates were more influenced by the indirect comparisons.

Meta-regression models were conducted to explore the impact of mean baseline lipid levels on the treatment effect. However, there was very limited evidence with which to estimate the meta-regression models, and the, although effects were very uncertain, did not indicate any effect modification by baseline mean lipid levels in the studies. Therefore, the committee agreed that the meta-regression models were not useful to inform any further analyses.

Cost effectiveness and resource use

No published economic evaluations were found that compared different lipid targets. Therefore, original economic modelling was undertaken.

Cost effectiveness modelling of treatment escalation

As noted above, the treatments available for escalation for people with CVD who are on a statin were found to be both effective and safe. Although the injectable therapies (inclisiran and the PCSK9 inhibitors) were more effective than ezetimibe, they are considerably more costly due to the acquisition cost (even at confidential price levels that are discounted for the NHS) and the need for health care professionals to administer injections. Inclisiran has a lower cost than the PCSK9 inhibitors, even though patients taking PCSK9 inhibitors can self-inject.

The committee agreed that the cost of escalation treatment will be at least partially offset by reduced admissions and procedures for cardiovascular disease; therefore, it is important to weigh up the cost savings and health gain against the cost of treatment.

For the population, ezetimibe was the most cost-effective escalation treatment, with a cost per QALY under £1000. However, further routine escalation to any injectable treatment would cost over £30,000 per QALY. It is clearly not cost-effective to offer the full range of treatments to everyone with CVD, so it is important to assess at which baseline lipid levels, escalation could be cost effective.

Cost effectiveness of escalation by baseline lipid level

The economic models was developed using two alternative approaches. For each approach, separate analyses were conducted using treatment effects based on LDL cholesterol reduction and non-HDL cholesterol reduction. In both approaches, the sequence of escalation from a statin was first ezetimibe and then inclisiran. They differed as follows:

In the first approach the lipid levels at which it is cost effective to escalate therapy were estimated separately for adding ezetimibe to a statin and then for adding inclisiran to ezetimibe and a statin.
The second approach looked at a single lipid level at which it was cost effective to escalate treatment.

In patients maintained on statin therapy, the first approach demonstrated the cost effectiveness (at £20,000 per QALY gained) of adding ezetimibe irrespective of the actual LDL cholesterol or non-HDL cholesterol level and therefore a threshold value for the introduction of ezetimibe was not defined. With all patients maintained on both statin and ezetimibe, the addition of inclisiran was only cost-effective for those individuals with LDL cholesterol levels above 3.1 mmol/litre (or 4.1 mmol/litre for non-HDL cholesterol).

The second economic model approach demonstrated that escalation was cost effective for people with LDL cholesterol levels above 2.2 mmol/litre (or 2.9 mmol/litre for non-HDL cholesterol) after treatment with a statin i.e. only patients with LDL cholesterol > 2.0 mmol/litre (or non-HDL cholesterol > 2.9 mmol/litre) despite receiving statin therapy would then be prescribed ezetimibe, and only if the target of LDL cholesterol 2.2 mmol/litre (or non-HDL cholesterol 2.9 mmol/litre) was still not achieved would inclisiran be added. However, there was uncertainty in the region between 2.0 and 2.2 as, in the probabilistic analysis, 2.0 was the most cost-effective target in around 40% of the simulation. It was noted that amongst the CVD population (all receiving statin therapy) used for these models, the mean LDL cholesterol was 1.9 mmol/litre prior to any therapy escalation.

The base case scenario of the second approach defined a specific escalation pathway involving statins, followed by ezetimibe plus statin and finally inclisiran plus ezetimibe plus statin. In practice, the pathway does not always follow this sequence. As specified in TA733, people may be escalated to inclisiran without first receiving ezetimibe based on current cholesterol level and clinical judgement. Scenario analyses were conducted for 3 alternative pathways allowing some people to start an injectable therapy without first receiving ezetimibe. The most cost-effective target increased to 2.4 mmol/litre in the pathway where people could receive ezetimibe alone, inclisiran alone or ezetimibe together with an injectable therapy. When combination therapies or PCSK9i were excluded, the cost-effective target remained at 2.2 mmol/litre LDL-C.

Within each approach, the model identified a strategy that was most cost effective (below £20,000 per QALY):

Treatment-specific cholesterol thresholds - Ezetimibe for all at outset and then add inclisiran above 3.1 mmol/litre LDL cholesterol (4.1 mmol/litre non-HDL cholesterol).
Singe cholesterol target - Statin therapy only, UNLESS a target value of LDL cholesterol 2.2 mmol/litre (non-HDL cholesterol 2.9 mmol/litre) has not been achieved.

The reason that the second approach had a lower optimal cholesterol threshold was because the cost effectiveness of escalation is based on the cost effectiveness of both ezetimibe and inclisiran combined, rather than just inclisiran alone. Comparing the two strategies with each other, the single target strategy saw fewer people on ezetimibe, more people on inclisiran. It had a higher cost and more QALYs but the cost per additional QALY was greater than £30,000 per QALY. Both strategies are likely to cost less than £20,000 per QALY compared to current practice, where escalation is uncommon and they would be cost saving compared with an LDL cholesterol target of 1.8 (non-HDL cholesterol 2.5 mmol/litre), as currently recommended in the NHS Quality Outcomes Framework.

The results were robust to sensitivity analysis, except that:

The inclisiran treatment threshold was lower when alternative utility scores were used.
Both targets were lower if a £30,000 per QALY threshold was used.
The single target was higher when people were less adherent to ezetimibe and lower when people were less adherent to inclisiran.
Both targets were higher if PCSK9 inhibitors were used instead of inclisiran.
Both targets were higher if a treatment effect was applied only to cardiovascular mortality (not to all-cause mortality) but this approach is likely to under-estimate the benefits of escalation.
The single target was slightly higher when a different treatment pathway allowing people to use inclisiran with or without ezetimibe was used.

However, the committee were satisfied that the base case analyses were based on the most plausible assumptions.

For each approach, models were run twice with treatment effects based first on LDL cholesterol and then separately based on non-HDL cholesterol. Although, the base case results of each model were consistent, the LDL-c targets were generally considered more robust for the following reasons:

There was more trial evidence for the estimates of the percentage reduction in LDL cholesterol than there were for the estimates of non-HDL cholesterol.
There was more statin trial evidence for the effect of LDL cholesterol on cardiovascular events than there was for the effect of non-HDL cholesterol on cardiovascular events. For some of the cardiovascular events the results had to be approximated as there was only empirical evidence for MI and stroke.

However, the committee agreed that a non-HDL cholesterol target should also be given when LDL cholesterol is not requested or calculated.

Committee interpretation and recommendations

The committee acknowledged that giving ezetimibe to everyone who has CVD and is on a statin and then inclisiran or other injectable for those above an LDL cholesterol of 3.1 mmol/litre would be a relatively low cost and efficient strategy. However, they chose to recommend treating people to a LDL cholesterol target of 2.0 mmol/litre for the following reasons:

A target that is similar to that recommended by other organizations would be more likely to lead to increased use of cost-effective treatments, including statins.
Although it would mean people at low levels of cholesterol do not get ezetimibe, it would mean people with LDL levels between 2.0 and 3.1 mmol/litre after eztemibe would get other lipid lowering treatment, and so it favours people in more need of treatment.
The target of 2.0 was found to be cost-effective in a significant proportion of the simulations of the probabilistic analysis and would enable the treatment of a larger population with elevated LDL-c levels, mitigating their high risk of future CVD events.

Using the distributions from the CPRD dataset, a 2.0 LDL cholesterol equivalent target that would lead to the same proportion (42%) of people escalating would be 2.6 non-HDL cholesterol. As an alternative approach, non-HDL cholesterol was calculated using the Friedewald equation and the mean triglyceride level of 1.4 mmol/litre. This method also resulted in a non-HDL cholesterol of 2.6 mmol/litre.

Given that the evidence showed that ezetimibe was cost effective regardless of the person’s lipid levels, the committee also decided that it could be considered for people with lipid levels below the agreed targets of 2.0 mmol/litre for LDL cholesterol and 2.6 mmol/litre for non-HDL cholesterol, taking into account the trade-off between increasing medication (the committee noted that a combination pill of Atorvastatin and ezetimibe is available in the USA), minimising risk and the burden of implementation which is most likely to fall within primary care.

It is expected that this update to the guideline will substantially increase prescribing of ezetimibe and inclisiran and that this will represent a substantial resource impact for the NHS. However, it will also be associated with reduced admissions for stroke, MI and cardiovascular procedures and longer survival for patients. Overall, the committee concluded that this target would increase NHS costs but would be cost effective.

People who are statin intolerant

Pre-consultation feedback on the draft guideline from external stakeholders highlighted the absence of recommendations on the treatment pathway for people who are statin intolerant and specifically the role of bempedoic acid. They also questioned if the draft treatment target applied to people who are statin-intolerant. The committee therefore made recommendations based on the technology appraisal TA694 Bempedoic acid with ezetimibe for treating primary hypercholesterolaemia or mixed dyslipidaemia and on economic modelling of people who are statin intolerant.

The committee discussed that statin intolerance is very difficult to define. The current guideline refers to trying three different statins whereas other definitions are less prescriptive, for example the presence of clinically significant adverse effects that represent an unacceptable risk to the patient or that may reduce compliance with therapy (NICE TA385 Ezetimibe for treating primary heterozygous familial and non-familial hypercholesterolaemia).

The committee discussed that the proportion of people who are unable to take statins due to side effects or adverse events is very small and therefore true statin intolerance is rare. The proportion of people reporting side effects in trials is often at a similar rate in the statin and placebo arms and evidence used to calculate the prevalence of statin intolerance does not take this into account.

The committee emphasised that statin therapy is the most effective method of reducing the risk of CVD events and that this should be the mainstay of treatment. They highlighted the importance of following recommendation 1.4.30 on strategies to use if someone reports adverse effects when taking a statin.

The committee discussed, but did not review, the evidence from the NICE technology appraisal on bempedoic acid (TA694), as well as from the CLEAR Outcomes trial that was published after TA694. They noted that people in the control arms of the trials were not on the optimal lipid lowering therapies, which could result in an over-estimation of the effectiveness of bempedoic acid. They also noted the high incidence of renal adverse events in CLEAR Outcomes. It is not clear if the observed changes to renal outcomes would have resulted in serious complications had the treatment not been stopped, or what form of monitoring would be helpful. In addition, the mean age of the people in this trial was 7 years lower than the mean age of the people with CVD in whom the drug would be offered in clinical practice. Therefore, the incidence of adverse events may be higher and a proportion are likely to be unable to tolerate bempedoic acid.

The committee discussed whether the target should be different in the statin intolerant population because of the different treatment options and associated costs. However, it was noted that this may introduce inequality regarding access to lipid-lowering treatment, and that the target at which escalation is cost effective did not change when the statin intolerant population was included in the model, largely because the prevalence of statin intolerance is relatively low. Therefore, the committee agreed that the target for people who are statin intolerant should be the same as for those who are on statin therapy, supported by the health economic sensitivity analysis. They made recommendations consistent with those in the NICE TA694 to offer ezetimibe and if this does not result in the person achieving the target or less, then other lipid lowering therapies should be offered in addition. Which therapy to offer should be discussed as part of shared decision making and depends on several different factors, for example bempedoic acid is an oral preparation whereas inclisiran, evolocumab and alirocumab are injectable formulations. The committee also highlighted that the recommendation would no longer be a cost-effective use of NHS resources if the number of people being labelled as statin intolerant and following the associated treatment pathway increased too far beyond the 9.1% estimate included in the model sensitivity analysis. Therefore, they emphasised the importance of trialling of statin therapy in line with the recommendations in this guideline before considering someone to be statin intolerant because the proportion who are truly statin intolerant is likely to be less than 9.1% and the best way to help people to achieve the target will be following the statin pathway in the majority of people. The committee noted that there is guidance from the Accelerated Access Collaborative for people who are statin intolerant.

A sensitivity analysis including people who are statin intolerant was added to the economic models which included a different escalation pathway with bempedoic acid. The sensitivity analysis found that the inclusion of this population would not affect the optimal LDL-c single target which remained 2.2 mmol/litre.

People at very high risk

The committee looked for a single LDL cholesterol target for all people with CVD and on a statin. Some people will be at higher cardiovascular risk due to risk factors other than their cholesterol levels, for example if they smoke or if they have had multiple CVD events. Potentially these people have even more to gain from lipid lowering therapy escalation. However, we do not know if a lower target would be cost-effective for these patients. We cannot be sure that the relationship between cholesterol reduction and cardiovascular outcomes, as measured by the CTTC, is the same as for the population as a whole and the gain in life expectancy could be less given their additional risk factors. These people are included in the trial and observational data inputting in to the model but were not analysed as a separate subgroup.

Other factors the committee took into account

The committee heard evidence from an expert witness; Andrew Black, vice Chair of the NICE indicator advisory committee (IAC). A written account of the testimony is provided in Appendix L. The testimony provided additional contextual information to the committee regarding what is considered when deciding on an indicator. The committee were informed of the request to develop indicators for cholesterol targets due to the existing recommendation in CG181 to aim for a 40% reduction in non-HDL cholesterol levels not being measurable in electronic clinical systems as the systems are unable to extract the two measurements to calculate the percentage, and in some cases due to baseline data being lacking even if percentages were calculated and entered manually. The lack of baseline cholesterol levels was a particular problem in secondary prevention when people may be initiated on treatment following occurrence of an acute event and the lipid level at that time not being recorded. The committee were also made aware of a draft lipid target that was put out to consultation by the IAC, with a non-HDL cholesterol value of 3.3 mmol/litre, but this was not accepted due to negative stakeholder feedback on both sides.

The committee discussed whether indicators could be based on treatment received rather than target levels, as targets could discourage treatment of people if their lipid levels are just below the target. A measure that incentivised increasing the number of people on recommended treatment may be of better value. It was noted, however, that in the case of lipid management this was problematic as the number of people on statins could be measured from electronic systems, but not those on high-intensity statins or a particular dose of statin. It was also not possible to capture whether a prescription had been filled by the person, or whether the medicines were taken and so adherence could not be captured.

The committee were also aware that NHS England had introduced an indicator for the 2023/24 Quality Outcomes Framework (QOF) in the absence of a NICE indicator. The QOF indicator included target lipid levels of lower than 2.5 mmol/litre non-HDL cholesterol and lower than 1.8 mmol/litre LDL cholesterol. The committee noted that the evidence-based treatment target demonstrated in the single target model approach developed as part of this update was broadly in line with this. Although slightly higher, the committee agreed it was the correct level to recommend in the guideline as it was based on a robust review and analysis of data. A target of 1.8 mmol/litre LDL had a cost per QALY gained that was substantially above £20,000 when compared to 2.0 mmol/litre. It would require many more people to use an injectable therapy and the opportunity cost to other NHS patients would be considerable.

The committee discussed that CG181 to date included recommendations for initial measurements for people starting on lipid lowering therapy, which stated that total cholesterol, HDL cholesterol and triglycerides should be measured, along with non-HDL cholesterol which is calculated from these. The recommendations specifically state that a fasting sample is not required, which would be needed for a robust calculation of LDL cholesterol. Although non-HDL cholesterol is more commonly used in primary care, for these reasons, the committee noted that guidance for other lipid lowering therapies includes eligibility based in part on LDL cholesterol levels. Other guidelines that have included lipid targets and the QOF include both non-HDL and LDL cholesterol. Therefore, the committee agreed that recommendations for targets needed to include both measures. They agreed the recommendation for what should be measured when starting on statin should clarify that total cholesterol, HDL cholesterol and triglyceride levels should be measured in order to calculate non-HDL cholesterol and LDL cholesterol, so as not to imply that LDL cholesterol needed to be measured directly.

Committee consensus opinion, informed by national audits, was that uptake of statins was suboptimal (there are a reasonably small number of CVD patients who are not on any statin but many who are most likely not on the highest dose/intensity that they could tolerate) even in those who had CVD. They agreed it was important to ensure that people with CVD were offered atorvastatin 80 mg, as recommended in this guideline, and if already on a statin, to ensure people were receiving the maximum tolerated high intensity statin dose. Evidence considered within this update demonstrated that the addition of ezetimibe to maximally tolerated statin would have a favourable impact on an individual’s lipid profile and would be cost-effective. Again, the committee were aware that ezetimibe prescribing at present was relatively low. The committee agreed that an increase in prescribing and uptake of ezetimibe in people with CVD could have a substantial impact on achieving lower LDL-c / non-HDL-c levels. The committee did however consider the pragmatic implications of recommending both high intensity statin therapy and ezetimibe to all patients with CVD, particularly given the limited experience and use of ezetimibe in both primary and secondary care. The implementation process would place a significant additional burden on primary care both in terms of a systematic review of all patients with CVD in order to offer ezetimibe therapy as well as the assessment of adherence, side-effects and impact of polypharmacy. In addition, many patients who are maintained on statin therapy believe their cholesterol levels to be “well controlled” and therefore the rationale for introducing another lipid lowering drug without a specific target to base this upon may lead to both confusion and reticence amongst patients. Furthermore, for those statin naive individuals with a new diagnosis of CVD, it is unclear as to whether or not introducing both high intensity statin and ezetimibe immediately would be deemed acceptable and appropriate given the potential impact on perceived adherence/tolerance of these therapies (particularly given that the majority of CVD event reduction is achieved by the high intensity statin alone). The committee therefore agreed that whilst there was persuasive cost-evidence to justify the routine use of ezetimibe (in addition to statin therapy) to all patients with established CVD, the various logistic/pragmatic factors described resulted in a consensus position that ezetimibe could be “considered” (as opposed to “offered”) to all patients with CVD, irrespective of their measured/calculated cholesterol values.

The committee also discussed that to achieve lower treatment targets, people starting from a high baseline LDL-c / non-HDL-c level, may require a number of medicines to reduce their lipid levels substantially. The committee highlighted the importance of shared decision making when discussing the risks and benefits of taking additional medicines. As noted, lipid lowering treatment options other than statins and ezetimibe are only available as subcutaneous injections. The committee noted that self-injection may pose a barrier for some people, such as people with certain cognitive or physical disabilities. However, there are support schemes available and these treatments are most commonly delivered in clinics at present, typically by practice or community nurses.

The committee agreed that the recommendations should not differ for older people or those who are frail, however, they noted that appropriateness of escalating treatment to all older/frail people should be determined by clinical judgement. Consideration of risk and benefits and factors such as polypharmacy, multimorbidity, frailty and life expectancy are particularly important in older age groups.

The RCGP and BMA position statement on use of inclisiran was also raised, which was more cautious about its use than the NICE technology appraisal recommendation. Particular concerns relating to the lack of outcome data or long-term data. Some of the committee considered that alongside the increased cost and resource implications, these were good reasons to be cautious about recommending low treatment targets that may necessitate more people to be prescribed inclisiran to achieve it, especially when the outcome data are still pending.

The committee highlighted that some groups of people are under prescribed statins for example people with peripheral artery disease and it is important that the recommendations are applied to all people with established cardiovascular disease.

1.1.10. Recommendations supported by this evidence review

This evidence review supports recommendations 1.7.1, 1.7.8 to 1.7.11 and 1.10.1 to 1.10.2.

1.1.11. References

1.: Ako J, Hibi K, Kozuma K, Miyauchi K, Morino Y, Shinke T et al Effect of alirocumab on coronary atheroma volume in Japanese patients with acute coronary syndromes and hypercholesterolemia not adequately controlled with statins: ODYSSEY J-IVUS rationale and design. Journal of Cardiology. 2018; 71(6):583–589 [PubMed: 29606415]

2.: Ako J, Hibi K, Tsujita K, Hiro T, Morino Y, Kozuma K et al Effect of Alirocumab on Coronary Atheroma Volume in Japanese Patients With Acute Coronary Syndrome The ODYSSEY J-IVUS Trial. Circulation journal: official journal of the Japanese Circulation Society. 2019; 83(10):2025–2033 [PubMed: 31434809]

3.: Arimura T, Miura S-i, Ike A, Sugihara M, Iwata A, Nishikawa H et al Comparison of the efficacy and safety of statin and statin/ezetimibe therapy after coronary stent implantation in patients with stable angina. Journal of Cardiology. 2012; 60(2):111–118 [PubMed: 22542530]

4.: Blazing MA, Giugliano RP, Cannon CP, Musliner TA, Tershakovec AM, White JA et al Evaluating cardiovascular event reduction with ezetimibe as an adjunct to simvastatin in 18,144 patients after acute coronary syndromes: final baseline characteristics of the IMPROVE-IT study population. American Heart Journal. 2014; 168(2):205–212e201 [PubMed: 25066560]

5.: Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P et al Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. The New England journal of medicine. 2015a; 372(25):2387–2397 [PubMed: 26039521]

6.: Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R et al Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. European Heart Journal. 2015; 36(19):1186–1194 [PMC free article: PMC4430683] [PubMed: 25687353]

7.: Cannon CP, Giugliano RP, Blazing MA, Harrington RA, Peterson JL, Sisk CM et al Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. American Heart Journal. 2008; 156(5):826–832 [PubMed: 19061694]

8.: Colhoun HM, Robinson JG, Farnier M, Cariou B, Blom D, Kereiakes DJ et al Efficacy and safety of alirocumab, a fully human PCSK9 monoclonal antibody, in high cardiovascular risk patients with poorly controlled hypercholesterolemia on maximally tolerated doses of statins: rationale and design of the ODYSSEY COMBO I and II trials. BMC Cardiovascular Disorders. 2014; 14:121 [PMC free article: PMC4190302] [PubMed: 25240705]

9.: Diaz R, Li QH, Bhatt DL, Bittner VA, Baccara-Dinet MT, Goodman SG et al Intensity of statin treatment after acute coronary syndrome, residual risk, and its modification by alirocumab: insights from the ODYSSEY OUTCOMES trial. European journal of preventive cardiology. 2021; 28(1):33–43 [PubMed: 33755145]

10.: El Shahawy M, Cannon CP, Blom DJ, McKenney JM, Cariou B, Lecorps G et al Efficacy and Safety of Alirocumab Versus Ezetimibe Over 2 Years (from ODYSSEY COMBO II). The American journal of cardiology. 2017; 120(6):931–939 [PubMed: 28750828]

11.: Gao F, Wang ZJ, Ma XT, Shen H, Yang LX, Zhou YJ. Effect of alirocumab on coronary plaque in patients with coronary artery disease assessed by optical coherence tomography. Lipids in Health and Disease. 2021; 20(1):106 [PMC free article: PMC8436513] [PubMed: 34511134]

12.: Giugliano RP, Desai NR, Kohli P, Rogers WJ, Somaratne R, Huang F et al Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet (London, England). 2012; 380(9858):2007–2017 [PMC free article: PMC4347805] [PubMed: 23141813]

13.: Han Y, Chen J, Chopra VK, Zhang S, Su G, Ma C et al ODYSSEY EAST: alirocumab efficacy and safety vs ezetimibe in high cardiovascular risk patients with hypercholesterolemia and on maximally tolerated statin in China, India, and Thailand. Journal of Clinical Lipidology. 2020; 14(1):98–108.e108 [PubMed: 31882376]

14.: Hao Y, Yang Y- L, Wang Y- C, Li J. Effect of the Early Application of Evolocumab on Blood Lipid Profile and Cardiovascular Prognosis in Patients with Extremely High-Risk Acute Coronary Syndrome. International Heart Journal. 2022; 63(4):669–677 [PubMed: 35831153]

15.: Hiro T, Hirayama A, Ueda Y, Komatsu S, Matsuoka H, Takayama T et al Rationale and design of a randomized clinical study to investigate the effect of ezetimibe, a cholesterol absorption inhibitor, on the regression of intracoronary plaque evaluated by non-obstructive angioscopy and ultrasound: The ZIPANGU study. Journal of Cardiology. 2014; 64(6):501–507 [PubMed: 24725763]

