Evidence review for the clinical and cost-effectiveness of drug-eluting stents

National Guideline Centre (UK)

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Evidence review for the clinical and cost-effectiveness of drug-eluting stents

Acute coronary syndromes

Evidence review F

NICE Guideline, No. 185

Authors

National Guideline Centre (UK).

London: National Institute for Health and Care Excellence (NICE); 2020 Nov.

ISBN-13: 978-1-4731-3902-2

1. Drug eluting stents

1.1. Review question: What is the clinical and cost effectiveness of drug-eluting stents in adults with acute coronary syndromes, including those with unstable angina or NSTEMI undergoing percutaneous coronary intervention and those with STEMI undergoing primary percutaneous coronary intervention?

1.2. Introduction

In 2008 drug-eluting stents were recommended in certain circumstances by NICE technology appraisal 152 ‘Drug-eluting stents for the treatment of coronary artery disease’:

Drug-eluting stents are recommended for use in percutaneous coronary intervention for the treatment of coronary artery disease, within their instructions for use, only if:
- the target artery to be treated has less than a 3-mm calibre or the lesion is longer than 15 mm, and
- the price difference between drug-eluting stents and bare-metal stents is no more than £300.⁸¹

This was on the basis of a systematic review of the evidence and cost effectiveness modelling. However, since then drug-eluting stents have continued to develop and new studies have been published. Audit data from 2016 reported that 92% of PCIs used stents and 90% used drug eluting stents and this varied only slightly by indication (that is, it was 89% in PPCI for STEMI).

This guideline will review the evidence for drug eluting stents compared to bare metal stents in people with ACS and partially update and replace the recommendations from TA152. It is important to note that TA152 covered all PCI whereas this guideline will only be updating recommendations in relation to people with ACS.

1.3. PICO table

For full details see the review protocol in appendix A.

1.4. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual.²⁸ Methods specific to this review question are described in the review protocol in appendix A.

Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy.

1.5. Clinical evidence

1.5.1. Included studies

Twenty-nine trials (fifty papers) were included in the review;⁷^, ¹³^, ¹⁴^, ¹⁷^–¹⁹^, ²²^, ²⁷^, ³²^–³⁶^, ⁴⁶^, ⁴⁷^, ⁵⁵^–⁵⁷^, ⁶¹^, ⁶⁷^, ⁷³^, ⁷⁵^, ⁷⁶^, ⁸⁸^–⁹¹^, ⁹⁴^–⁹⁶^, ¹⁰⁰^, ¹⁰²^–¹⁰⁵^, ¹⁰⁹^, ¹¹¹^–¹¹⁴^, ¹¹⁶^, ¹²¹^–¹²⁶^, ¹²⁸^, ¹³¹^, ¹³³ that evaluated drug-eluting stents versus bare metal stents. Evidence from these studies is summarised in the clinical evidence summary below (Table 4).

One relevant Cochrane review was identified for this evidence review.⁴² This Cochrane review’s PICO was similar to the PICO developed by the guideline committee. However, the Cochrane review did not have an upper limit for the outcome time-points. As seen in Table 1, the guideline committee agreed on reviewing outcome data that was reported up to 3 years. The studies included in the Cochrane were reviewed and included if applicable.

See also the study selection flow chart in appendix C, study evidence tables in appendix D, forest plots in appendix E and GRADE tables in appendix H.

1.5.2. Excluded studies

See the excluded studies list in appendix I.

1.5.3. Summary of clinical studies included in the evidence review

See appendix D for full evidence tables.

1.5.4. Quality assessment of clinical studies included in the evidence review

See appendix F for full GRADE tables.

1.6. Economic evidence

1.6.1. Included studies

Five health economic studies with the relevant comparison were included in this review.²⁴^, ⁴⁸^, ⁸¹^, ⁹³^, ¹⁰⁶^, ¹³⁵^, ¹³⁷ Note that two papers were identified for one study as one of these (Hill 2007⁴⁸) is the analysis undertaken to inform TA152.⁸¹ These are summarised in the health economic evidence profile below (Table 5) and the health economic evidence tables in Appendix H:.

1.6.2. Excluded studies

Fifteen economic studies relating to this review question were excluded due to a combination of methodological limitations and the availability of more applicable evidence.⁸^–¹⁰^, ²⁰^, ²¹^, ³⁹^, ⁴⁵^, ⁵²^, ⁵⁴^, ⁶⁵^, ⁶⁹^, ⁸⁷^, ¹¹⁷^, ¹¹⁸^, ¹²⁹ These are listed in Appendix I:, with reasons for exclusion given. Generally, these were studies that were published before the technology appraisal analysis, used treatment effects that were from clinical studies that did not meet the inclusion criteria or did not use QALYs.

See also the health economic study selection flow chart in Appendix G:.