16.: Hougaard M, Hansen HS, Thayssen P, Antonsen L, Junker A, Veien K et al Influence of ezetimibe in addition to high-dose atorvastatin therapy on plaque composition in patients with ST-segment elevation myocardial infarction assessed by serial: Intravascular ultrasound with iMap: the OCTIVUS trial. Cardiovascular revascularization medicine: including molecular interventions. 2017; 18(2):110–117 [PubMed: 27919638]

17.: Joshi S, Sharma R, Rao HK, Narang U, Gupta N. Efficacy of combination therapy of rosuvastatin and ezetimibe vs rosuvastatin monotherapy on lipid profile of patients with coronary artery disease. Journal of Clinical and Diagnostic Research. 2017; 11(12):oc28–oc31

18.: Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U et al Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. American Heart Journal. 2015; 169(6):906–915e913 [PubMed: 26027630]

19.: Koh KK, Nam CW, Chao T- H, Liu M- E, Wu C- J, Kim D- S et al A randomized trial evaluating the efficacy and safety of alirocumab in South Korea and Taiwan (ODYSSEY KT). Journal of Clinical Lipidology. 2018; 12(1):162–172e166 [PubMed: 29153823]

20.: Kohli P, Desai NR, Giugliano RP, Kim JB, Somaratne R, Huang F et al Design and rationale of the LAPLACE-TIMI 57 trial: a phase II, double-blind, placebo-controlled study of the efficacy and tolerability of a monoclonal antibody inhibitor of PCSK9 in subjects with hypercholesterolemia on background statin therapy. Clinical Cardiology. 2012; 35(7):385–391 [PMC free article: PMC4347804] [PubMed: 22714699]

21.: Kouvelos GN, Arnaoutoglou EM, Matsagkas MI, Kostara C, Gartzonika C, Bairaktari ET et al Effects of rosuvastatin with or without ezetimibe on clinical outcomes in patients undergoing elective vascular surgery: results of a pilot study. Journal of Cardiovascular Pharmacology and Therapeutics. 2013; 18(1):5–12 [PubMed: 22573476]

22.: Leiter LA, Zamorano JL, Bujas-Bobanovic M, Louie MJ, Lecorps G, Cannon CP et al Lipid-lowering efficacy and safety of alirocumab in patients with or without diabetes: A sub-analysis of ODYSSEY COMBO II. Diabetes, obesity & metabolism. 2017; 19(7):989–996 [PMC free article: PMC5485164] [PubMed: 28206704]

23.: Luo P, Li L, Wang LX, Zhu HH, Du S, Wu SL et al Effects of atorvastatin in combination with ezetimibe on carotid atherosclerosis in elderly patients with hypercholesterolemia. Genetics and molecular research: GMR. 2014; 13(2):2377–2384 [PubMed: 24737506]

24.: Luo P, Wang L, Zhu H, Du S, Wang G, Ding S. Impact of atorvastatin combined with ezetimibe for the treatment of carotid atherosclerosis in patients with coronary heart disease. Acta Cardiologica Sinica. 2016; 32(5):578–585 [PMC free article: PMC5052477] [PubMed: 27713607]

25.: Masuda J, Tanigawa T, Yamada T, Nishimura Y, Sasou T, Nakata T et al Effect of combination therapy of ezetimibe and rosuvastatin on regression of coronary atherosclerosis in patients with coronary artery disease. International Heart Journal. 2015; 56(3):278–285 [PubMed: 25902885]

26.: McCullough PA, Ballantyne CM, Sanganalmath SK, Langslet G, Baum SJ, Shah PK et al Efficacy and Safety of Alirocumab in High-Risk Patients With Clinical Atherosclerotic Cardiovascular Disease and/or Heterozygous Familial Hypercholesterolemia (from 5 Placebo-Controlled ODYSSEY Trials). The American journal of cardiology. 2018; 121(8):940–948 [PubMed: 29472008]

27.: Muller-Wieland D, Leiter LA, Cariou B, Letierce A, Colhoun HM, Del Prato S et al Design and rationale of the ODYSSEY DM-DYSLIPIDEMIA trial: lipid-lowering efficacy and safety of alirocumab in individuals with type 2 diabetes and mixed dyslipidaemia at high cardiovascular risk. Cardiovascular Diabetology. 2017; 16(1):70 [PMC free article: PMC5445362] [PubMed: 28545518]

28.: National Institute for Health and Clinical Excellence. The guidelines manual. London. National Institute for Health and Clinical Excellence, 2012. Available from: http://www.nice.org.uk/article/pmg6/

29.: Nicholls SJ, Kataoka Y, Nissen SE, Prati F, Windecker S, Puri R et al Effect of Evolocumab on Coronary Plaque Phenotype and Burden in Statin-Treated Patients Following Myocardial Infarction. JACC Cardiovascular imaging. 2022; 15(7):1308–1321 [PubMed: 35431172]

30.: Nicholls SJ, Nissen SE, Prati F, Windecker S, Kataoka Y, Puri R et al Assessing the impact of PCSK9 inhibition on coronary plaque phenotype with optical coherence tomography: rationale and design of the randomized, placebo-controlled HUYGENS study. Cardiovascular diagnosis and therapy. 2021; 11(1):120–129 [PMC free article: PMC7944215] [PubMed: 33708484]

31.: Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ P et al Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA. 2016; 316(22):2373–2384 [PubMed: 27846344]

32.: Oyama K, Giugliano RP, Blazing MA, Park J- G, Tershakovec AM, Sabatine MS et al Baseline Low-Density Lipoprotein Cholesterol and Clinical Outcomes of Combining Ezetimibe With Statin Therapy in IMPROVE-IT. Journal of the American College of Cardiology. 2021; 78(15):1499–1507 [PubMed: 34620406]

33.: Puri R, Nissen SE, Somaratne R, Cho L, Kastelein JJ P, Ballantyne CM et al Impact of PCSK9 inhibition on coronary atheroma progression: Rationale and design of Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV). American Heart Journal. 2016; 176:83–92 [PubMed: 27264224]

34.: Raber L, Ueki Y, Otsuka T, Losdat S, Haner JD, Lonborg J et al Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction: The PACMAN-AMI Randomized Clinical Trial. JAMA. 2022; 327(18):1771–1781 [PMC free article: PMC8978048] [PubMed: 35368058]

35.: Ran D, Nie H- J, Gao Y- L, Deng S- B, Du J- L, Liu Y- J et al A randomized, controlled comparison of different intensive lipid-lowering therapies in Chinese patients with non-ST-elevation acute coronary syndrome (NSTE-ACS): Ezetimibe and rosuvastatin versus high-dose rosuvastatin. International Journal of Cardiology. 2017; 235:49–55 [PubMed: 28291622]

36.: Ray KK, Del Prato S, Muller-Wieland D, Cariou B, Colhoun HM, Tinahones FJ et al Alirocumab therapy in individuals with type 2 diabetes mellitus and atherosclerotic cardiovascular disease: analysis of the ODYSSEY DM-DYSLIPIDEMIA and DM-INSULIN studies. Cardiovascular Diabetology. 2019; 18(1):149 [PMC free article: PMC6842201] [PubMed: 31706300]

37.: Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ et al Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. The New England journal of medicine. 2020; 382(16):1507–1519 [PubMed: 32187462]

38.: Rehberger Likozar A, Sebestjen M. Smoking and diabetes attenuate beneficial effects of PSCK9 inhibitors on arterial wall properties in patients with very high lipoprotein (a) levels. Atherosclerosis Plus. 2022; 50:1–9 [PMC free article: PMC9833244] [PubMed: 36643800]

39.: Ren Y, Zhu H, Fan Z, Gao Y, Tian N. Comparison of the effect of rosuvastatin versus rosuvastatin/ezetimibe on markers of inflammation in patients with acute myocardial infarction. Experimental and Therapeutic Medicine. 2017; 14(5):4942–4950 [PMC free article: PMC5704334] [PubMed: 29201198]

40.: Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M et al Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. The New England journal of medicine. 2015; 372(16):1489–1499 [PubMed: 25773378]

41.: Sabatine MS, Giugliano RP, Keech A, Honarpour N, Wang H, Liu T et al Rationale and design of the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk trial. American Heart Journal. 2016; 173:94–101 [PubMed: 26920601]

42.: Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA et al Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. The New England journal of medicine. 2017; 376(18):1713–1722 [PubMed: 28304224]

43.: Schmidt AF, Carter J- PL, Pearce LS, Wilkins JT, Overington JP, Hingorani AD et al PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. The Cochrane database of systematic reviews. 2020; 10:cd011748 [PMC free article: PMC8094613] [PubMed: 33078867]

44.: Schwartz GG, Bessac L, Berdan LG, Bhatt DL, Bittner V, Diaz R et al Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. American Heart Journal. 2014; 168(5):682–689 [PubMed: 25440796]

45.: Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R et al Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. The New England journal of medicine. 2018; 379(22):2097–2107 [PubMed: 30403574]

46.: Tsujita K, Sugiyama S, Sumida H, Shimomura H, Yamashita T, Yamanaga K et al Impact of Dual Lipid-Lowering Strategy With Ezetimibe and Atorvastatin on Coronary Plaque Regression in Patients With Percutaneous Coronary Intervention: The Multicenter Randomized Controlled PRECISE-IVUS Trial. Journal of the American College of Cardiology. 2015; 66(5):495–507 [PubMed: 26227186]

47.: Tsujita K, Sugiyama S, Sumida H, Shimomura H, Yamashita T, Yamanaga K et al Plaque REgression with Cholesterol absorption Inhibitor or Synthesis inhibitor Evaluated by IntraVascular UltraSound (PRECISE-IVUS Trial): Study protocol for a randomized controlled trial. Journal of Cardiology. 2015; 66(4):353–358 [PubMed: 25577723]

48.: Ueda Y, Hiro T, Hirayama A, Komatsu S, Matsuoka H, Takayama T et al Effect of Ezetimibe on Stabilization and Regression of Intracoronary Plaque - The ZIPANGU Study. Circulation journal: official journal of the Japanese Circulation Society. 2017; 81(11):1611–1619 [PubMed: 28592751]

49.: Wang J, Ai X- B, Wang F, Zou Y- W, Li L, Yi X- L. Efficacy of ezetimibe combined with atorvastatin in the treatment of carotid artery plaque in patients with type 2 diabetes mellitus complicated with coronary heart disease. International angiology: a journal of the International Union of Angiology. 2017; 36(5):467–473 [PubMed: 28641407]

50.: Wang X, Zhao X, Li L, Yao H, Jiang Y, Zhang J. Effects of Combination of Ezetimibe and Rosuvastatin on Coronary Artery Plaque in Patients with Coronary Heart Disease. Heart, Lung & Circulation. 2016; 25(5):459–465 [PubMed: 26687339]

51.: West AM, Anderson JD, Epstein FH, Meyer CH, Wang H, Hagspiel KD et al Low-density lipoprotein lowering does not improve calf muscle perfusion, energetics, or exercise performance in peripheral arterial disease. Journal of the American College of Cardiology. 2011; 58(10):1068–1076 [PMC free article: PMC3182461] [PubMed: 21867844]

52.: West AM, Anderson JD, Meyer CH, Epstein FH, Wang H, Hagspiel KD et al The effect of ezetimibe on peripheral arterial atherosclerosis depends upon statin use at baseline. Atherosclerosis. 2011; 218(1):156–162 [PMC free article: PMC3157540] [PubMed: 21570685]

53.: Zanchin C, Koskinas KC, Ueki Y, Losdat S, Haner JD, Bar S et al Effects of the PCSK9 antibody alirocumab on coronary atherosclerosis in patients with acute myocardial infarction: a serial, multivessel, intravascular ultrasound, near-infrared spectroscopy and optical coherence tomography imaging study-Rationale and design of the PACMAN-AMI trial. American Heart Journal. 2021; 238:33–44 [PubMed: 33951415]

54.: Zhan S, Tang M, Liu F, Xia P, Shu M, Wu X. Ezetimibe for the prevention of cardiovascular disease and all-cause mortality events. The Cochrane database of systematic reviews. 2018; 11:cd012502 [PMC free article: PMC6516816] [PubMed: 30480766]

Appendices

Appendix A. Review protocols

A.1. Review protocol for escalation of lipid modification therapy for secondary prevention of CVD

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A.2. Health economic review protocol

Not applicable.

Appendix B. Literature search strategies

The following literature search strategies were used for the following review:

In adults with CVD requiring escalation of therapy beyond statins, what is the effectiveness of lipid-lowering therapy?

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual. ²⁸

For more information, please see the Methodology review published as part of the accompanying documents for this guideline.

B.1. Clinical search literature search strategy

Searches were constructed using a PICO framework where population (P) terms were combined with Intervention (I) and in some cases Comparison (C) terms. Outcomes (O) are rarely used in search strategies as these concepts may not be indexed or described in the title or abstract and are therefore difficult to retrieve. Search filters were applied to the search where appropriate.

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B.2. Economic evaluation search strategy

Not applicable.

Appendix C. Effectiveness evidence study selection

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Appendix D. Effectiveness evidence

D.1. Key trial characteristics

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D.2. Evidence tables

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Appendix E. Forest plots: primary analyses

For all outcomes lower values are better, as this would represent either a greater reduction in cholesterol, a lower level of cholesterol at the study endpoint or fewer adverse events occurring.

E.1. Ezetimibe plus high or moderate intensity statin versus high or moderate statin in CVD secondary prevention

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E.2. PCSK9 monoclonal antibodies versus placebo or usual care in CVD secondary prevention

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E.3. PCSK9 monoclonal antibodies versus ezetimibe in CVD secondary prevention

Download PDF (195K)

E.4. PCSK9 monoclonal antibodies plus ezetimibe versus ezetimibe in CVD secondary prevention

Download PDF (170K)

E.5. Inclisiran versus placebo in CVD secondary prevention

Download PDF (179K)

Appendix F. Forest plots: sensitivity analyses

F.1. Ezetimibe plus high or moderate intensity statin versus high or moderate statin in CVD secondary prevention

F.1.1. Baseline lipid levels

Download PDF (192K)

F.1.2. Statin experience or intensity

Download PDF (249K)

F.2. PCSK9i versus placebo or usual care in CVD secondary prevention

F.2.1. Baseline lipid levels

Download PDF (201K)

F.2.2. Statin intensity

Download PDF (204K)

F.3. PCSK9i versus ezetimibe in CVD secondary prevention

F.3.1. Baseline lipid levels

Download PDF (186K)

F.3.2. Statin intensity

Download PDF (188K)

F.4. Inclisiran versus placebo in CVD secondary prevention

F.4.1. Statin intensity

Download PDF (136K)

Appendix G. GRADE tables

Download PDF (313K)

Appendix H. Economic evidence study selection

Not applicable

Appendix I. Economic evidence tables

Not applicable.

Appendix J. Health economic model

See separate economic analysis report.

Appendix K. Excluded studies

K.1. Clinical studies

Table 15

Studies excluded from the clinical review.

K.2. Health Economic studies

Not applicable.

Appendix L. Expert witness testimony

Andrew Black – GP, Vice Chair of the NICE Indicator Advisory Committee.

The below information was provided to the cardiovascular disease prevention guideline committee at the meeting on 30 March 2023. It reflects AB’s opinions and not necessarily those of the NICE Indicator Advisory Committee.

The NICE Indicator Advisory Committee (IAC) operationalise guidelines and quality standards (QS) for the NHS and wider audience. Providing indicators for cholesterol levels has been a challenge over the years. In mid-2022 NICE received a referral from NHS England to develop indicators that were suitable for the Quality and Outcomes Framework (QOF) ideally for the following QOF year (2023/24).

Indicators usually take 12–18 months to develop but the IAC was asked to develop an indicator around cholesterol targets in October 2022 for possible QOF adoption in April 2023. The particular issue was that in NICE guideline CG181 the recommendations state that a greater than 40% reduction in non-HDL cholesterol should be aimed for at 3 months for both primary and secondary prevention. However, the NICE IAC have consistently heard that this cannot be measured and extracted from electronic GP IT systems using the national General Practice Extraction Service (GPES). NHS digital cannot extract the 2 readings and calculate a percentage from that.

The IAC were asked to produce something for the 2023/24 QOF cycle. A sub-committee of the IAC was formed to develop an indicator as a holding measure, with a pragmatic threshold, pending the guidance from NICE’s clinical guideline committee. This was challenging for a number of reasons; determining an acceptable evidence-based target that would upset the least amount people, but also because there is evidence from the CVDPREVENT audit showing that recording of non-HDL cholesterol is poor. In March 2022 (using data from the previous 12 months), these data were missing in 52% of GP records, there was also a range where people were above 2.9mmol/litre and potentially 80% of practice population outside of this level (data are from academic in confidence analysis undertaken from CVDPREVENT audit for the IAC). The IAC discussed the different guidelines on the topic including the European Society Cardiology, Joint British Societies JBS 3 and British Heart Foundation recommendations, but all have slightly different targets levels.

There was discussion amongst the GPs on the IAC and cardiologists as to what they should do, taking these guidelines and relevant technology appraisals into account, as to where to put a holding threshold. The sub-committee decided on a non-HDL cholesterol level of 3.3mmol/l. Reasons for this included a feeling that a 40% reduction, based on baseline non-HDL cholesterol, would be getting towards a level of 3.3mmol/l. Furthermore, a NICE technology appraisal had used an LDL cholesterol level of 2.6mmol/litre which the subcommittee heard could be very broadly be translated into a non-HDL cholesterol of around 3.3mmol/litre for the initiation of a drug which was thought not to be primary care led, so it would be difficult to put levels below this in a QOF, where the level should be achievable by primary care alone. Another major factor was that the committee do not just take the QS or guideline and transfer recommendations directly into indicators. They take into consideration acceptability to the profession more generally and, to an extent, workload implications.

Once an indicator is agreed it goes to the NICE guidance executive to ratify and then goes to the NICE menu. NHS England and the BMA’s General Practitioners Committee (GPC) then decide if it should be included in QOF or not.

A number of indicators in the menu are not a straight carry across from the clinical guidelines. Indicators may start further away with a measured plan to bring them closer to the clinical / quality standard within 2 years, recognising the implications.

The level of 3.3 mmol/litre was put out for consultation as a proposed indicator. Response was negative on both sides. They received quite a lot of complaints saying it was too onerous, not practical and not feasible. However, there was also a strong pushback from the other side saying 3.3 mmol/litre was not hard enough and argued for a much lower level. As a result the proposed level was universally unpopular on both sides of the argument and it was difficult for the committee to justify a level without a guideline behind it. It was therefore decided to wait for the guideline committee to consider this issue. It is hoped the indicator will be in the system for next year after the guideline has published.

It was noted that NHS England has decided to create its own indicator for the 2023/24 QOF outside of the NICE process with a non-HDL cholesterol level of 2.5mmol/l. From the IAC discussions there was a steer from cardiologists that 2.5mmol/litre was becoming the more recognised standard, based on the accelerated access collaborative guidance, but the IAC did not proceed with this value as the proposed NICE indicator because of the lack of assurance that the methodology or health economics behind were as robust as would be expected for a NICE standard.

The indicator is: Percentage of patients on the QOF Coronary Heart Disease, Peripheral Arterial Disease, or Stroke/TIA Register, who have a recording of non-HDL cholesterol in the preceding 12 months that is lower than 2.5mmol/l, or where non-HDL cholesterol is not recorded a recording of LDL cholesterol in the preceding 12 months that is lower than 1.8mmol/l.

This has a points ratio of 16, with a threshold of 20–35% of patients.

The IAC will still create an indicator based on the NICE guideline for the NICE menu. There can be more acceptance of a NICE badged indicator because it is evidence based and will have gone through some degree of piloting and consultation. The GPC and other interested parties tend to trust indicators produced by NICE for QOF as being of higher standard than those that come through other routes.

Final

Evidence review underpinning recommendations 1.7.1, 1.7.8 to 1.7.11, 1.10.1 and 1.10.2

Developed by National Institute for Health and Care Excellence

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK602485PMID: 38588358

Table 1PICO characteristics of review question

Population	Inclusion: Adults (aged 18 years and older) with CVD. ≥50% of participants are receiving high or medium intensity statin therapy as background or randomised treatment. Exclusion: Children aged under 18 years of age. People who are intolerant of or have contraindications to statins. People with familial hypercholesterolaemia. People receiving renal replacement therapy. People with familial clotting disorders that increase cardiovascular risk. People with other monogenic disorders that increase cardiovascular risk. People at high risk of CVD or abnormalities of lipid metabolism because of endocrine or other secondary disease processes other than diabetes.
Interventions	Ezetimibe (+ high or medium intensity statin) Inclisiran (+ high or medium intensity statin) Alirocumab or evolocumab (+ high or medium intensity statin) - assuming a class effect for PCSK9 monoclonal antibodies Combinations of the above interventions (for example, inclisiran + ezetimibe + high or medium intensity statin; or alirocumab/evolocumab + ezetimibe + high or medium intensity statin)
Comparisons	Interventions compared with each other Placebo / no treatment High or medium intensity statin High intensity statins are defined as atorvastatin 20–80 mg or rosuvastatin 10–40 mg and medium intensity statins as atorvastatin 10 mg, fluvastatin 80 mg, rosuvastatin 5 mg or simvastatin 20–40 mg.
Outcomes	LDL-C (change from baseline: absolute change and % change) Non-HDL-C (change from baseline: absolute change and % change) Combined major adverse cardiovascular events (CVD death, nonfatal MI, nonfatal ischaemic stroke) (time-to-event) Quality of life, any validated measure (continuous) Treatment-related adverse effects (dichotomous): Myopathy/rhabdomyolysis New-onset diabetes Increased liver transaminases (>3-times upper-limit of normal) Cancer Gall-bladder related disease Injection site reactions Nausea Influenza
Study design	RCT, systematic review of RCTs or individual participant data meta-analysis of RCT data.

Table 2Summary of studies included in the evidence review

Author, year (trial name)

Population

Baseline LDL-C/non-HDL-C

Intervention

Comparison

Background treatment

Outcomes (follow-up time)

Indirectness

Ezetimibe

Arimura 2012³

People with stable angina and dyslipidaemia who were successfully implanted with a drug-eluting stent or a bare-metal stent.

N=50

Mean age (SD): 69 (8.5) years.

Previous CVD event: stable angina and coronary stent

Not reported

Ezetimibe 10 mg/day and atorvastatin 10 mg/day (medium intensity statin).

N=25

Atorvastatin 10 mg/day

N=25

All participants received aspirin and ticlopidine or clopidogrel throughout the study period.

LDL-C (mg/dl)

At 6–8 months

None

Cannon 2015a,⁵ Blazing 2014,⁴ Cannon 2008⁷ (study rationale and design), Oyama 2021³² (contains data on subgroup analysis)

IMPROVE-IT

People (≥50 years) hospitalised for an ACS

N=18,144

Mean age (SD): 63.6 (9.8) years

Qualifying ACS event: acute MI with or without ST-segment elevation on electrocardiography or high-risk UA

Mean (SD) in intervention vs comparison

LDL-C: 93.8 (nr) vs 93.8 (nr) mg/dl

Non-HDL-C: 120.5 (nr) vs 120.5 (nr)

Subgroup data for baseline LDL-C 50-<70 mg/dl; 70-<100mg/dl; 100–125 mg/dl

Simvastatin 40mg/d plus ezetimibe 10mg/d as fixed dose combination tablet.

Simvastatin dose increase to 80mg for LDL-C> 79mg/dl in 6% of patients

N=9067

Simvastatin 40mg/d (medium intensity) plus placebo.

Simvastatin increased to 80mg for LDL >79mg/dl in 27%.

N=9077

Matched between groups:

Aspirin: 97%

Thienopyridine: 86%

Beta-blocker: 87%

ACE inhibitor or ARB: 76%

LDL-C and non-HDL-C at 1 year (mg/dl)

MACE (death from cardiovascular causes, major coronary event or, nonfatal stroke). at 7 years

Myopathy, rhabdomyolysis, ALT, AST or both, cancer, gall-bladder-related adverse events at 7 years

Serious comparator indirectness: 27% in control group had the simvastatin dose increased to 80 mg

Hougaard 2017¹⁶

OCTIVUS

People with first STEMI, no prior treatment with statins or other lipid lowering drugs and a non-significant lesion in one of the two non-culprit coronary arteries.

N=87

Mean age (SD): 56.3 (10.1)

Previous CVD event: STEMI.

Mean (SD) in intervention vs comparison

LDL-C: 3.7 (0.7) vs 4.1 (0.9) mmol/l

Ezetimibe: atorvastatin 80mg/d (high-intensity) and ezetimibe 10mg/d

N=43

Placebo: atorvastatin 80mg/day and placebo

N=44

No baseline statin use. Background treatment not specified.

LDL-C (mmol/l) At 1 year

Adverse events: elevated liver enzymes

At 3 months

None

Joshi 2017¹⁷

People with CAD

N=80

Mean age (SD): 60.1 (10.5)

Previous CVD diagnosis: coronary artery disease (CAD)

Mean (SD)

LDL cholesterol:

162.68 (23.13) vs 153.38 (24.78) mg/dl

Non-HDL-C: not reported

Ezetimibe 10mg/d plus rosuvastatin 10mg/d (high-intensity statin)

N=40

Rosuvastatin 10mg/d

N=40

High intensity statins as part of study; unclear if at baseline.

Advised to follow lifestyle modifications, stop smoking, exercise regularly, avoid alcohol and have a low-fat diet.

Regular treatment of CAD including antiplatelets, beta-blockers, ACE inhibitors, nitrates was continued.

LDL-C (mg/dl)

Musculoskeletal side effects

Gastrointestinal side effects At 24 weeks

None

Kouvelos 2013²¹

People undergoing vascular surgery (peripheral artery disease)

N=262

Mean age (range): 71 (41 to 89) years

Previous CVD diagnosis: CAD or cardiac failure

Mean (SD) in intervention vs comparison

LDL-C: 148 (58.1) vs 143 (54.1) mg/dl

Ezetimibe 10mg/d + rosuvastatin 10mg/d

Starting 2 weeks prior to vascular surgery

N=126

Rosuvastatin 10mg/d (high-intensity statin)

N=136

For people already on statin, there was an 8-week washout period. All participants were under antiplatelet therapy for at least 3 weeks prior to the procedure. People who were enrolled and were already receiving beta-blocker therapy continued their medication. For those not already on a beta - blocker, bisoprolol (2.5 mg once daily) was initiated at the screening visit.

LDL-C mg/dl

At 1 year (after surgery)

Composite of death from cardiac causes, nonfatal acute MI, ischemic stroke and UA (also reported individually)

From month 1 to 12 of the follow-up

The same outcome was also reported for different time-points as follows:

Major adverse CV event (death from cardiac causes, nonfatal myocardial infarction, ischemic stroke, and unstable angina)

during 1 year follow-up

None

Luo 2014²³

Elderly hypercholesterolemic people with abnormal LDL-C levels despite undergoing lipid-lowering therapy for 3 months.

Mean age (SD): 66.7 (6.12) years

Previous CVD diagnosis: 83.3% coronary heart disease

Mean (SD) in intervention vs comparison

LDL-C: 3.27 (0.36) vs 3.31 (0.46) mmol/l

Non-HDL not reported

Ezetimibe + atorvastatin (10mg/d)

N=40

Atorvastatin 20mg once per night

N=44

No information

LDL-C (mmol/l)

Combined major cardiovascular events (MI or cardiovascular death)

At 12 months

None

Luo 2016²⁴

People with coronary heart disease confirmed by coronary angiography receiving lipid-lowering therapy for 3 months but not achieving standard goals for LDL-C levels <2.6mmol/l

N=148

Mean age (SD): 61.2 (10.7)

Previous CVD event/diagnosis: stroke or CHD

Mean (SD) in intervention vs comparison

LDL-C: 3.57 (0.38) vs 3.52 (0.46) mmol/l

HDL-C not reported.

Ezetimibe 10mg/d plus atorvastatin (20mg/d)

N=74

Atorvastatin 20mg/d

N=74

Secondary prevention drugs, such as aspirin, angiotensin II receptor antagonists, and hypoglycaemic drugs were routinely administered to both groups.

Statins and other LLTs not reported.

LDL-C (mmol/l)

Combined major cardiovascular events. (cardiac death, hospitalization for unstable angina, nonfatal myocardial infarction, coronary revascularization, and stroke)

Myopathy/rhabdomyolysis

At 12 months

None

Masuda 2015²⁵

People aged 20 to 80 years old with clinically stable angina pectoris PCI; LDL-C level higher than 100 mg/dl mmol/l at entry, regardless to prior administration of statins.

Mean age (SD): 67 (8.35) years

Previous CVD diagnosis: CAD

Mean (SD) in intervention vs comparison

LDL-C: 131.8 (25.6) vs 123 (27) mg/dl

Non HDL-C: 151.4 (29.4) vs 146.2 (35.6)

Ezetimibe 10mg/d + rosuvastatin 5mg/d (medium intensity statin)

N=19

Rosuvastatin 5mg/d (medium intensity statin)

N=21

At baseline:

Ezetimibe and rosuvastatin group:

Beta-blocker: 9 (42.9%)

ARB: 9 (42.9%)

ACE inhibitor: 2 (9.8%)

Oral glycaemic agent: 8 (38.1%)

Insulin:1 (4.8%)

Current smoking: 9 (42.9%)

Hypertension: 13 (61.9%)

Rosuvastatin group

Beta-blocker: 9 (47.4%)

ARB: 10 (52.6%)

ACE inhibitor: 3 (15.8%)

Oral glycaemic agent: 7 (36.8%)

Insulin: 0 (0%)

Current smoking: 4 (21.1%)

Hypertension: 17 (89.5%)

Baseline statin use: 42.9% vs 36.8% in intervention vs comparison

LDL-C (mg/dl)

Non-HDL (mg/dl)

Rhabdomyolysis

Creatine kinase >5x ULN AST or ALT >3x upper limit of normal

Myalgia

At 6 months

None

Ran 2017³⁵

NSTE-ACS

People undergoing percutaneous coronary intervention for non-ST-elevation acute coronary syndrome (NSTE-ACS)

N=125 (analysed 84)

Mean age (SD): 60.5 (7.5)

Previous CV event: non-STEMI, UA or stroke

Mean (SD) in intervention vs comparison

LDL-C: 141 (27) vs 141 (33) mg/dl

Non-HDL-C: 166 (30) vs 165 (35) mg/dl

Ezetimibe 10mg/d + rosuvastatin 10mg (high-intensity statin)

N=42

Rosuvastatin 10mg/d

N=42

All participants were treated with standard non-ST-elevation acute coronary syndrome drugs including aspirin, clopidogrel, B-blocker and angiotensin-converting enzyme inhibitors/angiotensin II receptor antagonists. Lipid lowering therapies started the day after percutaneous coronary intervention within 24 hours.

LDL-C (mg/dl)

non-HDL-C (mg/dl)

Muscle pain

Rhabdomyolysis

GI discomfort

Liver enzyme elevation

At 12 weeks

None

Ren 2017³⁹

People hospitalised within preceding 24 hours with acute myocardial infarction (including STEMI and non-STEMI)

N=113

Mean age (SD): 59 (2.2) years

Previous CVD event: Acute MI

Mean (SD) in intervention vs comparison

LDL-C: 3(0.96) vs 2.93 (1.02) mmol/l

Ezetimibe (10mg/d) + rosuvastatin (10mg/d)

N=55

Rosuvastatin 10mg/d (high intensity statin)

N=58

Participants received treatment according to common guidelines, including appropriate use of antiplatelet agents, anticoagulants, statins, B-blockers and revascularization.

Baseline statin in 9.1% and 10.5% in each group

LDL-C (mmol/l)

At 1 year

None

Tsujita 2015;^46,47

PRECISE-IVUS

People aged 30–85 years diagnosed with ACS or stable CHD, undergoing coronary angiography or PCI under intravascular ultrasound guidance with LDL-C ≥ 100mg/dl

N=246 (analysed 202)

Mean age (SD):66.5 (10) years

Previous CVD event/diagnosis: PCI, MI, stroke or PAD.

Mean (SD) interventions vs comparison

LDL-C: 109.8 (25.4) vs 108.3 (26.3) mg/dl

Atorvastatin dose titration with a treatment goal of LDL-C <70mg/dl

Plus

Ezetimibe 10mg/d

N=100

Atorvastatin: dose titration with a treatment goal of LDL-C <70mg/dl

N=102

Atorvastatin + ezetimibe group

Aspirin= 100%

Thienopyridines= 100%

Cilostazol= 1%

Sarpogrelate hydrochlorine= 2%

Warfarin= 5%

Nitrates= 6%

Beta-blockers= 41%

Calcium blockers= 44%

ACE inhibitors= 25%

Angiotensin II receptor blocker= 48%

Hypoglycaemic agents= 25%

Atorvastatin monotherapy group

Aspirin= 100%

Thienopyridines= 99%

Cilostazol= 0%

Sarpogrelate hydrochlorine= 2%

Warfarin= 1%

Nitrates= 14%

Beta-blockers= 50%

Calcium blockers= 34%

ACE inhibitors= 27%

Angiotensin II receptor blocker= 36%

Hypoglycaemic agents= 25%

Baseline statin use: 46% vs 48%

LDL-C (mg/dl)

CVD events (defined as cardiac death, myocardial infarction, target vessel revascularization (PCI or coronary artery bypass grafting))

Increased liver transaminases

At 10 months

Ueda 2017;⁴⁸ Hiro 2014¹⁵ (protocol)

ZIPANGU

People 20–80 with elective PCI with at least 1 yellow plaque of grade≥2 in the non-PCI target coronary artery segments and hypercholesterolemia (LDL-C >100mg/dl)

N=131

Mean age (SD): 69.5 (9.7)

Previous CV event/diagnosis: MI, angina pectoris, stroke, or PAD.

Mean (SD) intervention vs comparison

LDL-C: 101 (27) vs 100 (27) mg/dl

Ezetimibe 10mg/d plus atorvastatin 10mg/d (medium intensity) increased to 20mg (high intensity) if LDL-C >70mg/dl after 3 months

N=65

Atorvastatin 10mg/d increased to 20mg if LDL-C >100mg/dl at 3 months

N=66

Participants had counselling on lifestyle improvement. Diet and medical treatments for their complications or atherosclerosis prevention other than lipid management were administered comprehensively for all enrolled patients based on the individualised strategies of their doctors.

LDL-C (mg/dl)

At 9 months

Possible intervention indirectness: statin dose titration unlikely to be matched between arms.

Wang 2016⁵⁰

People with one or more atherosclerotic lesions near the middle of the coronary arteries; total cholesterol ≥5.2 mmol/l and/or LDL≥3.6 mmol/l

N=106

Mean age (SD): 48.9 (64.1) years

Previous CVD diagnosis: coronary artery disease

Mean (SD) intervention vs comparison

LDL-C: 3.62 (1.18) vs 3.48 (1.26) mmol/l

Ezetimibe plus rosuvastatin: both 10mg/night

N=50

Rosuvastatin 10mg/night

N=48

Ezetimibe + rosuvastatin group

Nitrate ester= 84%

Antiplatelet= 100%

Beta-receptor blocker= 78%

Calcium channel blocker= 30%

Low weight molecular heparin= 80%

Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker= 36%

Rosuvastatin group

Nitrate ester= 81%

Antiplatelet= 100%

Beta-receptor blocker= 73%

Calcium channel blocker= 27%

Low weight molecular heparin= 81%

Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker= 33%

LDL-C (mmol/l)

Rhabdomyolysis

Increased liver transaminases

Major adverse cardiac events (MI, cardiac death or stroke)

At 12 months

None

Wang 2017⁴⁹

People with carotid atherosclerosis, type 2 diabetes and CHD with LDL-C ≥2.6mmol/l after 3 months of statin treatment

N=100

Mean age (SD): 58 (9.5)

Previous CVD diagnosis: coronary artery disease

Mean (SD) intervention vs comparison

LDL-C: 3.53 (0.87) vs 3.45 (0.75) mmol/l

Ezetimibe 10mg/d plus atorvastatin 20mg/d

N=51

Atorvastatin 20mg/d

N=49

Other drugs for hypertension and arterial sclerosis such as aspirin, β-blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonist and hypoglycaemic drugs were routinely used in both groups.

LDL-C (mmol/l)

At 12 months

None

West 2011/2011a^51,52

People with PAD aged between 30 and 85 years with symptoms of intermittent claudication and an ankle-branchial index between 0.4 and 0.9; statin-naïve regardless of baseline LDL-C

N=44

Mean age (SD): 60.5 (9.2) years

Previous CVD diagnosis: PAD and 50% also CAD

Mean (SD) intervention vs comparison

LDL-C: 118 (41) vs 118 (34) mg/dl

Simvastatin 40mg/d plus ezetimibe 10mg/d

N=22

Simvastatin 40mg/d (medium-intensity statin)

N=22

Baseline treatment below but unclear if this was continued during the study:

Intervention vs comparison:

Aspirin 72% vs 69%

ACE inhibitor 28% vs 50%

ARB 22% vs 13%

B-blocker 33% vs 38%

LDL-C (mg/dl)

At 1 year

MACE (death, MI, stroke and transient ischemic attack)

At 2 years

None

PCSK9i versus placebo or usual care

Ako 2019²; Ako 2018¹ (rationale and design)

ODYSSEY J-IVUS

People with ACS and LDL-C ≥2.59mmol/l despite stable statin therapy, or who were not on statins with LDL-C levels above target after statin initiation. ACS was defined as STEMI, non-STEMI, and unstable angina.

N=206

Mean age (SD): 61.2 (10.9) years

Index ACS event: STEMI, NSTEMI, UA.

Mean (SD) in intervention vs comparison

Calculated LDL-C: 2.54 (0.60) vs 2.48 (0.57) mmol/l

Non-HDL-C: 3.21 (0.65) vs 3.22 (070) mmol/l

Alirocumab: 75mg every two weeks every 2 weeks; at week 14 the study allowed alirocumab dose increase to 150mg every 2 weeks if week 12 LDL-C was ≥2.59mmol/l

N=93

Usual care: atorvastatin ≥10mg/day or rosuvastatin ≥5mg/day; i.e. stable dose statin therapy, with optional dose adjustment. Non-statin, non-PCSK9 inhibitor LLTs could be added by investigators if LDL-C goal <2.59mmol/l (<100mg/dl) could not be achieved.

N=89

Stable dose statin therapy (atorvastatin or rosuvastatin) with/without other LLTs (added as seen fit by investigators to meet LDL-C targets)

LDL-C (mmol/l & mg/dl)

Non-HDL-C (mmol/l & mg/dl)

TEAEs (leading to death or discontinuation)

Injection-site reactions

Type 2 diabetes

Treatment emergent SAEs

Treatment emergent CVD events confirmed by adjudication (MI, Ischemic stroke, ischemia driven coronary revascularisation)

At 36 weeks

None

Gao 2021¹¹

People 18–80 years with stable CAD or ACS

N=61

Mean age (SD): 61.3 (9.4) years

Previous CVD event: MI, stroke, or ACS

Mean (SD) in intervention vs comparison.

LDL-C: 3.04 (0.78) vs 3.18 (0.97) mmol/l

Alirocumab 75mg every 2 weeks + high-intensity statin (atorvastatin 20mg/d or rosuvastatin 10mg/d)

N=30

Usual care: atorvastatin 20mg/d or rosuvastatin 10 mg/d

N=31

15/31 people received ezetimibe and statin combination therapy

Statin dose escalation or the addition of other concomitant non-statin lipid lowering therapies could be considered by physicians responsible for achieving the target LDL-C levels; Antithrombotic therapy and other concomitant medications were decided by their responsible physicians; all were prescribed antiplatelet therapy, and approximately 90% were treated with beta blockers.

Angiotensin converting enzyme inhibitors/angiotensin receptor blockers: 60% vs 64.5%

LDL-C (mmol/l) At 36 weeks

Adverse cardiac events (Cardiac death, MI, ischemia driven target lesion revascularisation)

Injection site reactions

Within 36-week follow-up

None

Giugliano 2012;¹² Kohli 2012²⁰ (protocol & rationale)

LAPLACE-TIMI-57

People aged 18–80 years with history of hypercholesterolaemia and fasting LDL-C concentration greater than 2.2 mmol/l while on a stable dose of statin (with or without ezetimibe) for at least 4 weeks.

N=315 (in groups relevant to the present review)

Mean age (range): 63 (55–69) years

Previous CVD event/diagnosis: 81% CVD: CAD, MI, coronary artery bypass graft percutaneous coronary intervention, cerebrovascular or peripheral arterial disease.

Mean (SD) in intervention vs comparison every 2 weeks vs intervention vs comparison every 4 weeks

LDL-C: 3.1 (0.6) vs 3.2(0.7) vs 3.1 (0.7) vs 3.2 (0.8) mmol/l

Non-HDL-C: 3.8 (0.7) vs 3.8 (0.8) vs 3.7 (0.8) vs 3.9 (0.9) mmol/lEE

Evolocumab: AMG 145 (human monoclonal IgG2 antibody against PCSK9)

140mg every 2 weeks (n=78)

420mg every 4 weeks (n=80)

Placebo every 2 weeks (n=78) or every 4 weeks (n=79)

Baseline statin use: 100% across groups except 97% in placebo every 4 weeks; high-intensity statin in 32% vs 24% vs 36% vs 25% in each group (intervention vs comparison every 2 weeks vs intervention vs comparison every 4 weeks)

Ezetimibe in 9% across groups except 10% in placebo every 4 weeks

LDL-C (mmol/l) non-HDL-C (mmol/l)

% change in LDL-C in subgroup analysis for LDL-C

<3.4mmol/l available vs LDL-C

<2.6mmol/l vs 2.6 to <3.4 mmol/l vs ≥3.4 mmol/l and subgroup with non-intensive statin regimen vs intensive statin regimen

Injection site reactions

Positively adjudicated clinical cardiovascular events (Acute coronary syndrome, coronary revascularisation, transient ischaemic attack, congestive heart failure requiring)

At week 12

29% were on high-intensity statins but that included simvastatin 80mg; statin intensity for 71% of participants randomised to arms extracted in the present review was not specified and approximately 10% in each comparison group were on statins not relevant to the review protocol (lovastatin, pitavastatin, or pravastatin low dose)

Kereiakes 2015;¹⁸ Colhoun 2014⁸ (rationale)

ODYSSEY COMBO I

Adults with established CVD (coronary heart disease) and LDL-C ≥70 mg/dl or coronary heart disease risk equivalents (e.g. diabetes with other risk factors or chronic kidney disease);

N=316

Mean age (SD): 63 (9.3) years

CHD history: 78%

Mean (SD) in intervention vs comparison

LDL-C: 100.2 (29.5) vs 106 (35.3) mg/dl

Non-HDL-C: 130 (34) vs 133.4 (39.8) mg/dl

Alirocumab 75mg every 2 weeks with potential dose increase to 150mgv if LDL-C >70mg/dl at week 8

N=209

Placebo injection

N=107

All participants were receiving a stable, maximally tolerated statin dose:

atorvastatin, 40–80 mg;

rosuvastatin, 20–40 mg;

simvastatin, 80 mg daily; or lower doses in cases of intolerance

Other lipid-lowering therapy also permitted: bile acid sequestrant, ezetimibe, niacin or omega-3 ≥1000 mg/day with stable dose ≥4 weeks; or fenofibrate with stable dose ≥6 weeks before enrolment.

99.5% statin use at baseline; 61.7% vs 64.5% high-intensity statin at baseline.

Other LLT at baseline: 38.2% vs 49.5%; ezetimibe: 7.2% vs 10.3%

LDL-C (mg/dl)

Non-HDL-C

At 24 weeks

Major adverse CVD events (CHD death, non-fatal MI or fatal/non-fatal stroke)

Injection-site reaction

Nausea

Influenza

At 52 weeks

None

Koh 2017¹⁹

ODYSSEY KT

Adults (aged ≥18 years) with high CV risk who had inadequately controlled hypercholesterolemia on maximally tolerated statin therapy at a stable dose for at least 4 weeks before screening.

N=199

Mean age (SD): 60.6 (9.8) years

Previous CVD diagnosis: Coronary heart disease: 99% vs 93.1% in each group

Mean (SD) in intervention vs comparison

Calculated LDL-C: 97 (27.8) vs 99.3 (25.2) mg/dl

Non-HDL-C: 123.9 (29) vs 128.4 (30.3) mg/dl

Alirocumab 75mg every 2 weeks, increased to 150mg at week 12 if LDL-C >70mg/dl at week 8, plus maximally tolerated statin

N=97

Placebo plus maximally tolerated statin

N=102

Maximally tolerated statins: atorvastatin 40 to 80 mg daily, rosuvastatin 20 mg daily, or simvastatin 40 mg daily. Patients were also eligible if they were receiving a daily dose of atorvastatin, rosuvastatin, or simvastatin considered appropriate by the investigator. Background treatment with LLTs other than statins was allowed for all patients, provided that they had been on a stable dose for at least 4 weeks before the screening visit.

Baseline statin use 100% (>70% high-intensity)

Other baseline LLT (e.g. ezetimibe, nutraceuticals) in 23%

LDL-C (mg/dl)

At 24 weeks

Injection site reactions

From first to last injection plus 70 days

Positively adjudicated CVD events (non-fatal MI, fatal/non-fatal ischemic stroke, ischemia driven coronary revascularisation procedure)

From first to last injection plus 70 days

New onset diabetes at 52 weeks

None

McCullough 2018²⁶

ODYSSEY Long Term

IPD analysis of subgroup of people with clinical ASVCD from ODYSSEY Long Term and ODYSSEY HIGH FH. ASCVD defined as: coronary heart disease, stroke and peripheral arterial disease, all of presumed atherosclerotic origin.

N= 1,853 (1827 analysed)

Mean age (SD): 61.3 (9.8) years

Previous CVD event/diagnosis: ACS, coronary revascularisation procedure, PAD, ischaemic stroke.

Mean (SD) in intervention vs comparison:

LDL-C: 120.1 (41.3) vs 122.8 (44.5) mg/dl

Non-HDL-C: 149.4 (45) vs 152.2 (48.9)

Alirocumab 150 mg every 2 weeks

N=1201

Placebo

N = 626

Maximally tolerated statin with or without additional lipid lowering therapy; no further details given.

Baseline statin use: 56.3% vs 59% high intensity and 29.2% vs 27.2% moderate intensity in intervention vs comparison groups.

LDL-C (mg/dl)

At 24 weeks

Analysis extracted includes data from the ASCVD subgroup of ODYSSEY LONG TERM (97%) and ODYSSEY HIGH FH (3%)

Nicholls 2016;³¹ Puri 2016³³ (protocol)

GLAGOV

Adults with at least 1 epicardial coronary stenosis of 20% or greater on clinically indicated coronary angiography and had a target vessel suitable for imaging with 50% or less visual obstruction; treated with a stable statin dose for at least 4 weeks and with LDL-C level of 80 mg/dl or higher or between 60 and 80 mg/dl with 1 major or 3 minor cardiovascular risk factors.

N=968

Mean age (SD): 59.8 (9.2) years

Previous CVD event/diagnosis: PCI or MI.

Mean (95% CI) in intervention vs comparison

LDL-C: 92.6 (90.1 to 95%) vs 92.4 (90 to 94.6%) mg/dl

Non-HDL-C: 119.4 (116.5 to 122.3%) vs 120.8 (117.9 to 123.7%) mg/dl

Evolocumab 420mg monthly (subcutaneous injection)

N=484

Placebo

N=484

Baseline statin use: 98%; high-intensity : 57.9% vs 59.9%; moderate intensity: 40.5% vs 38.2%; low intensity: 0.4 vs 0.2%

Baseline ezetimibe: 2.1%

LDL-C & HDL-C (mg/dl)

Combined major cardiovascular events (first major adverse CV event)

New onset diabetes

Increased liver transaminases

Injection site reactions

At 18 months

Lipid outcomes assessed over 18 months - protocol specified 12 months.