1.6.3. Summary of studies included in the economic evidence review

The tables below show additional cost effectiveness results from Hill 2007 (this analysis informed NICE TA152).⁴⁸

Table 8 summarises the stent prices used in the health economic studies. Current UK stent costs are provided in Table 10.

Table 9 summarises the treatment effects from the NGC systematic review and meta analyses reports in section 1.5 and the relevant treatment effects in the included economic analyses to aid interpretation. For models these are the reported treatment effects applied in the models. For within trial analyses these are the relative treatment effects from the relevant RCT or RCT subgroup. Specific details are provided under the table.

1.6.4. Health economic modelling

This area was not prioritised for new cost-effectiveness analysis.

1.6.5. Unit costs

Relevant unit costs are provided below to aid consideration of cost effectiveness.

Table 10 shows coronary stent costs from the NHS Supply Chain and local hospital estimates. Data about the usage of different types of drug eluting stents in the NHS was obtained the British Cardiovascular Intervention Society (BCIS) from 1st April 2017 to 31st March 2018 for people undergoing PCI for ACS. This was to inform calculation of a weighted average to reflect what types of stents are often used in practice. Data was not available on the different types of bare metal stents that are used in the NHS. In addition, committee members highlighted that their local costs were considerably lower than those in the NHS supply chain catalogue. As a result, average local costs and average NHS supply chain costs are provided based on weighted averages for drug-eluting stents.

1.7. Evidence statements

1.7.1. Clinical evidence statements

There was a clinically important benefit of drug eluting stents (DES) compared to bare metal stents (BMS) for all-cause mortality at 1 year (14049 participants in 22 studies, moderate quality evidence) and at 1-3 years (12999 participants in 12 studies, low quality evidence)
There was a clinically important benefit of DES compared to BMS for cardiac mortality at 1 year (12117 participants in 14 studies, moderate quality evidence) and at 1-3 years (12416 participants in 10 studies, low quality evidence)
There was a clinically important benefit of DES compared to BMS for target vessel failure up to 1 year (2041 participants in 4 studies, very low quality evidence) and at 1-3 years (703 participants in 3 studies, moderate quality evidence)
There was a clinically important benefit of DES compared to BMS for target vessel revascularisation up to 1 year (12858 participants in 18 studies, moderate quality evidence) and at 1-3 years (15141 participants in 3 studies, moderate quality evidence)
There was no clinically important difference of DES compared to BMS for definite or probable stent thrombosis up to 1 year (11405 participants in 12 studies, low quality evidence) and at 1-3 years (14390 participants in 12 studies, low quality evidence)
There was a clinically important benefit of DES compared to BMS for myocardial infarction (MI) up to 1 year (10780 participants in 20 studies, moderate quality evidence) and at 1-3 years (9456 participants in 10 studies, low quality evidence)
At 1 year, there was no clinically important difference of DES compared to BMS for bleeding (unspecified, 1467 participants in 2 studies, very low quality evidence), major bleeding (7395 participants in 6 studies, low quality evidence), minor bleeding (6595 participants in 5 studies, low quality evidence).
There was no clinically important difference of DES compared to BMS for major bleeding (5104 participants in 2 studies, very low quality evidence) or for minor bleeding (2314 participants in 1 study, very low quality evidence) at 1-3 years.
At 1 year, there was no clinically important difference of DES compared to BMS for in segment minimal luminal diameter (MLD; 346 participants in 2 studies, moderate quality evidence), for in stent MLD (1103 participants in 5 studies, moderate quality evidence), in lesion MLD (695 participants in 2 studies, low quality evidence), MLD proximal edge (37 participants in 1 study, low quality evidence), MLD distal edge (40 participants in 1 study, very low quality evidence) and MLD unspecified (5273 participants in 7 studies, very low quality evidence).

1.7.2. Health economic evidence statements

One cost-utility analysis found that in people with STEMI undergoing PCI bare metal stents was dominant (less costly and more effective) compared to drug-eluting stents. This analysis was assessed as partially applicable with potentially serious limitations.
One cost-utility analysis found that in people with ACS undergoing PCI drug-eluting stents was not cost effective compared to bare metal stents (ICER: £244,400 - £376,100 per QALY gained). This analysis was assessed as partially applicable with potentially serious limitations.
One cost-utility analysis found that in people with STEMI undergoing PCI drug-eluting stents was cost effective compared to bare metal stents (ICER: £4,180 per QALY gained. This analysis was assessed as partially applicable with potentially serious limitations.
One cost effectiveness analysis found that in people with STEMI, NSTEMI, unstable or stable angina undergoing PCI drug eluting stents was dominant (less costly and more effective) compared to bare metal stents. This analysis was assessed as partially applicable with potentially serious limitations.
One cost-utility analysis found that in people with stable coronary artery disease or ACS undergoing PCI with at least one stent with a diameter ≥3mm and ≤15 mm lesion, drug eluting stents was cost effective compared to bare metal stents (ICER: £15,105 per QALY gained). This analysis was assessed as partially applicable with potentially serious limitations.

1.8. The committee’s discussion of the evidence

1.8.1. Interpreting the evidence

1.8.1.1. The outcomes that matter most

The committee agreed that the following outcomes were critical for decision-making: all-cause mortality, cardiac mortality, target vessel failure, target lesion revascularisation (TLR), target vessel revascularisation (TVR), stent thrombosis, myocardial infarction and health-related quality of life. In the analyses, TLR outcome data was combined with TVR outcome data as the committee noted that by definition TVR encompasses TLR. The committee acknowledged that outcomes such as TLR and TVR were surrogate indicators of clinical effectiveness, but felt that they represent an important sense check for the clinical outcome measures.

The committee also agreed that the outcomes major bleeding, minor bleeding and minimal lumen diameter, were important for decision-making.

Outcome data was meta-analysed according to the pre-specified time-points agreed by the committee. These were ‘early’ (before one year or at one year) and ‘late’ (more than one year, until 3 years) reporting of the outcomes of interest.

Outcome data was identified for the majority of the outcomes. There was outcome data for all of the important and critical outcomes, except for health-related quality of life (a critical outcome).

1.8.1.2. The quality of the evidence

Twenty-nine randomised controlled trials were included in this review. One relevant Cochrane review was identified for this evidence review. The search strategy and search dates were updated. Papers included in the Cochrane review were assessed and included if they satisfied the PICO criteria for this review.

Overall, the evidence was graded from very low to moderate quality. There was serious risk of bias for a majority of the outcomes due to inadequate information reported in the studies about the process of randomisation. There were also concerns about the presence of imprecision for a majority of the evidence that was graded as very low or low quality.

There are many different types of DES containing a variety of pharmacological agents and polymer coatings. The committee elected to consider these as a single class as this would otherwise involve assessment of highly fragmented data. Differences in effectiveness between the various agents/stents cannot be excluded by this review, but the committee believe that any such variation would be small.

1.8.1.3. Benefits and harms

The evidence suggested benefits of using drug-eluting stents (DES) in terms of all-cause mortality, cardiac mortality, myocardial infarction, target vessel failure, target vessel revascularisation and MI up to 1 year and 1-3 years. However, the committee noted uncertainty in the evidence for several of these outcomes including those for all-cause and cardiac mortality, and this uncertainty was taken into account during decision-making. The data for bleeding risk, both major and minor, showed no difference between drug-eluting and bare metal stents.

The committee had not anticipated seeing any major difference in mortality, and although there was no definitive evidence of a mortality benefit some members felt there was a signal favouring DES in terms of mortality in the longer term.

The committee agreed there was no evidence of harm with DES and evidence of benefit, albeit with less certainty for some outcomes than others. They also noted the cost-effectiveness data described below and recommended the use of DES in people with acute STEMI undergoing revascularisation by primary PCI and people with unstable angina and NSTEMI undergoing revascularisation by PCI.

1.8.2. Cost effectiveness and resource use

Five economic evaluations were included for this review. These weren’t consistent in their conclusions regarding the cost-effectiveness of DES compared to BMS in people with ACS but they also varied in terms of their methods. The committee considered the methods in detail in the context of the clinical review above in order to come to a conclusion regarding the cost effectiveness of DES compared to BMS.

The analysis that informed NICE technology appraisal 152 which this review is partially updating found that DES were not cost-effective for non-elective patients overall (which was assumed to equate to ACS). Drug-eluting stents were found to be cost effective under some limited circumstances where cost differences between DES and BMS were reduced to £300 and the risk of revascularisation was high. The committee highlighted that DES have evolved since the time of this analysis and much more evidence is available now about the benefits of DES than at the time of the technology appraisal. The analysis only included treatment effects of target-vessel revascularisation whereas the clinical review found other effects, such as a reduction in MI and potentially a mortality benefit. The clinical review also found evidence of effects beyond 1 year but this analysis only employed a 1 year time horizon. The committee agreed that both these things may mean that health effects have not been fully captured. It was noted that the treatment effect for target-vessel revascularisation applied in this analysis was greater than that estimated in the clinical review for this update; however the longer term treatment effects and effects on other outcomes could outweigh this. The cost of DES has considerably reduced since the publication of this technology appraisal, which used costs ranging from £997 to £1,045 and a difference with BMS of around £700. Our estimates of current average costs for DES ranged from £250 to £380, with a difference of £170 to £300. It was agreed it was therefore likely that this analysis would under estimate the benefits of DES as understood from the current clinical evidence base and may overestimate the costs.