Nicholls 2022;²⁹ 2021³⁰ (protocol)

HUYGENS

People with NSTEMI with at least 1 non-culprit epicardial coronary stenosis ≥20% on angiography during NSTEMI

N=161

Mean age (SD): 60.5 (9.6) years

Previous CVD event/diagnosis: all had NSTEMI, some also had MI and percutaneous coronary intervention.

Mean (SD) in intervention vs comparison

LDL-C: 140 (34) vs 142.1 (32.3) mg/dl

Non-HDL-C: 130.9 (36.6) vs 133.4 (38.7)

Evolocumab420 mg monthly (via subcutaneous injection)

N=80

Placebo

N=81

Statins: overall 95% of study population taking statins at baseline; 80.7% high intensity statins, 13.7% moderate intensity and 0.6% low intensity statins. High-intensity statins: atorvastatin ≥40 mg, rosuvastatin ≥20 mg, simvastatin ≥80 mg daily. Moderate-intensity: atorvastatin 10 to <40 mg, rosuvastatin 5 to <20 mg, simvastatin 20 to <80 mg daily. Low-intensity statins: atorvastatin <10 mg, rosuvastatin <5 mg, simvastatin <20 mg daily.

4.9% treated with Ezetimibe at time of screening; 99% on antiplatelet therapy; 84% on beta-blockers; 72.7% on ACE inhibitor; 14.2% on angiotensin receptor blocker

LDL-C (mg/dl)

Non-HDL-C (mg/dl)

At week 50

Population indirectness as some participants (unclear how many) were receiving simvastatin 80 mg/d as part of being on high-intensity statins.

Raber 2022;³⁴ Zachin 2021⁵³ (rationale and design)

PACMAN-AMI

People undergoing PCI for Acute myocardial infarction (AMI: STEMI or non-STEMI)

N=300

Mean age (SD) 58.5 (9.7) years

NSTEMI: 47%; STEMI: 53%

Mean (SD) intervention vs comparison.

LDL-C: 154.8 (30.9) vs 150.9 (36.3) mg/dl

Non-HDL: 165.7 (34.5) vs 162.9 (35.3)

Alirocumab 150mg (biweekly via subcutaneous injection) + high-intensity statin (rosuvastatin 20mg/d)

Placebo (biweekly via subcutaneous injection) + rosuvastatin 20mg/d

Baseline statin use in 11.5% vs 13.2%; high-intensity: 7.4% vs 5.9% in intervention and comparison.

Other baseline lipid lowering treatments: 0% vs 0.7%

LDL-C (mg/dl)

Non-HDL-C (mg/dl)

Injection site reactions

At 52 weeks

None

Ray 2019;³⁶ Muller-Wieland 2017²⁷ (secondary publication)

ODYSSEY DM-DYSLIPIDEMIA & DM-INSULIN

People with established ASCVD receiving maximally tolerated statin who were enrolled in the DM-DYSLIPIDEMIA and DM-INSULIN studies. ASCVD was defined as CHD; acute and silent MI, and unstable angina, ischemic stroke, or PAD.

N=142 from the DM-DYSLIPIDEMIA trial; Mean age (SD): 65.1 (8.8) years

N=177 from the DM INSULIN trial (all with ASCVD and T2DM)

Mean age (SD) 65.8 (8.8) years

Previous CVD diagnosis: CHD approximately 90% in each group including MI, and coronary revascularisation.

Mean (SD) in alirocumab DM-DYSLIPIDEMIA vs usual care; alirocumab DM-INSULIN vs placebo

LDL-C: 108.3 (46.3) vs 109.4 (44); 107.2 (35.1) vs 111.9 (46.4) mg/dl

Non-HDL-C: 156.5 (48.4) vs 156.8 (43.3); 142.8 (41.5) vs 147 (54.9)

Alirocumab DM-DYSLEPIDIMIA: 75mg (with blinded dose increase to 150mg at week 12 if week 8 non-HDL-C was ≥100 mg/dl)

N=95

Alirocumab DM-INSULIN: 75mg every 2 weeks (with blinded dose increase to 150mg every 2 weeks at week 12 if week 8 LDL-C was ≥70mg/dl.

N=119

Usual care (DM-DYSLEPIDIMIA): every 2 weeks; with UC options selected before stratified randomization based on the investigator’s preference for each participant. The following five UC options were included: continued use of maximally tolerated statin therapy with no additional LLT, fenofibrate, ezetimibe, omega-3 fatty acid, and nicotinic acid, reflecting variability in regional practice and therapeutic options available at the time the study was conducted.

N=47

Placebo DM-INSULIN

N=58

DM-DYSLIPIDEMIA: stable maximally tolerated statin dose for ≥4 weeks prior to screening visit, without other lipid-lowering therapies (LLTs),

DM-INSULIN: Statins and other LLTs remained stable throughout the duration of the study.

Baseline statin use: 84.8%, 87.2%, 77.3%, 72.4% in each group (majority of which was high intensity in DM-DYSLIPIDEMIA and moderate intensity in DM-INSLUIN)

LDL-C (mg/dl)

Non-HDL-C (% change from baseline)

At 24 weeks

Influenza

Nausea

From first to last dose plus 70 days or day 225 (in alirocumab vs usual care)

Low % (less than 10% in each group) was on low-intensity statins.

Rehberger 2022³⁸

People ages 18–65 years with clinically stable CAD of at least 6 months after MI (with mean age <55 years at first coronary event).

N=100

Mean age (SD): 50.2 (9.1) years

Previous CVD diagnosis: coronary artery disease

Mean (SD) in alirocumab vs ezetimibe vs control groups

LDL-C: 2.3 (0.7) vs 2.4 (0.8) vs 2.4 (0.9) mmol/l

Alirocumab: 150mg subcutaneously every 2 weeks

N=35

Evolocumab: 140mg subcutaneously every 2 weeks

N=34

Control: standard lipid-lowering therapy with no PCSK9 inhibitors

N=31

All participants were treated with statins at the highest tolerated doses with or without ezetimibe, and all were treated with angiotensin-converting enzyme inhibitors, beta blockers and acetylsalicylic acid. One in each group received a calcium channel blocker.

LDL-C (mmol/l)

At 6 months

Type of statin received was not specified.

Sabatine 2017;⁴² Sabatine 2016⁴¹ (protocol)

FOURIER

People aged 40–85 with clinically evidence CVD (history of MI, non-haemorrhagic stroke or symptomatic PAD)

N=27,564

Mean age (SD): 62.5(9) years

Previous CVD diagnosis: MI, non-haemorrhagic stroke or PAD.

Median (IQR) in intervention vs comparison

LDL-C: 92 (80–109) vs 92 (80 to 109) mg/dl

Evolocumab 140mg subcutaneously every 2 weeks or 40mg monthly (based on patient preference)

N=13784

Matching placebo injections

N=13780

Optimised stable lipid-lowering therapy (at least atorvastatin 20 mg daily or equivalent), with or without ezetimibe.

At baseline, 69.3% of the patients were taking high-intensity statin therapy (defined as atorvastatin ≥40 mg, rosuvastatin ≥20 mg or simvastatin 80 mg)

LDL-C

Non-HDL-C

At 48 weeks

MACE (CVD death, MI or stroke)

At 36 months

Subgroup analysis based on baseline LDL-C (<80mg/dl vs 80-<92 mg/dl vs 92–109 mg/dl vs >109 mg/dl) and statin intensity (high vs not high) available

Rhabdomyolysis

New-onset diabetes

Increase liver transaminases

Injection site reaction

At 36 months

None

Schwartz 2018;⁴⁵ Diaz 2022⁹ (subgroup), Schwartz 2014⁴⁴ (protocol)

ODYSSEY OUTCOMES

People hospitalised with acute coronary syndrome (myocardial infarction or unstable angina) 1–12 months earlier, LDL-C at least 70 mg/dl, non-HDL-C at least 100mg/dl or Apo B level at least 80mg per dL, receiving statins at high-intensity dose or maximum tolerated dose

N=18,924

Mean age (SD): 58.5 (9.3) years

Previous CVD event/diagnosis:

MI: 19%

PCI: 17%

Coronary artery bypass grafting: 5.5%

Stroke: 3.2%

PAD: 4%

Index ACS event: 34% STEMI; 48% NSTEMI; 17% UA

Mean (SD) in intervention vs comparison.

LDL-C: 92(31) mg/dl in both groups

Non-HDL: 122 (35) vs 123(36) mg/dl

Alirocumab: 75mg subcutaneously every 2 weeks increased to 150mg if LDL-C remains ≥50mg/dl after 1 month

N=9462

Placebo

N=9462

Atorvastatin 40 or 80mg or rosuvastatin 20 or 40mg or maximal tolerated dose of one of the statins with or without lipid lowering therapies; National Cholesterol Education Program Adult Treatment Panel-III therapeutic lifestyle changes or equivalent throughout the study.

LDL-C (mg/dl) At 12 months

MACE (composite of death from CHD, nonfatal MI, fatal or nonfatal ischemic stroke or UA requiring hospitalisation)

At 4 years

Myopathy

New onset diabetes

Increased liver transaminases

Injection site reactions

At 4 years

None

PCSK9i versus ezetimibe

Cannon 2015;⁶ Colhoun 2014⁸ (rationale); El Shahawy 2017¹⁰ (104 week data); Leiter 2017²² (influenza outcome)

ODYSSEY COMBO II

People with hypercholesterolaemia and established CHD or CHD risk equivalents with LDL-C poorly controlled with a maximally tolerated daily dose of statin at stable dose for ≥4 weeks before screening

LDL-C ≥ 1.8 mmol/l (≥ 70 mg/dl) with history CHD

LDL-C ≥ 2.6 mmol/l (≥ 100 mg/dl) without history CHD

N=720

Mean age (SD): 61.5 (9.3) years

Previous CVD event/diagnosis: Documented history of CHD (acute MI Silent MI Unstable angina or Coronary revascularisation procedure): 91.2% and 88% in intervention and comparison.

Mean (SD) in intervention vs comparison

LDL-C: 2.8 (0.9) vs 2.7 (0.9) mmol/l

Non-HDL-C: 3.6 (1.0) vs 3.5 (1.0) mmol/l

Alirocumab: 75mg every 2 weeks with increase to 150mg at week 12 (if week 8LDL-C was ≥1.8 mmol/l) plus oral placebo for ezetimibe daily

N=479

Ezetimibe plus subcutaneous placebo (for alirocumab) every 2 weeks

N=241

Background statin: % in intervention vs comparison

Any statin: 99.8% vs 100%; high-intensity (40–80mg/d atorvastatin or 20–40mg/d rosuvastatin): 66.8 vs 66.4%; atorvastatin: 49.5% vs 66.4%; simvastatin: 21.9 vs 20.3%

LDL-C (mmol/l)

Non-HDL-C (mmol/l)

At week 24

Adjudicated cardiovascular events (CHD death, nonfatal MI, fatal/nonfatal ischemic stroke, UA hospitalisation, HF hospitalisation, ischemia driven coronary revascularisation) at 52 weeks

MACE (CHD death, nonfatal MI, ischemic stroke or unstable angina requiring hospitalisation at 104 weeks

Increased liver transaminases at 104 weeks

Local injection-site reactions at 104 weeks

Diabetes mellitus/Type 2 diabetes onset at 104 weeks

Influenza at 104 weeks

None

Han 2020¹³

ODYSSEY EAST

People with hypercholesterolemia and established CHD (97%) or CHD risk equivalents who were inadequately controlled with stable maximally tolerated statin therapy for at least 4 weeks

N=615

Mean age (SD): 58.6 (10.9) years

Mean (SD) in intervention vs comparison

LDL-C: 2.86 (1.25) vs 2.88 (1.29) mmol/l

Non-HDL-C: 3.58 (1.31) vs 3.63 (1.36) mmol/l

Alirocumab (subcutaneous): 75mg every 2 weeks with dose increase to 150mg every 2 weeks at week 12 if week 8 LDL-C was >1.81 mmol/l

N=407

Ezetimibe: 10mg daily (orally)

N=208

Maximally tolerated statins: atorvastatin 40 to 80 mg daily, rosuvastatin 20 to 40 mg daily, simvastatin 40 mg daily, or lower doses of these if there was a documented reason.

High-intensity statins in 68% at baseline

LDL-C

Non-HDL-C.

Injection site reactions

Positively adjudicated CVD events (CHD death, non-fatal MI, fatal or non-fatal ischemic stroke, UA requiring hospitalisation, congestive heart failure requiring hospitalisation, ischemia driven coronary revascularisation)

New onset diabetes/ Type 2 diabetes

At week 24

None

PCSK9i plus ezetimibe versus ezetimibe

Hao 2022¹⁴

People with extremely high-risk CHD diagnosed with ACS and receiving PCI treatment and LDL-C ≥ 3.0 mmol/l after statin therapy

N=136

Mean age (SD): 62.2 (11.9) years

Index ACS event in intervention vs comparison: STEMI 39.7% vs 41.18%; NSTEMI 50% vs 45.59%; UA 10.29% vs 13.24%

Mean (SD) in intervention vs comparison

LDL-C 3.54 (0.58) vs 3.52 (0.41) mmol/l

Evolocumab: 140mg every 2 weeks (subcutaneously within 48 hours after PCI) plus atorvastatin 40mg/d and ezetimibe 10mg/d

N=68

Control: atorvastatin 40mg/d and ezetimibe 10mg/d

N=61

All participants received standard PCI treatment and were implanted with drug-eluting stents.

Both control and evolocumab groups received atorvastatin 40 mg/day and ezetimibe 10 mg/day to lower lipids after PCI. The rest of the treatment drugs were used in accordance with the current guidelines.

LDL-C mmol/l

At 3-months

none

Inclisiran

Ray 2020³⁷

ORION 10 and 11

People aged ≥18 years with history of ASCVD (CHD, CVD or PAD) or ASCVD risk equivalents (type 2 diabetes, familiar hypercholesterolemia and 10-year risk of a CV event) and elevated LDL cholesterol levels at screening despite maximum tolerated statin.

Previous CVD diagnosis: >80% ASCVD across both trials

N=3,178

Mean age (SD): 65.4 (8.7) years

Mean (SD) in ORION 10 inclisiran vs placebo; ORION-11 inclisiran vs placebo

LDL-C: 104.5 (39.6) vs 104.8 (37); 107.2 (41.8) vs 103.7 (36.4) mg/dl

Non-HDL-C: 134 (44.5) vs 134.7 (43.5) ; 137.6 (46.9) vs 133.9 (41) mg/dl

ORION-10/11: inclisiran: 284mg as a 1.5ml subcutaneous injection (4 injections: day 1, 90, 270 and 450)

N=1,591

ORION 10/11: matching placebo

ORION 11: placebo

N=1,587

ORION-10: 89% on statins and 10% ezetimibe

ORION-11: 95% on statins and 7% ezetimibe

LDL-C

Non-HDL-C:

Days 510 and 540

MACE (non-adjudicated terms, including those classified within cardiac death, and any signs or symptoms of cardiac arrest, nonfatal myocardial infarction, or stroke)

Injection-site reaction

Increased liver transaminases

At day 540

None

: ACS: acute coronary syndrome; AMI: acute myocardial infarction; CAD: coronary artery disease; CHD: coronary heart disease; LDL-C: low-density lipoprotein cholesterol; LLT: Lipid-lowering therapy; MI: myocardial infarction; PCI: percutaneous coronary intervention; SAEs: serious adverse events; STEMI: ST elevation myocardial infarction; TEAEs: treatment emergent adverse events; every 2 weeks: every two weeks; UA: unstable angina

Table 3Clinical evidence summary: ezetimibe plus statin versus statin

Outcomes	№ of participants (studies)	Certainty (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	№ of participants (studies)	Certainty (GRADE)	Relative effect (95% CI)	Risk with statins	Risk difference with ezetimibe plus statins
LDL-C; (% change) follow-up: 6–12 months	322 (3 RCTs)	⨁⨁⨁◯ Moderate^a,b	-	The mean LDL-C (% change) ranged from −29 to −52.4%	MD 11.5% lower (15.66 lower to 7.33 lower)
LDL-C; mmol/l (combined final value and absolute change) follow-up: 12 weeks - 1 year	15270 (15 RCTs)	⨁◯◯◯ Very low^a,b,c,d	-	The range in mean change in LDL-C was −0.75 to −2.2 mmol/l and the range in mean final LDL-C value was 1.85 to 2.75 mmol/l	MD 0.41 mmol/l lower (0.47 lower to 0.34 lower)
non-HDL-C; (% change) follow-up: 6 months	40 (1 RCT)	⨁◯◯◯ Very low^a,b,e	-	The mean % change in non-HDL-C; was −34.8%	MD 15.5% lower (26.61 lower to 4.39 lower)
non-HDL-C; mmol/l (combined final value and absolute change) follow-up: 12 weeks to 1 year	12954 (3 RCTs)	⨁◯◯◯ Very low^a,b,f	-	The mean final value non-HDL-C was 2.4–2.8 mmol/l	MD 0.67 mmol/l lower (1 lower to 0.33 lower)
MACE follow-up: 6 months to 7 years	19067 (8 RCTs)	⨁⨁⨁◯ Moderate^g	RR 0.94 (0.90 to 0.98)	293 per 1,000	18 fewer per 1,000 (29 fewer to 6 fewer)
MACE - follow up > 2 years follow-up: 7 years	18144 (1 study)	⨁⨁⨁◯ Moderate^g	RR 0.94 (0.90 to 0.98)	302 per 1,000	18 fewer per 1,000 (30 fewer to 6 fewer)
MACE - follow up ≤ 2 years follow-up: 6 months to 2 years	923 (7 studies)	⨁⨁◯◯ Low^a,h	RR 0.91 (0.63 to 1.31)	111 per 1,000	13 fewer per 1,000 (43 fewer to 32 more)
MACE: HR follow-up: 7 years	18144 (1 RCT)	⨁⨁⨁◯ Moderate^g	HR 0.94 (0.89 to 0.98)		)
Adverse events - myopathy or rhabdomyolysis follow-up: 6 months to 6 years	18514 (5 RCTs)	⨁◯◯◯ Very low^a,g	OR 0.97 (0.57 to 1.64)	3 per 1,000	0 fewer per 1,000 (0 fewer to 0 more)ⁱ
Adverse events - raised liver transaminases follow-up: 6 months to 6 years	18696 (6 RCTs)	⨁⨁⨁◯ Moderate^a	RR 1.08 (0.90 to 1.30)	23 per 1,000	2 more per 1,000 (2 fewer to 7 more)
Adverse events - cancer follow-up: 6 years	18144 (1 RCT)	⨁⨁⨁⨁ High	RR 1.02 (0.93 to 1.13)	81 per 1,000	2 more per 1,000 (6 fewer to 10 more)
Adverse events - gallbladder-related AE follow-up: 6 years	18144 (1 RCT)	⨁⨁⨁◯ Moderate^a	RR 0.88 (0.75 to 1.03)	35 per 1,000	4 fewer per 1,000 (9 fewer to 1 more)

a: Downgraded by 1 increment if the confidence interval crossed one MID and by 2 increments if the confidence interval crossed two MIDs (0.8 and 1.25 for dichotomous outcomes; 0.5 * median of baseline SD of the intervention and control group for continuous outcomes).

b: Continuous MIDs: % change LDL-C: 9.45; absolute change LDL-C:0.35; % change non-HDL-C: 8.85; absolute change non-HDL-C: 0.455

c: Majority of evidence at high risk of bias (random effects study weighting). Reasons included such as high rates of missing data, imbalance in age between groups, insufficient information about randomisation procedures and potential deviation from randomised intervention in unblinded studies.

d: I² >50%; random effects model was used for the analysis due to heterogeneity unexplained by subgroup analysis

e: Very serious risk of bias due to between-group differences in age at baseline and high rate of missing outcome data.

f: I² >75%; random effects model was used for the analysis due to heterogeneity unexplained by subgroup analysis

g: All or the majority of evidence has serious intervention indirectness due to the proportion having the simvastatin dose increased from 40 to 80 mg being unbalanced between groups.

h: Follow-up <12 months in the majority of evidence based on weight in the meta-analysis.

i: Absolute effect calculated from risk difference.

Table 4Clinical evidence summary: PCSK9i versus placebo or usual care

Outcomes	№ of participants (studies) Follow-up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	№ of participants (studies) Follow-up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with placebo or usual care	Risk difference with PCSK9
% change LDL-C follow-up: 12–52 weeks	30644 (8 RCTs)	⨁⨁◯◯ Low^a,b	-	The mean % change LDL-C ranged from −13.4 to 6.3%	MD 54.62% lower (59.28 lower to 49.97 lower)
LDL-C absolute change or final value follow-up: 12–52 weeks (one using time-weighted average from baseline to 18 months)	30054 (10 RCTs)	⨁⨁◯◯ Low^a,b	-	The mean LDL-C absolute change ranged from −0.2 to −1.98 mmol/l	MD 1.43 mmol/l lower (1.56 lower to 1.3 lower)
non-HDL-C % change follow-up: 12–52 weeks	3090 (7 RCTs)	⨁⨁◯◯ Low^a,b	-	The mean non-HDL-C % change ranged from −14.4 to 4.3%	MD 42.47% lower (48.45 lower to 36.5 lower)
non-HDL-C absolute change or final value (mmol/l) follow-up: 36–52 weeks (one using time-weighted average from baseline to 18 months)	1825 (5 RCTs)	⨁⨁◯◯ Low^a	-	The mean non HDL-C absolute change (mmol/l) ranged from 0.028 to −1.77 mmol/l	MD 1.45 mmol/l lower (1.67 lower to 1.22 lower)
Major adverse CVD events/MACE (at 6 months to 4 years)	48232 (7 RCTs)	⨁⨁⨁◯ Moderate^c	RR 0.83 (0.78 to 0.88)	89 per 1,000	15 fewer per 1,000 (20 fewer to 11 fewer)
Major adverse CVD events/MACE - follow up > 2 years	46488 (2 RCTs)	⨁⨁⨁◯ Moderate^c	RR 0.83 (0.78 to 0.88)	89 per 1,000	15 fewer per 1,000 (20 fewer to 11 fewer)
Major adverse CVD events/MACE - follow up ≤ 2 years	1744 (5 RCTs)	⨁⨁⨁◯ Moderate^c	RR 0.85 (0.63 to 1.14)	103 per 1,000	15 fewer per 1,000 (38 fewer to 14 more)
MACE (at 36 months to 4 years)	46488 (2 RCTs)	⨁⨁⨁◯ Moderate^c	HR 0.83 (0.78 to 0.88)
Myopathy/rhabdomyolysis	46271 (2 RCTs)	⨁◯◯◯ Very low^c,d	RR 0.91 (0.63 to 1.32)	3 per 1,000	0 fewer per 1,000 (1 fewer to 1 more)
New-onset diabetes (at 52 weeks to 4 years)	31302 (4 RCTs)	⨁⨁⨁⨁ High	RR 1.00 (0.93 to 1.07)	86 per 1,000	0 fewer per 1,000 (6 fewer to 6 more)
Increased liver transaminases (at 18–36 months)	28532 (2 RCTs)	⨁⨁⨁⨁ High	RR 0.99 (0.83 to 1.18)	17 per 1,000	0 fewer per 1,000 (3 fewer to 3 more)
Injection-site reactions (at 12 weeks to 4 years)	48638 (7 RCTs)	⨁⨁⨁⨁ High	RR 1.57 (1.40 to 1.77)	18 per 1,000	10 more per 1,000 (7 more to 14 more)
Nausea	317 (2 RCTs)	⨁⨁◯◯ Low^c	RR 0.65 (0.15 to 2.85)	29 per 1,000	10 fewer per 1,000 (25 fewer to 53 more)

a: I² >75%; random effects model was used for the analysis due to heterogeneity unexplained by subgroup analysis

b: Continuous outcome MIDs: % change LDL-C = 13.85; absolute LDL-C: 0.37; % change non-HDL-C: 12.5; absolute non-HDL-C: 0.32.

c: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs (standard MIDs for dichotomous outcomes: 0.8 and 1.25)

d: Downgraded by 1 increment because the majority of the evidence was at high risk of bias (due to event rate for outcome being similar to number lost to follow-up)

Table 5Clinical evidence summary: PCSK9i versus ezetimibe

Outcomes	№ of participants (studies) Follow-up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	№ of participants (studies) Follow-up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with ezetimibe	Risk difference with PCSK9i
% change LDL-C follow-up: range 24 weeks to 52 weeks	1318 (2 RCTs)	⨁⨁⨁⨁ High^a	-	The mean % change LDL-C ranged from −18.3 to −20.3%	MD 33.5% lower (37.9 lower to 29.09 lower)
Final LDL-C follow-up: 24 weeks	707 (1 RCT)	⨁⨁⨁⨁ High	-	The mean final LDL-C was 2.1 mmol/l	MD 0.8 mmol/l lower (0.94 lower to 0.66 lower)
% change non-HDL-C follow-up: range 24 weeks to 52 weeks	1318 (2 RCTs)	⨁⨁⨁◯ Moderate^a,b	-	The mean % change non-HDL-C ranged from −19.2 to −19.4%	MD 25.25% lower (29.86 lower to 20.64 lower)
MACE/ Positively adjudicated CVD events (at 24 to 104 weeks)	1332 (2 RCTs)	⨁◯◯◯ Very low^c,d	RR 1.01 (0.58 to 1.76)	40 per 1,000	0 fewer per 1,000 (17 fewer to 31 more)
New-onset diabetes (at 24 to 104 weeks)	938 (2 RCTs)	⨁◯◯◯ Very low^d,e	RR 0.92 (0.47 to 1.80)	40 per 1,000	3 fewer per 1,000 (21 fewer to 32 more)
Increased liver transaminases-alanine aminotransferase >3 x ULN follow-up: 104 weeks	720 (1 RCT)	⨁⨁◯◯ Low^d	RR 2.52 (0.56 to 11.39)	8 per 1,000	13 more per 1,000 (4 fewer to 86 more)
Increased liver transaminases-aspartate aminotransferase >3 x ULN follow-up: 104 weeks	720 (1 RCT)	⨁⨁◯◯ Low^d	RR 5.53 (0.72 to 42.62)	4 per 1,000	19 more per 1,000 (1 fewer to 173 more)

a: Continuous outcome MIDs: % change LDL-C: 15.34; final LDL-C value: 4.5 mmol/l; % change non-HDL-C: 12.61

b: I² >50%

c: Downgraded by 1 increment for serious indirectness due to one of 1/2 studies reporting outcome at 24 weeks

d: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs (standard MIDs for dichotomous outcomes: 0.8 and 1.25)

e: Unclear if diabetes referred to new onset in one of the studies with the higher weight in the meta-analysis.

f: Downgraded by 1 increment as the evidence was at high risk of bias, due to it being unclear if the outcome was consistently recorded.