One other included analysis also suggested DES might not be cost effective for people with STEMI. This was based on an analysis of patient-level data from the TYPHOON RCT that was included in the clinical evidence review. In this analysis DES had higher costs and slightly lower QALYs. However, it was noted that the QALY loss with DES in this study appeared potentially inconsistent with the key clinical endpoints from the TYPHOON trial which suggested that DES had lower mortality, target-vessel revascularisation and stent thrombosis and it was unclear what was driving the slight QALY loss. In addition, methods appear to indicate that other cardiac and non-cardiac adverse events were also incorporated in the analysis and the committee agreed that many of these would not be related to the choice of stent and it was unclear if this was appropriate and how inclusion of these events were effecting QALYs. As noted above, the clinical review found evidence of effects beyond 1 year, and this analysis only employed a 1 year time horizon, which means health effects such as mortality may not have been fully captured. Given these issues the committee were concerned the conclusions of this analysis were not reliable.

The remaining 3 included analyses suggested that DES are cost effective compared to BMS. A model comparing two types of DES (paclitaxel and sirolimus stents) with each other and with BMS in people with ACS or stable angina undergoing PCI found DES dominated BMS with lower costs and an increase in life years. This analysis from a 2008 Norwegian perspective incorporated revascularisation, MI and mortality, used a lifetime horizon and applied treatment effects for 5 years. This was deemed appropriate by the committee as the clinical evidence review showed longer-term treatment effects and also a small mortality benefit, which indicates that people should be modelled over a lifetime to capture the difference in life years gained. Treatment effects were derived from a meta-analysis of 35 RCTs that included studies that were excluded from our clinical evidence review and it was somewhat difficult to assess the impact of this as the time points and outcomes used in the model did not exactly match those used in our review. However, relative treatment effects generally seemed similar or less favourable and the committee agreed that it didn’t seem likely that the benefits were being overestimated. In addition the baseline risks were also derived from the overall coronary artery disease population and were lower than seen in the clinical evidence review which is also unlikely to favour DES. In addition, the cost difference was higher than the current UK estimates, with the difference ranging from £312 to £408 for the two types of DES. QALYs were not estimated but given the life years are higher with DES this was not considered likely to impact conclusions.

A study comparing DES with BMS in a subgroup of people with stable disease or ACS undergoing PCI with at least one stent with a diameter >3mm and ≤15 mm lesion at baseline from the BASKET-PROVE RCT found that DES were cost-effective with an ICER of £15,105 per QALY gained. The within-trial analysis from a 2013 Swiss perspective used EQ-5D data collected over a 2 year follow-up period to estimate QALY gains. It was noted that QALY gains were quite small in this study. One limitation was that the analysis included people with stable disease and did not report the proportion that was ACS, however the BASKET-PROVE RCT reported that 64% had an ACS. Also, the time horizon of 2 years may not fully capture differences in costs and health outcomes, as the clinical evidence review showed differences in effects at 3 years. It was also unclear if survival was incorporated when calculating QALYs. One benefit was that this analysis showed that DES were cost-effective in a lower risk group, a group of people that the previous TA excluded from their recommendation. Therefore, this may indicate that DES are more cost-effective for a wider population. The difference in costs between DES and BMS was quite low, at £151. This is slightly less than current UK estimates.

An analysis based on the EXAMINATION RCT which was included in the clinical review also found that DES were cost effective in people with STEMI with an ICER of £4,180 per QALY gained. This analysis took a 2016 Spanish perspective and used 5-year patient level data from the RCT and a modelled extrapolation to a lifetime perspective. It incorporated mortality, MI, stent thrombosis and revascularisation. The committee noted that the NICE technology appraisal assumed a 1 month reduction in quality of life after having PCI, whereas this Spanish analysis applied a 1 year reduction. The committee noted that it is hard to determine how long quality of life would be impacted, however they agreed that the impact would be closer to 1 year and that 1 month was likely to be too short. The committee agreed that the QALY loss applied for 1 year for having repeat MI or stent thrombosis was appropriate. The committee noted that relative treatment effects in EXAMINATION trial were similar to those seen in our clinical review and the study was conducted in three European countries similar to the UK. It was agreed that this analysis was the most applicable and had the least methodological limitations of all the included analyses. They highlighted that the EXAMINATION trial had a broad inclusion criterion to ensure it was an all-comers population and so baseline risk and treatment effects were likely to most accurately reflect the real world. The committee agreed it was likely to be reasonable to generalise the conclusions from this analysis to the UA/NSTEMI population undergoing PCI.

In summary, although NICE technology appraisal 152 only found DES to be cost-effective under certain circumstances, newer analyses that incorporated other treatment effects and adopted longer time horizon generally found DES to be cost-effective. The committee concluded that there was sufficient evidence that DES are cost effective to support a recommendation for use of DES in people with ACS.