Table 6Clinical evidence summary: PCSK9i plus ezetimibe versus ezetimibe

Outcomes	№ of participants (studies) Follow-up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	№ of participants (studies) Follow-up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with ezetimibe	Risk difference with PCSK9i + ezetimibe
Final LDL-C (mmol/l) follow-up: 3 months	129 (1 RCT)	⨁⨁◯◯ Low^a,b	-	The mean final LDL-C was 1.27 mmol/l	MD 0.69 mmol/l lower (0.84 lower to 0.54 lower)

a: Very high risk of bias due to recruitment and randomisation method not being specified (leading to potential selection bias), and treatment being adjusted according to lipid control during follow-up in combination with lack of blinding.

b: Continuous MID: final LDL-C: 0.25

Table 7Clinical evidence summary: inclisiran versus placebo

Outcomes	№ of participants (studies) Follow-up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	№ of participants (studies) Follow-up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with placebo	Risk difference with Inclisiran
LDL-C % change follow-up: weighted average between 90 and 540 days	3178 (2 RCTs)	⨁⨁⨁◯ Moderate^a,b	-	NR	MD 51.49% lower (56.00 lower to 46.99 lower)
LDL-C absolute change (mmol/l) follow-up: weighted average between 90 and 540 days	3178 (2 RCTs)	⨁⨁⨁◯ Moderate^c	-	NR	MD 1.32 mmol/l lower (1.37 lower to 1.28 lower)
MACE (non-adjudicated terms) follow-up: 540 days	3174 (2 RCTs)	⨁⨁⨁◯ Moderate^d	RR 0.74 (0.59 to 0.93)	102 per 1,000	27 fewer per 1,000 (42 fewer to 7 fewer)
Increased liver transaminases - ALT >3xULN follow-up: 540 days	3174 (2 RCTs)	⨁◯◯◯ Very low^d,e	RR 0.99 (0.32 to 3.07)	4 per 1,000	0 fewer per 1,000 (3 fewer to 8 more)
Increased liver transaminases - AST >3xULN follow-up: 540 days	3174 (2 RCTs)	⨁◯◯◯ Very low^d,e	RR 0.66 (0.24 to 1.86)	6 per 1,000	2 fewer per 1,000 (4 fewer to 5 more)
Injection-site reactions follow-up: 540 days	3174 (2 RCTs)	⨁⨁◯◯ Low^e,f	RR 5.01 (1.52 to 16.54)	7 per 1,000	28 more per 1,000 (4 more to 108 more)

a: I² = 86%; random effects model was used for the analysis due to heterogeneity unexplained by subgroup analysis.

b: Continuous MIDs: % change LDL-C; 12.3; absolute change LDL-C: 0.495

c: I²= 84%; random effects model was used for the analysis due to heterogeneity unexplained by subgroup analysis.

d: Downgraded by 1 increment if the confidence interval crossed one MID and by 2 increments if the confidence interval crossed two MIDs (0.8 and 1.25 for dichotomous outcomes; 0.5 * median of baseline SD of the intervention and control group for continuous outcomes).

e: Event rate less than number lost to follow-up.

f: I² = 69%; random effects model was used for the analysis due to heterogeneity unexplained by subgroup analysis.

Table 15Studies excluded from the clinical review

Study	Exclusion reason
(2020) Efficacy of Evolocumab in Patients with Hypercholesterolemia. Kosin med j 35(2): 125–132	- Population not relevant to this review protocol: proportion with CVD not stated
Ah, Young-Mi; Jeong Minseob; Choi Hye Duck (2022) Comparative safety and efficacy of low-or moderate-intensity statin plus ezetimibe combination therapy and high-intensity statin monotherapy: A meta-analysis of randomized controlled studies. PloS one 17(3): e0264437 [PMC free article: PMC8896700] [PubMed: 35245303]	- Systematic review with no data of additional relevance SR with insufficient risk of bias assessment - used as a source of primary studies
Alvarez-Sala Luis A, Cachofeiro Victoria, Masana Luis et al (2008) Effects of fluvastatin extended-release (80 mg) alone and in combination with ezetimibe (10 mg) on low-density lipoprotein cholesterol and inflammatory parameters in patients with primary hypercholesterolemia: a 12-week, multicenter, randomized, open-label, parallel-group study. Clinical therapeutics 30(1): 84–97 [PubMed: 18343245]	- Population not relevant to this review protocol: <50% CVD excluded people with CVD event in the previous 3 months
Bach Richard G, Cannon Christopher P, Giugliano Robert P et al (2019) Effect of Simvastatin-Ezetimibe Compared With Simvastatin Monotherapy After Acute Coronary Syndrome Among Patients 75 Years or Older: A Secondary Analysis of a Randomized Clinical Trial. JAMA cardiology 4(9): 846–854 [PMC free article: PMC6647004] [PubMed: 31314050]	- Secondary publication of an included study that does not provide any additional relevant information
Baigent Colin, Landray Martin J, Reith Christina et al (2011) The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet (London, England) 377(9784): 2181–92 [PMC free article: PMC3145073] [PubMed: 21663949]	- Population not relevant to this review protocol: <50% CVD
Ballantyne Christie M, Abate Nicola, Yuan Zhong et al (2005) Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study. American heart journal 149(3): 464–73 [PubMed: 15864235]	- Follow-up <3 months
Ballantyne Christie M, Hoogeveen Ron C, Raya Joe L et al (2014) Efficacy, safety and effect on biomarkers related to cholesterol and lipoprotein metabolism of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg vs. simvastatin 40 or 80 mg plus ezetimibe 10 mg in high-risk patients: Results of the GRAVITY randomized study. Atherosclerosis 232(1): 86–93 [PubMed: 24401221]	- Comparator in study does not match that specified in this review protocol Incorrect comparison: all arms have ezetimibe, comparing different statins in combination
Ballantyne CM, Houri J, Notarbartolo A et al (2003) Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation 107(19): 2409–2415 [PubMed: 12719279]	- Population not relevant to this review protocol: <50% CVD
Ballantyne CM, Lipka LJ, Sager PT et al (2004) Long-term safety and tolerability profile of ezetimibe and atorvastatin coadministration therapy in patients with primary hypercholesterolaemia. International journal of clinical practice 58(7): 653–658 [PubMed: 15311720]	- Population not relevant to this review protocol: <50% CVD Very low rate of people with previous CVD (12%); partially indirect comparison as intervention did not start with high-intensity statins but some of the participants were then titrated to high-intensity
Bang Casper N, Greve Anders M, Boman Kurt et al (2012) Effect of lipid lowering on new-onset atrial fibrillation in patients with asymptomatic aortic stenosis: the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. American heart journal 163(4): 690–6 [PubMed: 22520536]	- Population not relevant to this review protocol: <50% CVD Incorrect population: not CVD and not on statins for CV risk reduction
Barrios V, Amabile N, Paganelli F et al (2005) Lipid-altering efficacy of switching from atorvastatin 10 mg/day to ezetimibe/simvastatin 10/20 mg/day compared to doubling the dose of atorvastatin in hypercholesterolaemic patients with atherosclerosis or coronary heart disease. International journal of clinical practice 59(12): 1377–86 [PubMed: 16351668]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin
Bays H, Gaudet D, Weiss R et al (2015) Alirocumab as Add-On to Atorvastatin Versus Other Lipid Treatment Strategies: ODYSSEY OPTIONS I Randomized Trial. Journal of clinical endocrinology and metabolism 100(8): 3140–3148 [PMC free article: PMC4524987] [PubMed: 26030325]	- Population not relevant to this review protocol: <80% CVD and suffiicient data from directly relevant populations
Bays H, Sapre A, Taggart W et al (2008) Long-term (48-week) safety of ezetimibe 10 mg/day coadministered with simvastatin compared to simvastatin alone in patients with primary hypercholesterolemia. Current medical research and opinion 24(10): 2953–2966 [PubMed: 18782465]	- Study does not include an intervention relevant to this protocol: includes low intensity statin Incorrect interventions (include S10 - low intensity; and S80 - contraindicated)
Bays Harold E, Leiter Lawrence A, Colhoun Helen M et al (2017) Alirocumab Treatment and Achievement of Non-High-Density Lipoprotein Cholesterol and Apolipoprotein B Goals in Patients With Hypercholesterolemia: Pooled Results From 10 Phase 3 ODYSSEY Trials. Journal of the American Heart Association 6(8) [PMC free article: PMC5586424] [PubMed: 28862926]	- Secondary analysis of 10 trials with no data of additional relevance
Bays Harold, Gaudet Daniel, Weiss Robert et al (2015) Alirocumab as Add-On to Atorvastatin Versus Other Lipid Treatment Strategies: ODYSSEY OPTIONS I Randomized Trial. The Journal of clinical endocrinology and metabolism 100(8): 3140–8 [PMC free article: PMC4524987] [PubMed: 26030325]	- Population not relevant to this review protocol ASCVD 61% and sufficient evidence from studies with>80% CVD population
Bays HE, Ose L, Fraser N et al (2004) A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clinical therapeutics 26(11): 1758–1773 [PubMed: 15639688]	- Population not relevant to this review protocol: proportion with CVD not stated
Ben-Yehuda Ori, Wenger Nanette K, Constance Christian et al (2011) The comparative efficacy of ezetimibe added to atorvastatin 10 mg versus uptitration to atorvastatin 40 mg in subgroups of patients aged 65 to 74 years or greater than or equal to 75 years. Journal of geriatric cardiology: JGC 8(1): 1–11 [PMC free article: PMC3390058] [PubMed: 22783278]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus higher dose of statin
Bittner Vera A, Szarek Michael, Philip E Aylward et al (2020) Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After Acute Coronary Syndrome. Journal of the American College of Cardiology 75(2): 133–144 [PubMed: 31948641]	- Secondary publication of an included study that does not provide any additional relevant information
Blazing MA B, Giugliano RP G, Wiviott SD W et al (2015) Muscle related complaints, serious adverse events vents and drug discontinuations in 17,706 subjects randomized to simvastatin or ezetimibe/simvastatin in the IMPROVE-IT study. European heart journal 36: 1151	- Conference abstract
Blazing Michael A, Giugliano Robert P, de Lemos James A et al (2016) On-treatment analysis of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT). American heart journal 182: 89–96 [PubMed: 27914504]	- Duplicate reference
Blom DJ, Hala T, Bolognese M et al (2014) A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. New England journal of medicine 370(19): 1809–1819 [PubMed: 24678979]	- Population not relevant to this review protocol: <50% CVD
Boccara Franck, Kumar Princy N, Caramelli Bruno et al (2020) Evolocumab in HIV-Infected Patients With Dyslipidemia: Primary Results of the Randomized, Double-Blind BEIJERINCK Study. Journal of the American College of Cardiology 75(20): 2570–2584 [PubMed: 32234462]	- Population not relevant to this review protocol: <50% CVD
Bohula May EA, Giugliano RP, Cannon CP et al (2015) Achievement of dual LDL-C (<70 mg/dl) and hs-CRP (<2 mg/L) goals more frequent with addition of ezetimibe and associated with better outcomes in IMPROVE-IT. European heart journal 36: 1060	- Full text paper not available
Bohula EA, Morrow DA, Giugliano RP et al (2017) Atherothrombotic Risk Stratification and Ezetimibe for Secondary Prevention. Journal of the American College of Cardiology 69(8): 911–921 [PubMed: 28231942]	- Secondary publication of an included study that does not provide any additional relevant information Study testing a model to predict CV death, MI or IS (absolute risk reduction) in the IMPROVE-IT population divided in different level of risk categories (low, intermediate, high) based on different variables; not relevant to review protocol
Bohula Erin A, Giugliano Robert P, Cannon Christopher P et al (2015) Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT. Circulation 132(13): 1224–33 [PubMed: 26330412]	- Secondary publication of an included study that does not provide any additional relevant information
Bohula Erin A, Giugliano Robert P, Leiter Lawrence A et al (2018) Inflammatory and Cholesterol Risk in the FOURIER Trial. Circulation 138(2): 131–140 [PubMed: 29530884]	- Secondary publication of an included study that does not provide any additional relevant information
Bohula Erin A, Wiviott Stephen D, Giugliano Robert P et al (2017) Prevention of Stroke with the Addition of Ezetimibe to Statin Therapy in Patients With Acute Coronary Syndrome in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation 136(25): 2440–2450 [PubMed: 28972004]	- Secondary publication of an included study that does not provide any additional relevant information IMPROVE-IT but focusing on people with stroke before randomisation
Bonaca Marc P, Nault Patrice, Giugliano Robert P et al (2018) Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation 137(4): 338–350 [PubMed: 29133605]	- Secondary publication of an included study that does not provide any additional relevant information
Brudi P, Reckless J P, Henry D P et al (2009) Efficacy of ezetimibe/simvastatin 10/40 mg compared to doubling the dose of low-, medium-and high-potency statin monotherapy in patients with a recent coronary event. Cardiology 113(2): 89–97 [PubMed: 19018143]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin
Burnett Heather, Fahrbach Kyle, Cichewicz Allie et al (2022) Comparative efficacy of non-statin lipid-lowering therapies in patients with hypercholesterolemia at increased cardiovascular risk: a network meta-analysis. Current medical research and opinion 38(5): 777–784 [PubMed: 35262430]	- Network meta-analysis with population not relevant to this review protocol Population does not entirely match protocol; individual studies assessed for inclusion.
Califf Robert M., Lokhnygina Yuliya, Cannon Christopher P. et al (2010) An update on the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) design. American Heart Journal 159(5): 705–709 [PubMed: 20435175]	- Secondary publication of an included study that does not provide any additional relevant information discussion of additional interim analysis of IMPROVE-IT trial
Cariou B, Leiter LA, Müller-Wieland D et al (2017) Efficacy and safety of alirocumab in insulin-treated patients with type 1 or type 2 diabetes and high cardiovascular risk: rationale and design of the ODYSSEY DM-INSULIN trial. Diabetes & metabolism 43(5): 453–459 [PubMed: 28347654]	- Trial protocol for a study not yet completed/reported Paper reports on methodology/design and inclusion criteria, no data available to extract.
Chaiyasothi Thanaputt, Nathisuwan Surakit, Dilokthornsakul Piyameth et al (2019) Effects of Non-statin Lipid-Modifying Agents on Cardiovascular Morbidity and Mortality Among Statin-Treated Patients: A Systematic Review and Network Meta-Analysis. Frontiers in pharmacology 10: 547 [PMC free article: PMC6540916] [PubMed: 31191304]	- Network meta-analysis with outcomes not relevant to this review protocol
Chiang Chern-En, Schwartz Gregory G, Elbez Yedid et al (2022) Alirocumab and Cardiovascular Outcomes in Patients With Previous Myocardial Infarction: Prespecified Subanalysis From ODYSSEY OUTCOMES. The Canadian journal of cardiology 38(10): 1542–1549 [PubMed: 35644332]	- Secondary publication of an included study that does not provide any additional relevant information
Constance Christian, Ben-Yehuda Ori, Wenger Nanette K et al (2014) Atorvastatin 10 mg plus ezetimibe versus titration to atorvastatin 40 mg: attainment of European and Canadian guideline lipid targets in high-risk subjects >=65 years. Lipids in health and disease 13: 13 [PMC free article: PMC3901347] [PubMed: 24411003]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus higher dose of statin
Cruz-Fernandez J M, Bedarida G V, Adgey J et al (2005) Efficacy and safety of ezetimibe co-administered with ongoing atorvastatin therapy in achieving low-density lipoprotein goal in patients with hypercholesterolemia and coronary heart disease. International journal of clinical practice 59(6): 619–27 [PubMed: 15924587]	- Follow-up <3 months
Daviglus Martha L, Ferdinand Keith C, Lopez J Antonio G et al (2021) Effects of Evolocumab on Low-Density Lipoprotein Cholesterol, Non-High Density Lipoprotein Cholesterol, Apolipoprotein B, and Lipoprotein(a) by Race and Ethnicity: A Meta-Analysis of Individual Participant Data From Double-Blind and Open-Label Extension Studies. Journal of the American Heart Association 10(1): e016839 [PMC free article: PMC7955505] [PubMed: 33325247]	- Systematic review with no data of additional relevance SR/MA of population subgroups not relevant to the protocol (by ethnicity, statin intolerant, T2D, HeFH, duration of follow-up)
Desai Nihar R, Giugliano Robert P, Zhou Jing et al (2014) AMG 145, a monoclonal antibody against PCSK9, facilitates achievement of national cholesterol education program-adult treatment panel III low-density lipoprotein cholesterol goals among high-risk patients: an analysis from the LAPLACE-TIMI 57 trial (LDL-C assessment with PCSK9 monoclonal antibody inhibition combined with statin thErapy-thrombolysis in myocardial infarction 57). Journal of the American College of Cardiology 63(5): 430–3 [PubMed: 24161333]	- Secondary publication of an included study that does not provide any additional relevant information
Desai Nihar R, Kohli Payal, Giugliano Robert P et al (2013) AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9, significantly reduces lipoprotein(a) in hypercholesterolemic patients receiving statin therapy: an analysis from the LDL-C Assessment with Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined with Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 trial. Circulation 128(9): 962–9 [PubMed: 23884353]	- Secondary publication of an included study that does not provide any additional relevant information
Eisen Alon, Cannon Christopher P, Blazing Michael A et al (2016) The benefit of adding ezetimibe to statin therapy in patients with prior coronary artery bypass graft surgery and acute coronary syndrome in the IMPROVE-IT trial. European heart journal 37(48): 3576–3584 [PubMed: 27569841]	- Secondary publication of an included study that does not provide any additional relevant information
Shahawy El, Mahfouz Cannon, Christopher Blom, Dirk et al (2016) Alirocumab Versus Ezetimibe Over 104 Weeks In Individuals With Hypercholesterolemia And High Cardiovascular Risk: Final Results From ODYSSEY COMBO II. Journal of Clinical Lipidology 10(3): 717–718	- Conference abstract Conference abstract relevant to included study
El-Tamalawy Mona Mohammed, Ibrahim Osama Mohamed, Hassan Timour Mostafa et al (2018) Effect of Combination Therapy of Ezetimibe and Atorvastatin on Remnant Lipoprotein Versus Double Atorvastatin Dose in Egyptian Diabetic Patients. Journal of clinical pharmacology 58(1): 34–41 [PubMed: 28858387]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin
Ennezat Pierre Vladimir, Guerbaai Raphaelle-Ashley, Marechaux Sylvestre et al (2023) Extent of Low-density Lipoprotein Cholesterol Reduction and All-cause and Cardiovascular Mortality Benefit: A Systematic Review and Meta-analysis. Journal of cardiovascular pharmacology 81(1): 35–44 [PMC free article: PMC9812424] [PubMed: 36027598]	- Systematic review with no data of additional relevance SR does not contain outcome of interest : CV and all cause mortality only
Farmer John (2009) The Vytorin on Carotid-Media Thickness and Overall Arterial Rigidity (VYCTOR) study. Expert review of cardiovascular therapy 7(9): 1057–60 [PubMed: 19764858]	- Study design not relevant to this review protocol: not randomised not a trial report: commentary piece
Farnier Michel, Jones Peter, Severance Randall et al (2016) Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial. Atherosclerosis 244: 138–46 [PubMed: 26638010]	- Population not relevant to this review protocol: <80% CVD and suffiicient data from directly relevant populations
Farnier Michel, Volpe Massimo, Massaad Rachid et al (2005) Effect of co-administering ezetimibe with on-going simvastatin treatment on LDL-C goal attainment in hypercholesterolemic patients with coronary heart disease. International journal of cardiology 102(2): 327–32 [PubMed: 15982505]	- Follow-up <3 months Insufficient follow-up: 6 weeks; partially incorrect comparison with some participants receiving low statin intensity as background treatment
Feldman Theodore, Koren Michael, Insull William Jr et al (2004) Treatment of high-risk patients with ezetimibe plus simvastatin coadministration versus simvastatin alone to attain National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals. The American journal of cardiology 93(12): 1481–6 [PubMed: 15194017]	- Population not relevant to this review protocol: <50% CVD 66% had coronary heart disease or risk equivalent, exact number of people with coronary heart disease was not specified and is likely <50%
Ference Brian A, Cannon Christopher P, Landmesser Ulf et al (2018) Reduction of low density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: an analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration. European heart journal 39(27): 2540–2545 [PMC free article: PMC6047439] [PubMed: 29020411]	- Review article but not a systematic review
Foody JoAnne M, Brown W Virgil, Zieve Franklin et al (2010) Safety and efficacy of ezetimibe/simvastatin combination versus atorvastatin alone in adults >=65 years of age with hypercholesterolemia and with or at moderately high/high risk for coronary heart disease (the VYTELD study). The American journal of cardiology 106(9): 1255–63 [PubMed: 21029821]	- Population not relevant to this review protocol: <50% CVD
Fujisue K, Nagamatsu S, Shimomura H et al (2018) Impact of statin-ezetimibe combination on coronary atheroma plaque in patients with and without chronic kidney disease - Sub-analysis of PRECISE-IVUS trial. International journal of cardiology 268: 23–26 [PubMed: 29925472]	- Secondary publication of an included study that does not provide any additional relevant information Not relevant subgroup analysis of included trial (originally excluded as population less than 50% of the population had previous statin use and intensity was unclear)
Fujisue Koichiro, Yamanaga Kenshi, Nagamatsu Suguru et al (2021) Effects of Statin Plus Ezetimibe on Coronary Plaques in Acute Coronary Syndrome Patients with Diabetes Mellitus: Sub-Analysis of PRECISE-IVUS Trial. Journal of atherosclerosis and thrombosis 28(2): 181–193 [PMC free article: PMC7957031] [PubMed: 32435011]	- Secondary publication of an included study that does not provide any additional relevant information
Ganda Om P, Plutzky Jorge, Sanganalmath Santosh K et al (2018) Efficacy and safety of alirocumab among individuals with diabetes mellitus and atherosclerotic cardiovascular disease in the ODYSSEY phase 3 trials. Diabetes, obesity & metabolism 20(10): 2389–2398 [PMC free article: PMC6175384] [PubMed: 29802688]	- Secondary publication of an included study that does not provide any additional relevant information
Gao Fei, Li Yue Ping, Ma Xiao Teng et al (2022) Effect of Alirocumab on Coronary Calcification in Patients With Coronary Artery Disease. Frontiers in cardiovascular medicine 9: 907662 [PMC free article: PMC9120536] [PubMed: 35600486]	- Secondary publication of an included study that does not provide any additional relevant information
Gao Jing, Liu Jing-Yu, Lu Peng-Ju et al (2021) Effects of Evolocumab Added to Moderate-Intensity Statin Therapy in Chinese Patients With Acute Coronary Syndrome: The EMSIACS Trial Study Protocol. Frontiers in physiology 12: 750872 [PMC free article: PMC8650150] [PubMed: 34887772]	- Trial protocol for a study not yet completed/reported
Gencer Baris, Mach Francois, Murphy Sabina Aet al (2020) Efficacy of Evolocumab on Cardiovascular Outcomes in Patients With Recent Myocardial Infarction: A Prespecified Secondary Analysis From the FOURIER Trial. JAMA cardiology 5(8): 952–957 [PMC free article: PMC7240652] [PubMed: 32432684]	- Secondary publication of an included study that does not provide any additional relevant information
Geng Qiang, Li Xuan, Sun Qingjiao et al (2022) Efficacy and safety of PCSK9 inhibition in cardiovascular disease: a meta-analysis of 45 randomized controlled trials. Cardiology journal 29(4): 574–581 [PMC free article: PMC9273234] [PubMed: 34581425]	- Systematic review does not fully match review PICO - used as a source of primary studies
Ginsberg HN, Rader DJ, Raal FJ et al (2016) Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia and LDL-C of 160 mg/dl or Higher. Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy 30(5): 473–483 [PMC free article: PMC5055560] [PubMed: 27618825]	- Population not relevant to this review protocol: >20% familial hypercholesterolemia
Giugliano Robert P, Gencer Baris, Wiviott Stephen D et al (2020) Prospective Evaluation of Malignancy in 17,708 Patients Randomized to Ezetimibe Versus Placebo: Analysis From IMPROVE-IT. JACC. CardioOncology 2(3): 385–396 [PMC free article: PMC8352126] [PubMed: 34396246]	- Secondary publication of an included study that does not provide any additional relevant information aives HR and cancer locations (not required per protocol); N with cancer already available in primary report
Giugliano Robert P, Keech Anthony, Murphy Sabina A et al (2017) Clinical Efficacy and Safety of Evolocumab in High-Risk Patients Receiving a Statin: Secondary Analysis of Patients With Low LDL Cholesterol Levels and in Those Already Receiving a Maximal-Potency Statin in a Randomized Clinical Trial. JAMA cardiology 2(12): 1385–1391 [PMC free article: PMC5815002] [PubMed: 29117276]	- Secondary publication of an included study that does not provide any additional relevant information
Giugliano Robert P, Pedersen Terje R, Park Jeong-Gun et al (2017) Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet (London, England) 390(10106): 1962–1971 [PubMed: 28859947]	- Secondary publication of an included study that does not provide any additional relevant information FOURIER sub-analysis by statin intensity already reported in primary report.
Giugliano Robert P, Pedersen Terje R, Saver Jeffrey L et al (2020) Stroke Prevention With the PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibitor Evolocumab Added to Statin in High-Risk Patients With Stable Atherosclerosis. Stroke 51(5): 1546–1554 [PubMed: 32312223]	- Secondary publication of an included study that does not provide any additional relevant information Sub analysis of included study with no additional data of relevance (subgroup with prior stroke)
Giugliano Robert P, Wiviott Stephen D, Blazing Michael A et al (2017) Long-term Safety and Efficacy of Achieving Very Low Levels of Low-Density Lipoprotein Cholesterol: A Prespecified Analysis of the IMPROVE-IT Trial. JAMA cardiology 2(5): 547–555 [PMC free article: PMC5814987] [PubMed: 28291866]	- Secondary publication of an included study that does not provide any additional relevant information Subgroup analysis for safety and efficacy outcomes based on LDL-C levels achieved at 1 month not baseline LDL-C levels.
Giugliano RP, Cannon C, Blazing M et al (2015) Baseline LDL-C and clinical outcomes with addition of ezetimibe to statin in 18,144 patients post ACS. Journal of the American College of Cardiology 65(10suppl1): a4	- Conference abstract Poster/abstract about IMPROVE-IT trial, no extractable data
Giugliano RP, Cannon CP, Blazing MA et al (2018) Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With Versus Without Diabetes Mellitus: results From IMPROVE-IT (Improved Reduction of Outcomes: vytorin Efficacy International Trial). Circulation 137(15): 1571–1582 [PubMed: 29263150]	- Secondary publication of an included study that does not provide any additional relevant information Subaroup analysis of data from included trial, subgroups not of interest based on review protocol. Diabetes. New onset not reported
Giugliano RP, Wiviott SD, Fuchs CS et al (2015) Prospectivev evaluation of cancer in 18,144 patients randomized to ezetimibe vs placebo: a prespecified analysis from the IMPROVE IT trial. European heart journal 36: 181	- Conference abstract Conference abstract: malignancy endpoints of IMPROVE-IT trial, no new data
Goldberg AC, Sapre A, Liu J et al (2004) Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Mayo Clinic proceedings 79(5): 620–629 [PubMed: 15132403]	- Population not relevant to this review protocol: <50% CVD
Greve Anders M, Bang Casper N, Berg Ronan M G et al (2015) Resting heart rate and risk of adverse cardiovascular outcomes in asymptomatic aortic stenosis: the SEAS study. International journal of cardiology 180: 122–8 [PubMed: 25438232]	- Population not relevant to this review protocol Incorrect population: heart failure and no other qualifying condition
Greve Anders M, Boman Kurt, Gohlke-Baerwolf Christa et al (2012) Clinical implications of electrocardiographic left ventricular strain and hypertrophy in asymptomatic patients with aortic stenosis: the Simvastatin and Ezetimibe in Aortic Stenosis study. Circulation 125(2): 346–53 [PubMed: 22147903]	- Population not relevant to this review protocol Incorrect population: heart failure and no other qualifying condition
Guedeney Paul, Sorrentino Sabato, Giustino Gennaro et al (2021) Indirect comparison of the efficacy and safety of alirocumab and evolocumab: a systematic review and network meta-analysis. European heart journal. Cardiovascular pharmacotherapy 7(3): 225–235 [PubMed: 32275743]	- Network meta-analysis with intervention/comparisons not relevant to this review protocol (alirocumab vs evolocumab)
Hamdan Righab, Hajj Fouad, Kadry Zeina et al (2011) Benefit and tolerability of the coadministration of ezetimibe and atorvastatin in acute coronary syndrome patients. Le Journal medical libanais. The Lebanese medical journal 59(2): 65–9 [PubMed: 21834489]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin
Han YL, Ma YY, Su GH et al (2020) Efficacy and safety of alirocumab versus ezetimibe in high cardiovascular risk Chinese patients with hyperlipidemia: ODYSSEY EAST Study-Chinese sub-population analysis. Zhonghua xin xue guan bing za zhi 48(7): 593–599 [PubMed: 32842270]	- Study not reported in English
Hao Qiukui, Aertgeerts Bert, Guyatt Gordon et al (2022) PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events: a clinical practice guideline with risk-stratified recommendations. BMJ (Clinical research ed.) 377: e069066 [PubMed: 35508320]	- Data not reported in an extractable format or a format that can be analysed Clinical practice guideline
Hibi K, Sonoda S, Kawasaki M et al (2018) Effects of Ezetimibe-Statin Combination Therapy on Coronary Atherosclerosis in Acute Coronary Syndrome. Circulation journal 82(3): 757–766 [PubMed: 29212965]	- Comparator in study does not match that specified in this review protocol Incorrect comparison, pitavastatin not part of the review protocol
Hirayama A, Honarpour N, Yoshida M et al (2014) Effects of evolocumab (AMG 145), a monoclonal antibody to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk--primary results from the phase 2 YUKAWA study. Circulation journal 78(5): 1073–1082 [PubMed: 24662398]	- Population not relevant to this review protocol: <50% CVD
Hirayama Atsushi, Yamashita Shizuya, Ruzza Andrea et al (2019) Long-Term Treatment With Evolocumab Among Japanese Patients - Final Report of the OSLER Open-Label Extension Studies. Circulation journal: official journal of the Japanese Circulation Society 83(5): 971–977 [PubMed: 30930429]	- Secondary publication of an included study that does not provide any additional relevant information
Holme Ingar, Boman Kurt, Brudi Philippe et al (2010) Observed and predicted reduction of ischemic cardiovascular events in the Simvastatin and Ezetimibe in Aortic Stenosis trial. The American journal of cardiology 105(12): 1802–8 [PubMed: 20538134]	- Population not relevant to this review protocol: <50% CVD previous CVD was part of the exclusion criteria
Hougaard M, Hansen HS, Junker A et al (2014) Effect of ezetimibe in addition to statin therapy in statin naive STEMI patients assessed by optical coherence tomography and intravascular ultrasound with iMap (the OCTIVUS trial). Journal of the American College of Cardiology 64(11suppl1): b112	- Conference abstract
Hougaard Mikkel, Hansen Henrik Steen, Thayssen Per et al (2020) Influence of Ezetimibe on Plaque Morphology in Patients with ST Elevation Myocardial Infarction Assessed by Optical Coherence Tomography: An OCTIVUS Sub-Study. Cardiovascular revascularization medicine: including molecular interventions 21(11): 1417–1424 [PubMed: 31097383]	- Secondary publication of an included study that does not provide any additional relevant information
Huang Yen-Chu, Chang Chia-Hao, Tsai Yuan-Hsiung et al (2022) PCSK9 inhibition in patients with acute stroke and symptomatic intracranial atherosclerosis: protocol for a prospective, randomised, open-label, blinded end-point trial with vessel-wall MR imaging. BMJ open 12(4): e060068 [PMC free article: PMC9058777] [PubMed: 35487727]	- Trial protocol for a study not yet completed/reported
Inazawa Takeshi, Sakamoto Kentaro, Kohro Takahide et al (2013) RESEARCH (Recognized effect of Statin and ezetimibe therapy for achieving LDL-C Goal), a randomized, doctor-oriented, multicenter trial to compare the effects of higher-dose statin versus ezetimibe-plus-statin on the serum LDL-C concentration of Japanese type-2 diabetes patients design and rationale. Lipids in health and disease 12: 142 [PMC free article: PMC3852628] [PubMed: 24094079]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin Population: history of CAD in 10–15%, stroke <3%; incorrect comparison - double dose statin
Jackowska Paulina, Chalubinski Maciej, Luczak Emilia et al (2019) The influence of statin monotherapy and statin-ezetimibe combined therapy on FoxP3 and IL 10 mRNA expression in patients with coronary artery disease. Advances in clinical and experimental medicine: official organ Wroclaw Medical University 28(9): 1243–1248 [PubMed: 31430072]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus higher dose of statin