The committee noted that the use of DES is common practice. Audit data obtained from BCIS showed that from April 2017 to March 2018 91% of all PCIs used a stent during the procedure. Of these procedures that used stents, 97% used DES. Therefore, the committee concluded that a recommendation for DES would not be a change in practice and would not result in a substantial resource impact to the NHS in the England.

1.8.3. Other factors the committee took into account

The committee noted that design of DES has changed, and by implication improved, since they were first introduced whereas bare-metal stents have not changed appreciably. Some of the studies considered in this review used older versions of DES and it was therefore considered that the benefits of currently used DES might be greater than indicated by the results presented here.

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121.: Valgimigli M, Campo G, Gambetti S, Bolognese L, Ribichini F, Colangelo S et al. Three-year follow-up of the MULTIcentre evaluation of Single high-dose Bolus TiRofiban versus Abciximab with Sirolimus-eluting STEnt or Bare-Metal Stent in Acute Myocardial Infarction StudY (MULTISTRATEGY). International Journal of Cardiology. 2013; 165(1):134–141 [PubMed: 21864917]
122.: Valgimigli M, Campo G, Percoco G, Bolognese L, Vassanelli C, Colangelo S et al. Comparison of angioplasty with infusion of tirofiban or abciximab and with implantation of sirolimus-eluting or uncoated stents for acute myocardial infarction: The MULTISTRATEGY randomized trial. JAMA. 2008; 299(15):1788–99 [PubMed: 18375998]
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129.: van Hout BA, Serruys PW, Lemos PA, van den Brand MJ, van Es G, Lindeboom WK et al. One year cost effectiveness of sirolimus eluting stents compared with bare metal stents in the treatment of single native de novo coronary lesions: An analysis from the RAVEL trial. Heart. 2005; 91(4):507–512 [PMC free article: PMC1768841] [PubMed: 15772214]
130.: Vink MA, Dirksen MT, Suttorp MJ, Tijssen JG, van Etten J, Patterson MS et al. 5-year follow-up after primary percutaneous coronary intervention with a paclitaxel-eluting stent versus a bare-metal stent in acute ST-segment elevation myocardial infarction: A follow-up study of the PASSION (Paclitaxel-Eluting Versus Conventional Stent in Myocardial Infarction with ST-Segment Elevation) trial. JACC: Cardiovascular Interventions. 2011; 4(1):24–9 [PubMed: 21251625]
131.: Violini R, Musto C, De Felice F, Nazzaro MS, Cifarelli A, Petitti T et al. Maintenance of long-term clinical benefit with sirolimus-eluting stents in patients with ST-segment elevation myocardial infarction 3-year results of the SESAMI (sirolimus-eluting stent versus bare-metal stent in acute myocardial infarction) trial. Journal of the American College of Cardiology. 2010; 55(8):810–4 [PubMed: 20170821]
132.: Wiemer M, Serruys PW, Miquel-Hebert K, Neumann FJ, Piek JJ, Grube E et al. Five-year long-term clinical follow-up of the XIENCE V everolimus eluting coronary stent system in the treatment of patients with de novo coronary artery lesions: The SPIRIT FIRST trial. Catheterization and Cardiovascular Interventions. 2010; 75(7):997–1003 [PubMed: 20517959]
133.: Wijnbergen I, Helmes H, Tijssen J, Brueren G, Peels K, van Dantzig JM et al. Comparison of drug-eluting and bare-metal stents for primary percutaneous coronary intervention with or without abciximab in ST-segment elevation myocardial infarction: DEBATER: The Eindhoven reperfusion study. JACC: Cardiovascular Interventions. 2012; 5(3):313–22 [PubMed: 22440498]
134.: Wijnbergen I, Tijssen J, Brueren G, Peels K, van Dantzig JM, Veer MV et al. Long-term comparison of sirolimus-eluting and bare-metal stents in ST-segment elevation myocardial infarction. Coronary Artery Disease. 2014; 25(5):378–83 [PubMed: 24736301]
135.: Wisloff T, Atar D, Sonbo Kristiansen I. Cost effectiveness of drug-eluting stents as compared with bare metal stents in patients with coronary artery disease. American Journal of Therapeutics. 2013; 20(6):596–601 [PubMed: 21822114]
136.: Witzenbichler B, Wohrle J, Guagliumi G, Peruga JZ, Brodie BR, Dudek D et al. Paclitaxel-eluting stents compared with bare metal stents in diabetic patients with acute myocardial infarction: the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial. Circulation: Cardiovascular Interventions. 2011; 4(2):130–8 [PubMed: 21364152]
137.: Zbinden R, von Felten S, Wein B, Tueller D, Kurz DJ, Reho I et al. Impact of stent diameter and length on in-stent restenosis after DES vs BMS implantation in patients needing large coronary stents-A clinical and health-economic evaluation. Cardiovascular Therapeutics. 2017; 35(1):19–25 [PubMed: 27662632]
138.: Zellweger MJ, Kaiser C, Brunner-La Rocca HP, Buser PT, Osswald S, Weiss P et al. Value and limitations of target-vessel ischemia in predicting late clinical events after drug-eluting stent implantation. Journal of Nuclear Medicine. 2008; 49(4):550–6 [PubMed: 18344439]
139.: Zellweger MJ, Kaiser C, Jeger R, Brunner-La Rocca HP, Buser P, Bader F et al. Coronary artery disease progression late after successful stent implantation. Journal of the American College of Cardiology. 2012; 59(9):793–9 [PubMed: 22361397]