Janik Matthew J, Urbach Dorothea V, van Nieuwenhuizen Elane et al (2021) Alirocumab treatment and neurocognitive function according to the CANTAB scale in patients at increased cardiovascular risk: A prospective, randomized, placebo-controlled study. Atherosclerosis 331: 20–27 [PubMed: 34303265]	- Population not relevant to this review protocol Proportion with CVD not stated
Japaridze L; Sadunishvili M; Megreladze I (2016) COMBINATION THERAPY EFFECTIVENESS OF EZETIMIBE AND ATORVASTATIN IN PATIENTS WITH ACUTE CORONARY SYNDROME. Georgian medical news: 15–22 [PubMed: 27119829]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin
Japaridze Lasha and Sadunishvili Maia (2017) The short-term effect of atorvastatin plus ezetimibe therapy versus atorvastatin monotherapy on clinical outcome in acute coronary syndrome patients by gender. Kardiologia polska 75(8): 770–778 [PubMed: 28553847]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin
Jukema J Wouter, Szarek Michael, Zijlstra Laurien E et al (2019) Alirocumab in Patients With Polyvascular Disease and Recent Acute Coronary Syndrome: ODYSSEY OUTCOMES Trial. Journal of the American College of Cardiology 74(9): 1167–1176 [PubMed: 30898609]	- Secondary publication of an included study that does not provide any additional relevant information
Jukema J Wouter, Zijlstra Laurien E, Bhatt Deepak L et al (2019) Effect of Alirocumab on Stroke in ODYSSEY OUTCOMES. Circulation 140(25): 2054–2062 [PMC free article: PMC6919220] [PubMed: 31707788]	- Secondary publication of an included study that does not provide any additional relevant information
Kanbayashi K, Yamaguchi J, Fujii S et al (2017) The impact of serum sitosterol level on clinical outcomes in acute coronary syndrome patients with dyslipidemia: a subanalysis of HIJ PROPER. European heart journal. Conference: european society of cardiology, ESC congress 2017. Spain 38(supplement1): 237	- Conference abstract
Kasmas S H, Izar M C, Franca C N et al (2012) Differences in synthesis and absorption of cholesterol of two effective lipid-lowering therapies. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 45(11): 1095–101 [PMC free article: PMC3854149] [PubMed: 22801416]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus higher dose of statin
Kastelein JJ, Ginsberg HN, Langslet G et al (2015) ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. European heart journal 36(43): 2996–3003 [PMC free article: PMC4644253] [PubMed: 26330422]	- Population not relevant to this review protocol: >20% familial hypercholesterolaemia
Kastelein JJ, Strony J, Sager PT et al (2004) The ENHANCE trial: ezetimibe and simvastatin in hypercholesterolemia enhances atherosclerosis regression. Stroke 35(6): e258	- Population not relevant to this review protocol: >20% familial hypercholesterolaemia People with familial hypercholesterolemia (100%)
Kastelein JJ P, Sager PT, De Groot E et al (2005) Comparison of ezetimibe plus simvastatin versus simvastatin monotherapy on atherosclerosis progression in familial hypercholesterolemia: design and rationale of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial. American heart journal 149(2): 234–239 [PubMed: 15846260]	- Population not relevant to this review protocol: >20% familial hypercholesterolaemia People with familiar hypercholesterolemia (100%)
Kastelein John J P, Kereiakes Dean J, Cannon Christopher P et al (2017) Effect of alirocumab dose increase on LDL lowering and lipid goal attainment in patients with dyslipidemia. Coronary artery disease 28(3): 190–197 [PMC free article: PMC5400401] [PubMed: 27740972]	- Secondary analysis of trials with no data of additional relevance to the protocol
Katoh A, Hattori Y, Yoshikwa N et al (2017) The effects of ezetimibe on coronary plaque volume in patients with stable angina pectoris previously treated with statins. European heart journal. Conference: european society of cardiology, ESC congress 2017. Spain 38(supplement1): 188	- Conference abstract
Kawada-Watanabe E, Ogawa H, Koyanagi R et al (2017) Rationale, design features, and baseline characteristics: the Heart Institute of Japan-PRoper level of lipid lOwering with Pitavastatin and Ezetimibe in acute coRonary syndrome (HIJ-PROPER). Journal of cardiology 69(3): 536–541 [PubMed: 27349705]	- Comparator in study does not match that specified in this review protocol Incorrect comparison, pitavastatin not part of the review protocol
Kawamura M, Watanabe T, Sakamoto K et al (2015) RESEARCH: superior effect of ezetimibe was sustained on LDL-C level and the rate of achievement of target value in a 52-week analysis. Diabetologia 58(1suppl1): 82	- Conference abstract
Kereiakes Dean J, Lepor Norman E, Gerber Robert et al (2018) Efficacy and safety of alirocumab in patients with or without prior coronary revascularization: Pooled analysis of eight ODYSSEY phase 3 trials. Atherosclerosis 277: 211–218 [PubMed: 30025648]	- Data not reported in an extractable format or a format that can be analysed
Khan Safi U, Riaz Haris, Rahman Hammad et al (2019) Association of baseline LDL-C with total and cardiovascular mortality in patients using proprotein convertase subtilisin-kexin type 9 inhibitors: A systematic review and metaanalysis. Journal of clinical lipidology 13(4): 538–549 [PMC free article: PMC7294511] [PubMed: 31278046]	- Systematic review with no data of additional relevance does not contain any outocmes of relevance to this protocol
Khan Safi U, Talluri Swapna, Riaz Haris et al (2018) A Bayesian network meta-analysis of PCSK9 inhibitors, statins and ezetimibe with or without statins for cardiovascular outcomes. European journal of preventive cardiology 25(8): 844–853 [PubMed: 29569492]	- Systematic review with no data of additional relevance SR does not contain any outocomes of relevance to this protocol
Khan Safi U, Yedlapati Siva H, Lone Ahmad N et al (2022) PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis. BMJ (Clinical research ed.) 377: e069116 [PubMed: 35508321]	- Network meta-analysis with outcomes not relevant to this review protocol
Khan Sajjad A, Naz Arshi, Qamar Masood Muhammad et al (2020) Meta-Analysis of Inclisiran for the Treatment of Hypercholesterolemia. The American journal of cardiology 134: 69–73 [PubMed: 32892993]	- Systematic review with no data of additional relevance Included ORION 9, which was in those with Familial Hypercholesterolemia which was not relevant to the protocol. Paper added no extra relevant data on ORION 10 and 11 already identified.
Kim Byeong-Keuk, Hong Sung-Jin, Lee Yong-Joon et al (2022) Long-term efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING): a randomised, open-label, non-inferiority trial. Lancet (London, England) 400(10349): 380–390 [PubMed: 35863366]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin
Kinouchi K, Ichihara A, Bokuda K et al (2013) Effects of adding ezetimibe to fluvastatin on kidney function in patients with hypercholesterolemia: a randomized control trial. Journal of atherosclerosis and thrombosis 20(3): 245–256 [PubMed: 23197250]	- Population not relevant to this review protocol: <50% CVD Population with hypercholesterolemia and no previous CVD
Kinouchi K, Ichihara A, Bokuda K et al (2012) Ezetimibe preserves renal function in hypercholesterolemic patients treated with fluvastatin. Journal of hypertension 30: e214	- Conference abstract
Kiyosue Arihiro, Honarpour Narimon, Kurtz Christopher et al (2016) A Phase 3 Study of Evolocumab (AMG 145) in Statin-Treated Japanese Patients at High Cardiovascular Risk. The American journal of cardiology 117(1): 40–7 [PubMed: 26547291]	- Population not relevant to this review protocol: <50% CVD
Koenig W., Conde L.G., Landmesser U. et al (2022) Efficacy and Safety of Inclisiran in Patients with Polyvascular Disease: Pooled, Post Hoc Analysis of the ORION-9, ORION-10, and ORION-11 Phase 3 Randomized Controlled Trials. Cardiovascular Drugs and Therapy [PubMed: 36550348]	- Systematic review with no data of additional relevance Included ORION 9, which was in those with Familial Hypercholesterolemia which was not relevant to the protocol. Paper added no extra relevant data on ORION 10 and 11 already identified.
Koh KK, Nam C-W, Chao T-H et al (2017) A randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of alirocumab in high cardiovascular risk patients with hypercholesterolemia not adequately controlled with their lipidmodifying therapy in South Korea and Taiwan. Journal of the American College of Cardiology 69(11): 1664	- Conference abstract
Koren M, Sabatine M, Giugliano R et al (2019) Final Report of the OSLER-1 Study: long-Term Evolocumab for the Treatment of Hypercholesterolemia. Journal of clinical lipidology 13(3): e53–e54	- Conference abstract
Koren MJ, Giugliano RP, Raal FJ et al (2014) Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation 129(2): 234–243 [PubMed: 24255061]	- Population not relevant to this review protocol: <50% CVD
Koren MJ, Roth EM, McKenney JM et al (2015) Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: a phase II pooled analysis. Postgraduate medicine. 127 (2) (pp 125–132), 2015. Date of publication: 01 jan 2015. [PubMed: 25609019]	- Secondary analysis of trials with no data of additional relevance to the protocol
Koren MJ, Sabatine MS, Giugliano RP et al (2017) Long-term low-density lipoprotein cholesterol-lowering efficacy, persistence, and safety of evolocumab in treatment of hypercholesterolemia: results up to 4 years from the open-label OSLER-1 extension study. JAMA cardiology 2(6): 598–607 [PMC free article: PMC5815032] [PubMed: 28291870]	- Population not relevant to this review protocol: <50% CVD
Koskinas Konstantinos C, Siontis George C M, Piccolo Raffaele et al (2018) Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials. European heart journal 39(14): 1172–1180 [PubMed: 29069377]	- Systematic review does not fully match review PICO - used as a source of primary studies SR includes comparisons not relevant to the protocl. Used as a source of primary studies (only 2 relevant and both already ordered)
Kouvelos GN, Arnaoutoglou EM, Milionis HJ et al (2015) The effect of adding ezetimibe to rosuvastatin on renal function in patients undergoing elective vascular surgery. Angiology 66(2): 128–135 [PubMed: 24458801]	- Secondary publication of an included study that does not provide any additional relevant information
Landmesser Ulf, Haghikia Arash, Leiter Lawrence A et al (2021) Effect of inclisiran, the small-interfering RNA against proprotein convertase subtilisin/kexin type 9, on platelets, immune cells, and immunological biomarkers: a pre-specified analysis from ORION-1. Cardiovascular research 117(1): 284–291 [PubMed: 32243492]	- Secondary publication of an included study that does not provide any additional relevant information
Landmesser Ulf, McGinniss Jennifer, Steg Ph Gabriel et al (2022) Achievement of ESC/EAS LDL-C treatment goals after an acute coronary syndrome with statin and alirocumab. European journal of preventive cardiology 29(14): 1842–1851 [PubMed: 35708715]	- Secondary publication of an included study that does not provide any additional relevant information
Lee Ju-Hee, Kang Hyun-Jae, Kim Hyo-Soo et al (2013) Effects of ezetimibe/simvastatin 10/20 mg vs. atorvastatin 20 mg on apolipoprotein B/apolipoprotein A1 in Korean patients with type 2 diabetes mellitus: results of a randomized controlled trial. American journal of cardiovascular drugs: drugs, devices, and other interventions 13(5): 343–51 [PubMed: 23728830]	- Population not relevant to this review protocol: <50% CVD
Lee Yong-Joon, Cho Jae Young, You Seng Chan et al (2022) Moderate-intensity statin with ezetimibe vs. high-intensity statin in patients with diabetes and atherosclerotic cardiovascular disease in the RACING trial. European heart journal [PubMed: 36529993]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin
Leiter LA, Cariou B, Müller-Wieland D et al (2017) Efficacy and safety of alirocumab in insulin-treated individuals with type 1 or type 2 diabetes and high cardiovascular risk: the ODYSSEY DM-INSULIN randomized trial. Diabetes, obesity & metabolism 19(12): 1781–1792 [PMC free article: PMC5698740] [PubMed: 28905478]	- Population not relevant to this review protocol: <50% CVD
Leiter Lawrence A, Teoh Hwee, Kallend David et al (2019) Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status: The ORION-1 Randomized Clinical Trial. Diabetes care 42(1): 173–176 [PubMed: 30487231]	- Population not relevant to this review protocol: <80% CVD and suffiicient data from directly relevant populations - Comparator in study does not match that specified in this review protocol Inclisiran not at licensed dose.
Liu Zhi, Hao Hengjian, Yin Chunlin et al (2017) Therapeutic effects of atorvastatin and ezetimibe compared with double-dose atorvastatin in very elderly patients with acute coronary syndrome. Oncotarget 8(25): 41582–41589 [PMC free article: PMC5522285] [PubMed: 28177908]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin
Lorenzatti AJ, Eliaschewitz FG, Chen Y et al (2019) Randomised study of evolocumab in patients with type 2 diabetes and dyslipidaemia on background statin: primary results of the BERSON clinical trial. Diabetes, obesity & metabolism 21(6): 1455–1463 [PMC free article: PMC6594020] [PubMed: 30821053]	- Population not relevant to this review protocol: <80% CVD and suffiicient data from directly relevant populations
Lorenzatti Alberto J, Eliaschewitz Freddy G, Chen Yundai et al (2018) Rationale and design of a randomized study to assess the efficacy and safety of evolocumab in patients with diabetes and dyslipidemia: The BERSON clinical trial. Clinical cardiology 41(9): 1117–1122 [PMC free article: PMC6489947] [PubMed: 29962050]	- Population not relevant to this review protocol: <50% CVD Population does not match protocol: not all on statins and not all CVD
Lorenzi Maria, Ambegaonkar Baishali, Baxter Carl A et al (2019) Ezetimibe in high-risk, previously treated statin patients: a systematic review and network meta-analysis of lipid efficacy. Clinical research in cardiology: official journal of the German Cardiac Society 108(5): 487–509 [PubMed: 30302558]	- Network meta-analysis with intervention/comparisons not relevant to this review protocol adding ezetimibe vs doubling the dose of statin
Luan Yi, Wang Min, Zhao Liding et al (2021) Safety and Efficacy of Perioperative Use of Evolocumab in Myocardial Infarction Patients: Study Protocol for a Multicentre Randomized Controlled Trial. Advances in therapy 38(4): 1801–1810 [PubMed: 33638801]	- Trial protocol for a study not yet completed/reported
Luo L, Yuan X, Huang W et al (2015) Safety of coadministration of ezetimibe and statins in patients with hypercholesterolaemia: a metaanalysis. Internal medicine journal 45(5): 546–57 [PubMed: 25644680]	- Systematic review does not fully match review PICO - used as a source of primary studies SR: insufficient reporting of included study caracteristics. majority of studies have follow up <3 months. Remaining studies cross checked for relevance and ordered if appropriate
Ma Wenfang, Guo Xiying, Ma Yiming et al (2021) Meta-analysis of randomized clinical trials comparing PCSK9 monoclonal antibody versus ezetimibe/placebo in patients at high cardiovascular risk. Atherosclerosis 326: 25–34 [PubMed: 34004550]	- Systematic review does not fully match review PICO - used as a source of primary studies SR does not contain a comparison relevant to the protocol (pooled ‘ezetimibe and placebo, and includes populations not relevant to the protocol (FH, non CVD, statin naïve)
Ma Wenrui, Pan Qinyuan, Pan Defeng et al (2021) Efficacy and Safety of Lipid-Lowering Drugs of Different Intensity on Clinical Outcomes: A Systematic Review and Network Meta-Analysis. Frontiers in pharmacology 12: 713007 [PMC free article: PMC8567017] [PubMed: 34744709]	- Systematic review does not fully match review PICO - used as a source of primary studies
Madan Mina, Vira Tasnim, Rampakakis Emmanouil et al (2012) A Randomized Trial Assessing the Effectiveness of Ezetimibe in South Asian Canadians with Coronary Artery Disease or Diabetes: The INFINITY Study. Advances in preventive medicine 2012: 103728 [PMC free article: PMC3529456] [PubMed: 23304534]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus higher dose of statin
Magnuson EA, Chinnakondepalli K, Vilain K et al (2015) Impact of ezetimibe on hospitalization-related costs among patients with a recent acute coronary syndrome: results from the improve-it trial. Circulation 132(nopagination) [PubMed: 28506979]	- Conference abstract
Matsue Yuya, Matsumura Akihiko, Suzuki Makoto et al (2013) Differences in action of atorvastatin and ezetimibe in lowering low-density lipoprotein cholesterol and effect on endothelial function: randomized controlled trial. Circulation journal: official journal of the Japanese Circulation Society 77(7): 1791–8 [PubMed: 23603824]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin
McCormack T, Harvey P, Gaunt R et al (2010) Incremental cholesterol reduction with ezetimibe/simvastatin, atorvastatin and rosuvastatin in UK General Practice (IN-PRACTICE): randomised controlled trial of achievement of Joint British Societies (JBS-2) cholesterol targets. International journal of clinical practice 64(8): 1052–61 [PubMed: 20487050]	- Follow-up <3 months
Meaney Alejandra, Ceballos Guillermo, Asbun Juan et al (2009) The VYtorin on Carotid intima-media thickness and overall arterial rigidity (VYCTOR) study. Journal of clinical pharmacology 49(7): 838–47 [PubMed: 19443679]	- Study does not include an intervention relevant to this protocol: includes low intensity statin Population & comparison not relevant: majority had previously received statins at low and very low doses, comparison included statin not relevant to review protocol, unclear if population had previous CVD
Moreira Flavio Tocci, Ramos Silvia Cristina, Monteiro Andrea Moreira et al (2014) Effects of two lipid lowering therapies on immune responses in hyperlipidemic subjects. Life sciences 98(2): 83–7 [PubMed: 24447629]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus higher dose of statin
Moriarty PM, Thompson PD, Cannon CP et al (2015) Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. Journal of clinical lipidology 9(6): 758–769 [PubMed: 26687696]	- Population not relevant to this review protocol: >50% statin intolerant Population does not meet protocol: participants were intolerant to statins and approximately 50% had CVD with results not given separately for CVD vs CV risk factors populations
Morrone Doralisa, Weintraub William S, Toth Peter P et al (2012) Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis 223(2): 251–61 [PubMed: 22410123]	- Systematic review does not fully match review PICO - used as a source of primary studies SR with majority of studies not reporting at time point reelvant to the protocol (<12 weeks); and limited to Merck-sopnsored studies (not truly systematic)
Mortensen Martin B, Sand Niels-Peter, Busk Martin et al (2022) Influence of intensive lipid-lowering on CT derived fractional flow reserve in patients with stable chest pain: Rationale and design of the FLOWPROMOTE study. Clinical cardiology 45(10): 986–994 [PMC free article: PMC9574753] [PubMed: 36056636]	- Data not reported in an extractable format or a format that can be analysed Design and data analysis plan but no results presented
Mu Guangyan, Xiang Qian, Zhou Shuang et al (2020) Efficacy and Safety of PCSK9 Monoclonal Antibodies in Patients at High Cardiovascular Risk: An Updated Systematic Review and Meta-Analysis of 32 Randomized Controlled Trials. Advances in therapy 37(4): 1496–1521 [PubMed: 32108309]	- Systematic review does not fully match review PICO - used as a source of primary studies SR population doesn’t match protocpl: CVD or high CV risk population; all relevant studies already identified.
Muller-Wieland D, Rader DJ, Moriarty PM et al (2019) Efficacy and Safety of Alirocumab 300 mg Every 4 Weeks in Individuals with Type 2 Diabetes on Maximally Tolerated Statin. Journal of clinical endocrinology and metabolism [PMC free article: PMC6763278] [PubMed: 31166599]	- Population not relevant to this review protocol: <80% CVD and suffiicient data from directly relevant populations
Murphy Sabina A, Cannon Christopher P, Blazing Michael A et al (2016) Reduction in Total Cardiovascular Events With Ezetimibe/Simvastatin Post-Acute Coronary Syndrome: The IMPROVE-IT Trial. Journal of the American College of Cardiology 67(4): 353–361 [PubMed: 26821621]	- Duplicate reference FOURIER sub-analysis already reported in primary report.
Murphy Sabina A, Pedersen Terje R, Gaciong Zbigniew A et al (2019) Effect of the PCSK9 Inhibitor Evolocumab on Total Cardiovascular Events in Patients With Cardiovascular Disease: A Prespecified Analysis From the FOURIER Trial. JAMA cardiology 4(7): 613–619 [PMC free article: PMC6537798] [PubMed: 31116355]	- Secondary publication of an included study that does not provide any additional relevant information
Nakamura Takamitsu, Hirano Mitsumasa, Kitta Yoshinobu et al (2012) A comparison of the efficacy of combined ezetimibe and statin therapy with doubling of statin dose in patients with remnant lipoproteinemia on previous statin therapy. Journal of cardiology 60(1): 12–7 [PubMed: 22445441]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin
Nakano Yasuhiro, Yamamoto Mitsutaka, Matoba Tetsuya et al (2022) Association between Serum Oxysterols and Coronary Plaque Regression during Lipid-Lowering Therapy with Statin and Ezetimibe: Insights from the CuVIC Trial. Journal of atherosclerosis and thrombosis [PMC free article: PMC10406650] [PubMed: 36450458]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus higher dose of statin Statins could be chosen by investigator from any high, medium or low dose options and proportions used not stated
Navar Ann Marie, Roe Matthew T, White Jennifer A et al (2019) Medication Discontinuation in the IMPROVE-IT Trial. Circulation. Cardiovascular quality and outcomes 12(1): e005041 [PMC free article: PMC6541480] [PubMed: 30630361]	- Secondary publication of an included study that does not provide any additional relevant information
Navarese Eliano P, Robinson Jennifer G, Kowalewski Mariusz et al (2018) Association Between Baseline LDL-C Level and Total and Cardiovascular Mortality After LDL-C Lowering: A Systematic Review and Meta-analysis. JAMA 319(15): 1566–1579 [PMC free article: PMC5933331] [PubMed: 29677301]	- Systematic review does not fully match review PICO - used as a source of primary studies SR does not contain outcomes of relevance to the protocol: total or CV mortality only
Nicholls Stephen J, Ray Kausik K, Ballantyne Christie M et al (2017) Comparative effects of cholesteryl ester transfer protein inhibition, statin or ezetimibe on lipid factors: The ACCENTUATE trial. Atherosclerosis 261: 12–18 [PubMed: 28412650]	- Population not relevant to this review protocol: <80% CVD and suffiicient data from directly relevant populations
Nielsen Olav W, Sajadieh Ahmad, Sabbah Muhammad et al (2016) Assessing Optimal Blood Pressure in Patients With Asymptomatic Aortic Valve Stenosis: The Simvastatin Ezetimibe in Aortic Stenosis Study (SEAS). Circulation 134(6): 455–68 [PubMed: 27486164]	- Population not relevant to this review protocol: <50% CVD Incorrect population: not CVD and not on statins for CV risk reduction
Nissen SE, Stroes E, Dent-Acosta RE et al (2016) Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: the GAUSS-3 Randomized Clinical Trial. JAMA 315(15): 1580–1590 [PubMed: 27039291]	- Population not relevant to this review protocol: >50% statin intolerant
Nissen Steven E and Nicholls Stephen J (2017) Results of the GLAGOV trial. Cleveland Clinic journal of medicine 84(12suppl4): e1–e5 [PubMed: 29281604]	- Secondary publication of an included study that does not provide any additional relevant information
Oh Minyoung, Kim Hyunji, Shin Eon Woo et al (2020) Comparison of High-Dose Rosuvastatin Versus Low-Dose Rosuvastatin Plus Ezetimibe on Carotid Atherosclerotic Plaque Inflammation in Patients with Acute Coronary Syndrome. Journal of cardiovascular translational research 13(6): 900–907 [PubMed: 32367340]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus higher dose of statin
Oh Minyoung, Kim Hyunji, Shin Eon Woo et al (2019) Effects of ezetimibe/simvastatin 10/10 mg versus Rosuvastatin 10 mg on carotid atherosclerotic plaque inflammation. BMC cardiovascular disorders 19(1): 201 [PMC free article: PMC6700958] [PubMed: 31426749]	- Study does not include an intervention relevant to this protocol: includes low intensity statin
Oh Pyung Chun, Jang Albert Youngwoo, Ha Kyungeun et al (2021) Effect of Atorvastatin (10 mg) and Ezetimibe (10 mg) Combination Compared to Atorvastatin (40 mg) Alone on Coronary Atherosclerosis. The American journal of cardiology 154: 22–28 [PubMed: 34238445]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus higher dose of statin
Oikawa S, Yamashita S, Nakaya N et al (2017) Efficacy and Safety of Long-term Coadministration of Fenofibrate and Ezetimibe in Patients with Combined Hyperlipidemia: results of the EFECTL Study. Journal of atherosclerosis and thrombosis 24(1): 77–94 [PMC free article: PMC5225135] [PubMed: 27397061]	- Population not relevant to this review protocol: <50% CVD Incorrect comparison; Very low rate of previous CVD (<50%)
Okada K, Kimura K, Iwahashi N et al (2012) The mechanism of long-term low-density lipoprotein cholesterol lowering effect of ezetimibe-plus-statin combination therapy in coronary artery disease patients; compared with double-dose statin therapy. Journal of the American College of Cardiology 59(13suppl1): e1541	- Conference abstract
Okada Kozo, Iwahashi Noriaki, Endo Tsutomu et al (2012) Long-term effects of ezetimibe-plus-statin therapy on low-density lipoprotein cholesterol levels as compared with double-dose statin therapy in patients with coronary artery disease. Atherosclerosis 224(2): 454–6 [PubMed: 22892323]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin
Okada Kozo, Kimura Kazuo, Iwahashi Noriaki et al (2011) Clinical usefulness of additional treatment with ezetimibe in patients with coronary artery disease on statin therapy. From the viewpoint of cholesterol metabolism.-. Circulation journal: official journal of the Japanese Circulation Society 75(10): 2496–504 [PubMed: 21817821]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin
Otake Hiromasa, Sugizaki Yoichiro, Toba Takayoshi et al (2019) Efficacy of alirocumab for reducing plaque vulnerability: Study protocol for ALTAIR, a randomized controlled trial in Japanese patients with coronary artery disease receiving rosuvastatin. Journal of cardiology 73(3): 228–232 [PubMed: 30579806]	- Population not relevant to this review protocol
Otake Hiromasa, Tanimura Kosuke, Sugizaki Yoichiro et al (2019) Effect of Alirocumab and Rosuvastatin or Rosuvastatin Alone on Lipid Core Plaque in Coronary Artery Disease Seen on Near-Infrared Spectroscopy Intravascular Ultrasound (ANTARES). Circulation reports 1(2): 107–111 [PMC free article: PMC7890294] [PubMed: 33693121]	- Trial protocol for a study not yet completed/reported
Oyama Kazuma, Giugliano Robert P, Tang Minao et al (2021) Effect of evolocumab on acute arterial events across all vascular territories: results from the FOURIER trial. European heart journal 42(47): 4821–4829 [PubMed: 34537830]	- Secondary publication of an included study that does not provide any additional relevant information post-hoc analysis of included study with no additional data of relevance
Palathingal J.T., Vijayan D., Drisya Rajan C. et al (2020) A randomised controlled study of high dose statin versus statin plus ezetimibe therapy in patients with acute coronary syndrome. International Journal of Biomedical Science 16(4): 52–67	- Data not reported in an extractable format or a format that can be analysed Study only reports mean LDL-C at baseline and follow-up in graph format so data cannot be utilised
Pearson Thomas, Denke Margo, McBride Patrick et al (2005) Effectiveness of the addition of ezetimibe to ongoing statin therapy in modifying lipid profiles and attaining low-density lipoprotein cholesterol goals in older and elderly patients: subanalyses of data from a randomized, double-blind, placebo-controlled trial. The American journal of geriatric pharmacotherapy 3(4): 218–28 [PubMed: 16503317]	- Follow-up <3 months
Pokharel Yashashwi, Chinnakondepalli Khaja, Vilain Katherine et al (2017) Impact of Ezetimibe on the Rate of Cardiovascular-Related Hospitalizations and Associated Costs Among Patients With a Recent Acute Coronary Syndrome: Results From the IMPROVE-IT Trial (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation. Cardiovascular quality and outcomes 10(5) [PubMed: 28506979]	- Secondary publication of an included study that does not provide any additional relevant information
Pytel Edyta, Bukowska Bozena, Koter-Michalak Maria et al (2017) Effect of intensive lipid-lowering therapies on cholinesterase activity in patients with coronary artery disease. Pharmacological reports: PR 69(1): 150–155 [PubMed: 27923158]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus higher dose of statin
Pytel Edyta, Jackowska Paulina, Chwatko Grazyna et al (2016) Intensive statin therapy, used alone or in combination with ezetimibe, improves homocysteine level and lipid peroxidation to a similar degree in patients with coronary artery diseases. Pharmacological reports: PR 68(2): 344–8 [PubMed: 26922537]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus higher dose of statin
Qian Juying, Li Zhanquan, Zhang Xuelian et al (2022) Efficacy and Tolerability of Ezetimibe/Atorvastatin Fixed-dose Combination Versus Atorvastatin Monotherapy in Hypercholesterolemia: A Phase III, Randomized, Active-controlled Study in Chinese Patients. Clinical therapeutics 44(10): 1282–1296 [PubMed: 36182594]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin
Ray Kausik K, Colhoun Helen M, Szarek Michael et al (2019) Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial. The lancet. Diabetes & endocrinology 7(8): 618–628 [PubMed: 31272931]	- Secondary publication of an included study that does not provide any additional relevant information
Ray Kausik K, Ginsberg Henry N, Davidson Michael H et al (2016) Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab With Control. Circulation 134(24): 1931–1943 [PMC free article: PMC5147039] [PubMed: 27777279]	- Secondary analysis of 10 trials with no data of additional relevance
Ray Kausik K, Landmesser Ulf, Leiter Lawrence A et al (2017) Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. The New England journal of medicine 376(15): 1430–1440 [PubMed: 28306389]	- Population not relevant to this review protocol: <80% CVD and suffiicient data from directly relevant populations Previous CVD was less than 80% in each treatment arm and not licensed dose