Appendices

Appendix A. Review protocols

Table 11Review protocol: Clinical and cost-effectiveness of drug-eluting stents

ID	Field	Content
I	Review question	5.1 What is the clinical and cost effectiveness of drug-eluting stents in adults with acute coronary syndromes, including those with unstable angina or NSTEMI undergoing percutaneous coronary intervention and those with STEMI undergoing primary percutaneous coronary intervention?
II	Type of review question	Intervention A review of health economic evidence related to the same review question was conducted in parallel with this review. For details see the health economic review protocol for this NICE guideline.
III	Objective of the review	To determine the comparative effectiveness of bare metal stents and drug eluting stents. Rationale for including this question: CG167 does not make any recommendations on the use of PPCI using drug-eluting stents in patients with STEMI. It refers to the general recommendation in TA 152 (see section XIV below). New evidence on the efficacy and safety of drug eluting stents has been identified and warrants a review as it may provide enough evidence to make a recommendation. It would also be useful to extrapolate this question to the UA/NSTEMI population
IV	Eligibility criteria – population / disease / condition / issue / domain	Patients with UA/NSTEMI and those with STEMI intended for treatment with a stent Include PCI for various indications only if reports populations separately Populations: Can include global ACS population and can include papers specifically looking at NSTEMI and STEMI, - pathophysiology is the same and the long term mechanistic results shouldn’t be different. Main benefit is a reduction in repeat revascularisation For studies including stable and unstable disease, include only if majority is ACS - >50% - For studies that have stable and ACS and have reported ACS separately use ACS data only
V	Eligibility criteria – intervention(s) / exposure(s) / prognostic factor(s)	Drug eluting stents including: Sirolimus Everolimus Paclitaxel Rapamycin Paclitaxel & Cilostazol Ridaforolimus Novolimus Zotarolimus Include stents with or without bioabsorbable poylmers Not comparing DES to DES and BMS to BMS
VI	Eligibility criteria – comparator(s) / control or reference (gold) standard	Bare metal stents including: Cobalt Chronium Platinium Chronium Stainless Steel
VII	Outcomes and prioritisation	CRITICAL Time points: early ≤1 and later >1-3 year All-cause mortality Cardiac mortality TVF- target vessel failure TLR and TVR – target lesion and target vessel revascularisation Stent thrombosis(definite and/or probable) (record if assessed using optical coherence tomography (OCT), Intravascular ultrasound (IVUS) or angio) Myocardial infarction Health-related quality of life including EQ5D and SF-36. All data for the stated quality of life measures will be collected. Only overall scores will be reported for meta-analysis and GRADE. IMPORTANT Bleeding- Where possible, bleeding outcomes will be categorised into: Major bleeding (including BARC 3-5 and as reported by author) Minor bleeding (including BARC 2, TIMI and as reported by author). The following hierarchy of bleeding scales will be used: BARC Author’s definition TIMI GUSTO MLD - Minimal lumen diameter (measuring how much restenosis there is)- surrogate marker for TLR and TVR
VIII	Eligibility criteria – study design	Randomised Controlled Trials (RCT) Systematic Reviews (SR) of RCTs
IX	Other inclusion exclusion criteria	Exclude endothelial progenitor cell (EPC) capture Bioabsorbable scaffolds – these are not stents – include DES with bioabsorbable polymer but exclude any that are re-absorbed
X	Proposed sensitivity / subgroup analysis, or metaregression	If there is heterogeneity (P-value is <0.1 or I² is >50%), the following subgroups will be investigated: diameter and number of stents if possible (length and width)-> = 3mm width and length 15 STEMI and NSTEMI duration of antiplatelet therapy differential usage of antiplatelet therapy renal disease/renal insufficiency older patients (>75) Diabetes Mixed Stable and ACS restenosis A statement will be included about subgroup analyses that have been conducted. However, only those analyses that explain heterogeneity will be reported.
XI	Selection process – duplicate screening / selection / analysis	Studies will be sifted by title and abstract. Potentially relevant publications obtained in full text and assessed against the inclusion criteria specified in this protocol. A sample of a minimum of 10% of the abstract lists will be double-sifted by a senior research fellow and any discrepancies discussed and rectified.
XII	Data management (software)	EndNote will be used for reference management, sifting, citations and bibliographies. EviBASE will be used for data extraction and quality assessment for clinical studies. MS Excel will be used for data extraction and critical appraisal for health economic studies. Pairwise meta-analyses will be performed using Cochrane Review Manager (RevMan5). GRADEpro will be used to assess the quality of evidence for each outcome.
XIII	Information sources – databases and dates	Clinical search databases to be used: Medline, Embase, Cochrane Library Language: Restrict to English only Supplementary search techniques: backward citation searching
XIV	Identify if an update	This question is an update of TA 152 Recommendation in TA 152 states the following: Drug-eluting stents are recommended for use in percutaneous coronary intervention for the treatment of coronary artery disease, within their instructions for use, only if: the target artery to be treated has less than a 3-mm calibre or the lesion is longer than 15 mm, and the price difference between drug-eluting stents and bare-metal stents is no more than £300.
XV	Author contacts	ACS@nice.org.uk
XVI	Highlight if amendment to previous protocol	For details please see section 4.5 of Developing NICE guidelines: the manual.
XVII	Search strategy – for one database	For details please see appendix B
XVIII	Data collection process – forms / duplicate	A standardised evidence table format will be used, and published as appendix/ces [X] of the evidence report.
XIX	Data items – define all variables to be collected	For details please see evidence tables in Appendix D (clinical evidence tables) or H (health economic evidence tables).
XX	Methods for assessing bias at outcome / study level	Standard study checklists were used to critically appraise individual studies. For details please see section 6.2 of Developing NICE guidelines: the manual The risk of bias across all available evidence was evaluated for each outcome using an adaptation of the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE) toolbox’ developed by the international GRADE working group http://www.gradeworkinggroup.org/ [Please document any deviations/alternative approach when GRADE isn’t used or if a modified GRADE approach has been used for non-intervention or non-comparative studies.]
XXI	Criteria for quantitative synthesis	For details please see section 6.4 of Developing NICE guidelines: the manual.
XXII	Methods for quantitative analysis – combining studies and exploring (in)consistency	For details please see the separate Methods report for this guideline.
XXIII	Meta-bias assessment – publication bias, selective reporting bias	For details please see section 6.2 of Developing NICE guidelines: the manual. [Consider exploring publication bias for review questions where it may be more common, such as pharmacological questions, certain disease areas, etc. Describe any steps taken to mitigate publication bias, such as examining trial registries.]
XXIV	Confidence in cumulative evidence	For details please see sections 6.4 and 9.1 of Developing NICE guidelines: the manual.
XXV	Rationale / context – what is known	For details please see the introduction to the evidence review.
XXVI	Describe contributions of authors and guarantor	A multidisciplinary committee [www.nice.org.uk/guidance/ng185/history] developed the evidence review. The committee was convened by the National Guideline Centre (NGC) and chaired by Margaret Lally in line with section 3 of Developing NICE guidelines: the manual. Staff from NGC undertook systematic literature searches, appraised the evidence, conducted meta-analysis and cost-effectiveness analysis where appropriate, and drafted the evidence review in collaboration with the committee. For details please see Developing NICE guidelines: the manual.
XXVII	Sources of funding / support	NGC is funded by NICE and hosted by the Royal College of Physicians.
XXVIII	Name of sponsor	NGC is funded by NICE and hosted by the Royal College of Physicians.
XXIX	Roles of sponsor	NICE funds NGC to develop guidelines for those working in the NHS, public health and social care in England.
XXX	PROSPERO registration number	Not registered