Ray Kausik K, Raal Frederick J, Kallend David G et al (2023) Inclisiran and cardiovascular events: a patient-level analysis of phase III trials. European heart journal 44(2): 129–138 [PMC free article: PMC9825807] [PubMed: 36331326]	- Secondary analysis of trials with no data of additional relevance to the protocol
Ray Kausik K, Troquay Roel P T, Visseren Frank L J et al (2023) Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial. The lancet. Diabetes & endocrinology [PubMed: 36620965]	- Study design not relevant to this review protocol: not randomised incorrect study design: non-randomised open label extension study
Ray KK, Ginsberg HN, Davidson MH et al (2016) Reductions in Atherogenic Lipids and Major Cardiovascular Events: a Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab to Control. Circulation [PMC free article: PMC5147039] [PubMed: 27777279]	- Secondary analysis of 10 trials with no data of additional relevance - Duplicate reference
Ray KK, Leiter LA, M?ller-Wieland D et al (2018) Alirocumab vs usual lipid-lowering care as add-on to statin therapy in individuals with type 2 diabetes and mixed dyslipidaemia: the ODYSSEY DM-DYSLIPIDEMIA randomized trial. Diabetes, obesity & metabolism 20(6): 1479–1489 [PMC free article: PMC5969299] [PubMed: 29436756]	- Population not relevant to this review protocol: <50% CVD
Ray KK, Stoekenbroek RM, Kallend D et al (2019) Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels: one-Year Follow-up of the ORION-1 Randomized Clinical Trial. JAMA cardiology 4(11): 1067–1075 [PMC free article: PMC6763983] [PubMed: 31553410]	- Population not relevant to this review protocol: <80% CVD and suffiicient data from directly relevant populations - Study does not contain an intervention relevant to this review protocol; inclisiran not at licensed dose
Reckless J P D, Henry P, Pomykaj T et al (2008) Lipid-altering efficacy of ezetimibe/simvastatin 10/40 mg compared with doubling the statin dose in patients admitted to the hospital for a recent coronary event: the INFORCE study. International journal of clinical practice 62(4): 539–54 [PubMed: 18266852]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin
Reith C, Staplin N, Herrington WG et al (2017) Effect on non-vascular outcomes of lowering LDL cholesterol in patients with chronic kidney disease: results from the Study of Heart and Renal Protection. BMC nephrology 18(1): 147 [PMC free article: PMC5412040] [PubMed: 28460629]	- Population not relevant to this review protocol: <50% CVD CKD patients receiving maintenance dialysis; excluding people with prior MI or coronary revascularization; 15% had history of vascular disease; no further info to suggest participants matched the protocol definition of CVD
Robinson J.G., Davidson M.H., Shah A. et al (2007) Efficacy and safety of ezetimibe and ezetimibe plus statin therapy in patients aged under 65, 65–74 and 75 years and older. Aging Health 3(6): 691–705	- Population not relevant to this review protocol: <80% CVD and suffiicient data from directly relevant populations
Robinson Jennifer G Ballantyne Christie M, Grundy Scott M et al (2009) Lipid-altering efficacy and safety of ezetimibe/simvastatin versus atorvastatin in patients with hypercholesterolemia and the metabolic syndrome (from the VYMET study). The American journal of cardiology 103(12): 1694–702 [PubMed: 19539078]	- Population not relevant to this review protocol: <50% CVD
Robinson Jennifer G, Colhoun Helen M, Bays Harold E et al (2014) Efficacy and safety of alirocumab as add-on therapy in high-cardiovascular-risk patients with hypercholesterolemia not adequately controlled with atorvastatin (20 or 40 mg) or rosuvastatin (10 or 20 mg): design and rationale of the ODYSSEY OPTIONS Studies. Clinical cardiology 37(10): 597–604 [PMC free article: PMC4282386] [PubMed: 25269777]	- Population not relevant to this review protocol: <80% CVD and suffiicient data from directly relevant populations
Robinson Jennifer G, Rogers William J, Nedergaard Bettina S et al (2014) Rationale and design of LAPLACE-2: a phase 3, randomized, double-blind, placebo- and ezetimibe-controlled trial evaluating the efficacy and safety of evolocumab in subjects with hypercholesterolemia on background statin therapy. Clinical cardiology 37(4): 195–203 [PMC free article: PMC6649582] [PubMed: 24481874]	- Population not relevant to this review protocol: <50% CVD 32% CVD
Robinson JG, Nedergaard BS, Rogers WJ et al (2014) Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA 311(18): 1870–1882 [PubMed: 24825642]	- Population not relevant to this review protocol: <50% CVD 35% of High intensity statin population had CVD and 21% of moderate intensity statins
Rodney RA, Sugimoto D, Wagman B et al (2006) Efficacy and safety of coadministration of ezetimibe and simvastatin in African-American patients with primary hypercholesterolemia. Journal of the National Medical Association 98(5): 772–778 [PMC free article: PMC2569293] [PubMed: 16749654]	- Population not relevant to this review protocol: <50% CVD 10% had coronary heart disease and participants with a CV event 3 months prior to randomisation were excluded; no further details to suaaest population had CVD
Roeters van Lennep Henk W O, Liem An Ho, Dunselman Peter H J M et al (2008) The efficacy of statin monotherapy uptitration versus switching to ezetimibe/simvastatin: results of the EASEGO study. Current medical research and opinion 24(3): 685–94 [PubMed: 18226326]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin
Rosen Jeffrey B, Jimenez Jose G, Pirags Valdis et al (2013) A comparison of efficacy and safety of an ezetimibe/simvastatin combination compared with other intensified lipid-lowering treatment strategies in diabetic patients with symptomatic cardiovascular disease. Diabetes & vascular disease research 10(3): 277–86 [PubMed: 23288881]	- Follow-up <3 months
Rosenson Robert S, Daviglus Martha L, Handelsman Yehuda et al (2019) Efficacy and safety of evolocumab in individuals with type 2 diabetes mellitus: primary results of the randomised controlled BANTING study. Diabetologia 62(6): 948–958 [PMC free article: PMC6509076] [PubMed: 30953107]	- Population not relevant to this review protocol: <80% CVD and sufficient data from directly relevant populations
Rossebo Anne B, Pedersen Terje R, Allen Christopher et al (2007) Design and baseline characteristics of the simvastatin and ezetimibe in aortic stenosis (SEAS) study. The American journal of cardiology 99(7): 970–3 [PubMed: 17398194]	- Population not relevant to this review protocol: <50% CVD Incorrect publication type : PhD thesis; incorrect population: heart vavle disease
Roth Eli M, Moriarty Patrick M, Bergeron Jean et al (2016) A phase III randomized trial evaluating alirocumab 300 mg every 4 weeks as monotherapy or add-on to statin: ODYSSEY CHOICE I. Atherosclerosis 254: 254–262 [PubMed: 27639753]	- Population not relevant to this review protocol: <50% CVD Population with CV risk not previous CVD
Roth Eli M, Taskinen Marja-Riitta, Ginsberg Henry N et al (2014) Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. International journal of cardiology 176(1): 55–61 [PubMed: 25037695]	- Population not relevant to this review protocol: <50% CVD
Sabatine Marc S, De Ferrari Gaetano M, Giugliano Robert P et al (2018) Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease: Analysis From FOURIER. Circulation 138(8): 756–766 [PubMed: 29626068]	- Secondary publication of an included study that does not provide any additional relevant information
Sabatine Marc S, Giugliano Robert P, Keech Anthony C et al (2017) Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. The New England journal of medicine 376(18): 1713–1722 [PubMed: 28304224]	- Review article but not a systematic review
Sabatine Marc S, Giugliano Robert P, Wiviott Stephen D et al (2015) Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. The New England journal of medicine 372(16): 1500–9 [PubMed: 25773607]	- Population not relevant to this review protocol: <50% CVD
Sabatine Marc S, Leiter Lawrence A, Wiviott Stephen D et al (2017) Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. The lancet. Diabetes & endocrinology 5(12): 941–950 [PubMed: 28927706]	- Secondary publication of an included study that does not provide any additional relevant information
Sakamoto K, Kawamura M, Watanabe T et al (2017) Effect of ezetimibe add-on therapy over 52 weeks extension analysis of prospective randomized trial (RESEARCH study) in type 2 diabetes subjects. Lipids in health and disease 16(1): 122 [PMC free article: PMC5483302] [PubMed: 28646901]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin Pitavastatin (received by 36.7% of the study population, not part of the review protocol); Paper linked to Inazawa paper where very low % of previous CVD
Samuel Essie, Watford Maya, Egolum Ugochukwu O et al (2022) Inclisiran: A First-in-Class siRNA Therapy for Lowering Low-Density Lipoprotein Cholesterol. The Annals of pharmacotherapy: 10600280221105169 [PubMed: 35775133]	- Review article but not a systematic review narrative review used as source of references
Sattar Naveed, Preiss David, Robinson Jennifer G et al (2016) Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data. The lancet. Diabetes & endocrinology 4(5): 403–10 [PubMed: 26868195]	- Systematic review does not fully match review PICO - used as a source of primary studies systematic review includes populations not relevant to the protocol (FH). Used as a source of primary studies
Sawayama Y (2011) Low-dose pravastatin plus ezetimibe verus standard-dose pravastatin: the effect on the carotid atherosclerosis of patients with hypercholesterolemia. Atherosclerosis supplements 12(1): 180	- Conference abstract
Sawayama Yasunori, Maeda Shinji, Ohnishi Hachiro et al (2010) Efficacy and safety of ezetimibe for Japanese patients with dyslipidaemia: The ESSENTIAL Study. Clinical drug investigation 30(3): 157–66 [PubMed: 20155988]	- Comparator in study does not match that specified in this review protocol Incorrect comparison: ezetimibe alone vs ezetimibe + low intensity statin
Schmidt A.F., Pearce L.S., Wilkins J.T. et al (2015) PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2015(6): cd011748 [PMC free article: PMC8094613] [PubMed: 33078867]	- More recent systematic review included that covers the same topic Cochrane review including studies with people without CVD; included studies were checked for inclusion in the present review individually using a more recent version (2020) of the same Cochrane review
Schmidt A.F., Pearce L.S., Wilkins J.T. et al (2017) PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2017(4): cd011748 [PMC free article: PMC6478267] [PubMed: 28453187]	- More recent systematic review included that covers the same topic Cochrane review including studies with people without CVD; included studies were checked for inclusion in the present review individually using a more recent version (2020) of the same Cochrane review
Schmidt Amand F, Pearce Lucy S, Wilkins John T et al (2017) PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. The Cochrane database of systematic reviews 4: cd011748 [PMC free article: PMC6478267] [PubMed: 28453187]	- Duplicate reference
Schwartz Gregory G, Gabriel Steg Philippe, Bhatt Deepak L et al (2021) Clinical Efficacy and Safety of Alirocumab After Acute Coronary Syndrome According to Achieved Level of Low-Density Lipoprotein Cholesterol: A Propensity Score-Matched Analysis of the ODYSSEY OUTCOMES Trial. Circulation 143(11): 1109–1122 [PMC free article: PMC7969166] [PubMed: 33438437]	- Secondary publication of an included study that does not provide any additional relevant information
Schwartz Gregory G, Szarek Michael, Bittner Vera A et al (2021) Lipoprotein(a) and Benefit of PCSK9 Inhibition in Patients With Nominally Controlled LDL Cholesterol. Journal of the American College of Cardiology 78(5): 421–433 [PMC free article: PMC8822604] [PubMed: 34325831]	- Secondary publication of an included study that does not provide any additional relevant information
Sharp Collaborative Group (2010) Study of Heart and Renal Protection (SHARP): randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease. American heart journal 160(5): 785–794e10 [PubMed: 21095263]	- Population not relevant to this review protocol: <50% CVD
Shaya Fadia Tohme, Sing Krystal, Milam Robert et al (2020) Lipid-Lowering Efficacy of Ezetimibe in Patients with Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta-Analyses. American journal of cardiovascular drugs: drugs, devices, and other interventions 20(3): 239–248 [PMC free article: PMC7266788] [PubMed: 31724105]	- Systematic review with no data of additional relevance 12 included studies already assessed for inclusion
Stanifer JW, Charytan DM, White J et al (2017) Benefit of Ezetimibe Added to Simvastatin in Reduced Kidney Function. Journal of the American Society of Nephrology: JASN 28(10): 3034–3043 [PMC free article: PMC5619955] [PubMed: 28507057]	- Secondary publication of an included study that does not provide any additional relevant information Subgroup under investigation (different levels of kidney function) not relevant to the current review
Steg P.G., Szarek M., Bhatt D.L. et al (2019) Effect of Alirocumab on Mortality after Acute Coronary Syndromes: An Analysis of the ODYSSEY OUTCOMES Randomized Clinical Trial. Circulation 140(2): 103–112 [PMC free article: PMC6661243] [PubMed: 31117810]	- Secondary publication of an included study that does not provide any additional relevant information
Stiekema LC A, Stroes ES G, Verweij SL et al (2019) Persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment. European heart journal 40(33): 2775–2781 [PMC free article: PMC6933872] [PubMed: 30561610]	- Population not relevant to this review protocol: <50% CVD
Stoekenbroek Robert M, Kallend David, Wijngaard Peter Lj et al (2018) Inclisiran for the treatment of cardiovascular disease: the ORION clinical development program. Future cardiology 14(6): 433–442 [PubMed: 30375244]	- Review article but not a systematic review
Stojakovic T, de Campo A, Scharnagl H et al (2010) Differential effects of fluvastatin alone or in combination with ezetimibe on lipoprotein subfractions in patients at high risk of coronary events. European journal of clinical investigation 40(3): 187–94 [PubMed: 20067513]	- Population not relevant to this review protocol: <50% CVD
Stroes E, Guyton JR, Farnier M et al (2015) Efficacy and safety of 150 mg and 300 mg every 3 weeks in patients with poorly controlled hypercholesterolemia: the ODYSSEY CHOICE I and CHOICE II studies. Journal of the American College of Cardiology abstract: exhibit991	- Population not relevant to this review protocol: >50% statin intolerant
Stroes E, Guyton JR, Lepor N et al (2016) Efficacy and Safety of Alirocumab 150 mg Every 4 Weeks in Patients With Hypercholesterolemia Not on Statin Therapy: the ODYSSEY CHOICE II Study. Journal of the American Heart Association 5(9) [PMC free article: PMC5079013] [PubMed: 27625344]	- Population not relevant to this review protocol: >50% statin intolerant
Strony John, Yang Bo, Hanson Mary E et al (2008) Long-term safety and tolerability of ezetimibe coadministered with simvastatin in hypercholesterolemic patients: a randomized, 12-month double-blind extension study. Current medical research and opinion 24(11): 3149–57 [PubMed: 18842166]	- Study does not include an intervention relevant to this protocol: includes low intensity statin
Suzuki H, Watanabe Y, Kumagai H et al (2013) Comparative efficacy and adverse effects of the addition of ezetimibe to statin versus statin titration in chronic kidney disease patients. Therapeutic advances in cardiovascular disease 7(6): 306–315 [PubMed: 24280596]	- Population not relevant to this review protocol: <50% CVD Population: no previous CVD/ CVD presence in approximately 3% of the study population
Szarek Michael, Steg Ph Gabriel, DiCenso Dina et al (2019) Alirocumab Reduces Total Hospitalizations and Increases Days Alive and Out of Hospital in the ODYSSEY OUTCOMES Trial. Circulation. Cardiovascular quality and outcomes 12(11): e005858 [PubMed: 31707826]	- Secondary publication of an included study that does not provide any additional relevant information
Szarek Michael, White Harvey D, Schwartz Gregory G et al (2019) Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events: The ODYSSEY OUTCOMES Trial. Journal of the American College of Cardiology 73(4): 387–396 [PubMed: 30428396]	- Secondary publication of an included study that does not provide any additional relevant information
Takase Susumu, Matoba Tetsuya, Nakashiro Soichi et al (2017) Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting: The CuVIC Trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction After Coronary Stenting), a Multicenter Randomized Controlled Trial. Arteriosclerosis, thrombosis, and vascular biology 37(2): 350–358 [PubMed: 27932353]	- Comparator in study does not match that specified in this review protocol Incorrect comparison: statin dosing not matched in control and intervention aroups. Exact statin use unclear and mostly moderate intensity, includina Pitavastatin
Talasaz Azita H, Ho Ai-Chen Jane, Bhatty Fawzia et al (2021) Meta-analysis of clinical outcomes of PCSK9 modulators in patients with established ASCVD. Pharmacotherapy 41(12): 1009–1023 [PubMed: 34657313]	- Systematic review does not fully match review PICO - used as a source of primary studies RoB per study not per outcome, limited selection of relevant studies due to restrictions on comparators and duration of follow up being stricter than protocol
Tan Huilian, Liu Ling, Zheng Qinghou et al (2021) Effects of Combined Lipid-Lowering Therapy on Low-Density Lipoprotein Cholesterol Variability and Cardiovascular Adverse Events in Patients with Acute Coronary Syndrome. Advances in therapy 38(6): 3389–3398 [PubMed: 34018147]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus higher dose of statin
Teramoto T, Kobayashi M, Tasaki H et al (2016) Efficacy and Safety of Alirocumab in Japanese Patients With Heterozygous Familial Hypercholesterolemia or at High Cardiovascular Risk With Hypercholesterolemia Not Adequately Controlled With Statins?- ODYSSEY JAPAN Randomized Controlled Trial. Circulation journal 80(9): 1980–1987 [PubMed: 27452202]	- Population not relevant to this review protocol: <50% CVD
Teramoto Tamio, Kiyosue Arihiro, Ishigaki Yasushi et al (2019) Efficacy and safety of alirocumab 150mg every 4 weeks in hypercholesterolemic patients on non-statin lipid-lowering therapy or lowest strength dose of statin: ODYSSEY NIPPON. Journal of cardiology 73(3): 218–227 [PubMed: 30509509]	- Population not relevant to this review protocol: >20% familial hypercholesterolemia Incorrect population: majority not on statin, >20% FH and <50% CVD
Teramoto Tamio, Kondo Akira, Kiyosue Arihiro et al (2017) Efficacy and safety of alirocumab in patients with hypercholesterolemia not adequately controlled with non-statin lipid-lowering therapy or the lowest strength of statin: ODYSSEY NIPPON study design and rationale. Lipids in health and disease 16(1): 121 [PMC free article: PMC5474052] [PubMed: 28623954]	- Population not relevant to this review protocol: >50% statin intolerant
Toth Peter P, Bray Sarah, Villa Guillermo et al (2022) Network Meta-Analysis of Randomized Trials Evaluating the Comparative Efficacy of Lipid-Lowering Therapies Added to Maximally Tolerated Statins for the Reduction of Low-Density Lipoprotein Cholesterol. Journal of the American Heart Association 11(18): e025551 [PMC free article: PMC9683660] [PubMed: 36073669]	- Systematic review with no data of additional relevance SR not entirely matching protocol in terms of populations and various comparisons; included studies checked for inclusion
Toth Peter P, Worthy Gillian, Gandra Shravanthi R et al (2017) Systematic Review and Network Meta-Analysis on the Efficacy of Evolocumab and Other Therapies for the Management of Lipid Levels in Hyperlipidemia. Journal of the American Heart Association 6(10) [PMC free article: PMC5721820] [PubMed: 28971955]	- Systematic review does not fully match review PICO - used as a source of primary studies SR not entirely matching protocol in terms of populations and various comparisons; individiual studies checked for inclusion
Tripoten M.I., Pogorelova O.A., Zubareva M.Y. et al (2010) Arterial wall function in patients with coronary heart disease and dyslipidemia, comparative efficacy of ezetimibe, statins and their combination. Artery Research 4(4): 157–158	- Conference abstract
Tsujita K, Yamanaga K, Komura N et al (2016) Lipid profile associated with coronary plaque regression in patients with acute coronary syndrome: subanalysis of PRECISE-IVUS trial. Atherosclerosis 251: 367–372 [PubMed: 27318866]	- Secondary publication of an included study that does not provide any additional relevant information no relevant outcomes
Tsujita Kenichi, Yamanaga Kenshi, Komura Naohiro et al (2016) Synergistic effect of ezetimibe addition on coronary atheroma regression in patients with prior statin therapy: Subanalysis of PRECISE-IVUS trial. European journal of preventive cardiology 23(14): 1524–8 [PubMed: 27296705]	- Secondary publication of an included study that does not provide any additional relevant information
Turgeon Ricky D, Tsuyuki Ross T, Gyenes Gabor T et al (2018) Cardiovascular Efficacy and Safety of PCSK9 Inhibitors: Systematic Review and Meta-analysis Including the ODYSSEY OUTCOMES Trial. The Canadian journal of cardiology 34(12): 1600–1605 [PubMed: 30527147]	- Systematic review does not fully match review PICO - used as a source of primary studies Population does not directly meet protocol: not limited to people with previous CVD; individual references checked
Vallejo-Vaz Antonio J, Ray Kausik K, Ginsberg Henry N et al (2019) Associations between lower levels of low-density lipoprotein cholesterol and cardiovascular events in very high-risk patients: Pooled analysis of nine ODYSSEY trials of alirocumab versus control. Atherosclerosis 288: 85–93 [PubMed: 31349086]	- Secondary publication of an included study that does not provide any additional relevant information subgroup analysis of included study with no relevant additional data
Wang Hong-Fei, Mao Yu-Cheng, Xu Xin-Yi et al (2022) Effect of alirocumab and evolocumab on all-cause mortality and major cardiovascular events: A meta-analysis focusing on the number needed to treat. Frontiers in cardiovascular medicine 9: 1016802 [PMC free article: PMC9755489] [PubMed: 36531722]	- Systematic review with no GRADE assessment - used as a source of primary studies SR with ROB by study only, includes studies with and without CVD.
Wang Nelson, Fulcher Jordan, Abeysuriya Nishan et al (2020) Intensive LDL cholesterol-lowering treatment beyond current recommendations for the prevention of major vascular events: a systematic review and metaanalysis of randomised trials including 327 037 participants. The lancet. Diabetes & endocrinology 8(1): 36–49 [PubMed: 31862150]	- Systematic review does not fully match review PICO - used as a source of primary studies SR including comparisons not relevant to this protocol (majority of studies were statin vs placebo); used as source of primary studies
Wang Nelson, Woodward Mark, Huffman Mark D et al (2022) Compounding Benefits of Cholesterol-Lowering Therapy for the Reduction of Major Cardiovascular Events: Systematic Review and Meta-Analysis. Circulation. Cardiovascular quality and outcomes 15(6): e008552 [PubMed: 35430872]	- Systematic review does not fully match review PICO - used as a source of primary studies SR including comparisons not relevant to this protocol (majority of stuides were statin vs placebo); used as source of primary stydies
Wang Shifei, Xiu Jiancheng, Liao Wangjun et al (2019) Relative Effect of Current Intensive Lipid-Lowering Drugs on Cardiovascular Outcomes in Secondary Prevention - A Meta-Analysis of 12 Randomized Trials. Circulation journal: official journal of the Japanese Circulation Society 83(6): 1356–1367 [PubMed: 31006730]	- Systematic review does not fully match review PICO - used as a source of primary studies does not contain a comparison relevant to the protocol (pooled ‘more’ vs ‘less’ intensive lipid lowering strategies
Wang Wanting; Feng Zhaoqiang; Bai Jinghui (2021) Effects of alirocumab on cardiovascular events and all-cause mortality: a systematic review and meta-analysis. Reviews in cardiovascular medicine 22(3): 873–881 [PubMed: 34565085]	- Systematic review with no data of additional relevance all relevant studies included in more directly relevant SR
Wang Xing, Wen Dingke, Chen Yuqi et al (2022) PCSK9 inhibitors for secondary prevention in patients with cardiovascular diseases: a bayesian network meta-analysis. Cardiovascular diabetology 21(1): 107 [PMC free article: PMC9202167] [PubMed: 35706032]	- Systematic review with no data of additional relevance NMA not including all relevant comparators. Used as a source of primary studies
West AM A (2010) Type of lipid lowering therapy impacts atherosclerosis progression in peripheral arterial disease as assessed by CMR. Journal of cardiovascular magnetic resonance: 192	- Conference abstract
Wiviott Stephen D, Giugliano Robert P, Morrow David A et al (2020) Effect of Evolocumab on Type and Size of Subsequent Myocardial Infarction: A Prespecified Analysis of the FOURIER Randomized Clinical Trial. JAMA cardiology 5(7): 787–793 [PMC free article: PMC7191470] [PubMed: 32347885]	- Secondary publication of an included study that does not provide any additional relevant information
Wright R Scott, Ray Kausik K, Raal Frederick J et al (2021) Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis. Journal of the American College of Cardiology 77(9): 1182–1193 [PubMed: 33663735]	- Secondary publication of an included study that does not provide any additional relevant information
Wu Na-Qiong, Guo Yuan-Lin, Zhu Cheng-Gang et al (2018) Comparison of statin plus ezetimibe with double-dose statin on lipid profiles and inflammation markers. Lipids in health and disease 17(1): 265 [PMC free article: PMC6260646] [PubMed: 30470229]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus higher dose of statin
Xia Jiachun, Wang Xinyue, Zhou Jun et al (2022) Impact of early PCSK9 inhibitor treatment on heart after percutaneous coronary intervention in patients with STEMI: Design and rationale of the PERFECT II trial. Frontiers in cardiovascular medicine 9: 1009674 [PMC free article: PMC9540492] [PubMed: 36211588]	- Trial protocol for a study not yet completed/reported
Yamanaga K, Tsujita K, Sugiyama S et al (2015) The impact of statin-ezetimibe combination therapy in patients with decreased cholesterol absorption ability. Circulation 132(nopagination)	- Conference abstract
Zhan S., Xia P., Tang M. et al (2017) Ezetimibe for the prevention of cardiovascular disease and all-cause mortality events. Cochrane Database of Systematic Reviews 2017(1): cd012502 [PMC free article: PMC6516816] [PubMed: 30480766]	- More recent systematic review included that covers the same topic
Zhang Yue, Suo Yanrong, Yang Lin et al (2022) Effect of PCSK9 Inhibitor on Blood Lipid Levels in Patients with High and Very-High CVD Risk: A Systematic Review and Meta-Analysis. Cardiology research and practice 2022: 8729003 [PMC free article: PMC9072011] [PubMed: 35529059]	- Systematic review with no data of additional relevance systematic review includes populations not relevant to the protocol (FH). Used as a source of primary studies
Zhao Zinan, Hu Xin, Zhang Yatong et al (2020) Cardiovascular and safety events of PCSK9 inhibitors in statin-treated patients with cardiovascular risk: A Systematic Review and Meta-Analysis. Journal of pharmacy & pharmaceutical sciences: a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 23: 422–436 [PubMed: 33137282]	- Systematic review with no data of additional relevance overlaps with included SR (Cochrane review), and includes no additional studies or outcomes of relevance. Includes fewer studies and outcomes.
Zhao Zonglei, Du Song, Shen Shuxin et al (2019) Comparative efficacy and safety of lipid-lowering agents in patients with hypercholesterolemia: A frequentist network meta-analysis. Medicine 98(6): e14400 [PMC free article: PMC6380691] [PubMed: 30732185]	- Systematic review with no data of additional relevance overlaps with included SR (Cochrane review), and includes no additional studies or outcomes of relevance. Includes fewer studies and outcomes.
Zieve Franklin, Wenger Nanette K, Ben-Yehuda Ori et al (2010) Safety and efficacy of ezetimibe added to atorvastatin versus up titration of atorvastatin to 40 mg in Patients > or = 65 years of age (from the ZETia in the ELDerly [ZETELD] study). The American journal of cardiology 105(5): 656–63 [PubMed: 20185012]	- Comparator in study does not match that specified in this review protocol: ezetimibe plus statin versus double dose of statin
Zinellu A, Sotgia S, Loriga G et al (2012) Oxidative stress improvement is associated with increased levels of taurine in CKD patients undergoing lipid-lowering therapy. Amino acids 43(4): 1499–1507 [PubMed: 22278741]	- Population not relevant to this review protocol: <50% CVD Patients with CKD, but no evidence of CVD
Zinellu A, Sotgia S, Mangoni AA et al (2015) Impact of cholesterol lowering treatment on plasma kynurenine and tryptophan concentrations in chronic kidney disease: relationship with oxidative stress improvement. Nutrition, metabolism, and cardiovascular diseases: NMCD 25(2): 153–159 [PubMed: 25534866]	- Population not relevant to this review protocol: <50% CVD Patients with CKD, but no evidence of CVD
Zinellu A, Sotgia S, Mangoni AA et al (2016) Effect of cholesterol lowering treatment on plasma markers of endothelial dysfunction in chronic kidney disease. Journal of pharmaceutical and biomedical analysis 129: 383–388 [PubMed: 27454090]	- Population not relevant to this review protocol: <50% CVD Patients with CKD, but no evidence of CVD
Zinellu A, Sotgia S, Pisanu E et al (2012) LDL S-homocysteinylation decrease in chronic kidney disease patients undergone lipid lowering therapy. European journal of pharmaceutical sciences 47(1): 117–123 [PubMed: 22659373]	- Population not relevant to this review protocol: <50% CVD Patients with CKD, but no evidence of CVD
Nutrition, metabolism, and cardiovascular diseases: NMCD 27(9): 822–829 [PubMed: 28755807]	- Population not relevant to this review protocol: <50% CVD Patients with CKD, but no evidence of CVD
Zou YC, Lu Y, Bai J et al (2016) Effect of ezetimibe combined with low-dose atorvastain calcium on carotid atherosclerosis in elderly patients with coronary heart disease. Journal of the american geriatrics society. Conference: 5th chinese congress on gerontology and health industry, CCGI 2016. China. Conference start: 20160902. Conference end: 20160904 64: 328	- Study does not include an intervention relevant to this protocol: includes low intensity statin Paper not available; no relevant treatment: low dose statins