Table 12Health economic review protocol

Review question	All questions – health economic evidence
Objectives	To identify health economic studies relevant to any of the review questions.
Search criteria	Populations, interventions and comparators must be as specified in the clinical review protocol above. Studies must be of a relevant health economic study design (cost–utility analysis, cost-effectiveness analysis, cost–benefit analysis, cost–consequences analysis, comparative cost analysis). Studies must not be a letter, editorial or commentary, or a review of health economic evaluations. (Recent reviews will be ordered although not reviewed. The bibliographies will be checked for relevant studies, which will then be ordered.) Unpublished reports will not be considered unless submitted as part of a call for evidence. Studies must be in English.
Search strategy	A health economic study search will be undertaken using population-specific terms and a health economic study filter – see appendix B below.
Review strategy	Studies not meeting any of the search criteria above will be excluded. Studies published before 2003, abstract-only studies and studies from non-OECD countries or the USA will also be excluded. Studies published after 2003 that were included in the previous guidelines will be reassessed for inclusion and may be included or selectively excluded based on their relevance to the questions covered in this update and whether more applicable evidence is also identified. Each remaining study will be assessed for applicability and methodological limitations using the NICE economic evaluation checklist which can be found in appendix H of Developing NICE guidelines: the manual (2014).⁸⁰ Inclusion and exclusion criteria If a study is rated as both ‘Directly applicable’ and with ‘Minor limitations’ then it will be included in the guideline. A health economic evidence table will be completed and it will be included in the health economic evidence profile. If a study is rated as either ‘Not applicable’ or with ‘Very serious limitations’ then it will usually be excluded from the guideline. If it is excluded then a health economic evidence table will not be completed and it will not be included in the health economic evidence profile. If a study is rated as ‘Partially applicable’, with ‘Potentially serious limitations’ or both then there is discretion over whether it should be included. Where there is discretion The health economist will make a decision based on the relative applicability and quality of the available evidence for that question, in discussion with the guideline committee if required. The ultimate aim is to include health economic studies that are helpful for decision-making in the context of the guideline and the current NHS setting. If several studies are considered of sufficiently high applicability and methodological quality that they could all be included, then the health economist, in discussion with the committee if required, may decide to include only the most applicable studies and to selectively exclude the remaining studies. All studies excluded on the basis of applicability or methodological limitations will be listed with explanation in the excluded health economic studies appendix below. The health economist will be guided by the following hierarchies. Setting: UK NHS (most applicable). OECD countries with predominantly public health insurance systems (for example, France, Germany, Sweden). OECD countries with predominantly private health insurance systems (for example, Switzerland). Studies set in non-OECD countries or in the USA will be excluded before being assessed for applicability and methodological limitations. Health economic study type: Cost–utility analysis (most applicable). Other type of full economic evaluation (cost–benefit analysis, cost-effectiveness analysis, cost–consequences analysis). Comparative cost analysis. Non-comparative cost analyses including cost-of-illness studies will be excluded before being assessed for applicability and methodological limitations. Year of analysis: The more recent the study, the more applicable it will be. Studies published in 2003 or later (including any such studies included in the previous guideline(s)) but that depend on unit costs and resource data entirely or predominantly from before 2003 will be rated as ‘Not applicable’. Studies published before 2003 (including any such studies included in the previous guidelines) will be excluded before being assessed for applicability and methodological limitations. Quality and relevance of effectiveness data used in the health economic analysis: The more closely the clinical effectiveness data used in the health economic analysis match with the outcomes of the studies included in the clinical review the more useful the analysis will be for decision-making in the guideline. The following will be rated as ‘Very serious limitations’ and excluded: economic analyses undertaken as part of clinical studies that are excluded from the clinical review; economic models where relative treatment effects are based entirely on studies that are excluded from the clinical review.

Appendix B. Literature search strategies

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual.⁸⁰

For more information, please see the Methods report 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 for interventions as these concepts may not be well described in title, abstract or indexes and therefore difficult to retrieve. Search filters were applied to the search where appropriate.

Table 13Database date parameters and filters used

Database

Dates searched

Search filter used

Medline (OVID)

1946 – 24 June 2019

Exclusions

Randomised controlled trials

Systematic review studies

Embase (OVID)

1974 – 24 June 2019

Exclusions

Randomised controlled trials

Systematic review studies

The Cochrane Library (Wiley)

Cochrane Reviews to 2019 Issue 6 of 12

CENTRAL to 2019 Issue 6 of 12

None

Medline (Ovid) search terms

1.	Acute Coronary Syndrome/ or Angina Pectoris/ or Angina, Unstable/ or Coronary Thrombosis/ or exp Myocardial Infarction/
2.	Heart Arrest/
3.	(acute coronary adj2 syndrome*).ti,ab.
4.	((myocardial or heart) adj infarct*).ti,ab.
5.	(heart adj (attack* or event*)).ti,ab.
6.	((heart or cardiac) adj arrest*).ti,ab.
7.	(coronary adj2 thrombos*).ti,ab.
8.	(stemi or st-segment or st segment or st-elevation or st elevation).ti,ab.
9.	“non-ST-segment elevation”.ti,ab.
10.	(non-STEMI or NSTEMI or nonSTEMI).ti,ab.
11.	“Q wave myocardial infarction”.ti,ab.
12.	“non Q wave MI”.ti,ab.
13.	(NSTE-ACS or STE-ACS).ti,ab.
14.	(subendocardial adj3 infarct*).ti,ab.
15.	((unstable or variant) adj2 angina*).ti,ab.
16.	(unstable adj2 coronary).ti,ab.
17.	or/1-16
18.	letter/
19.	editorial/
20.	news/
21.	exp historical article/
22.	Anecdotes as Topic/
23.	comment/
24.	case report/
25.	(letter or comment*).ti.
26.	or/18-25
27.	randomized controlled trial/ or random*.ti,ab.
28.	26 not 27
29.	animals/ not humans/
30.	exp Animals, Laboratory/
31.	exp Animal Experimentation/
32.	exp Models, Animal/
33.	exp Rodentia/
34.	(rat or rats or mouse or mice).ti.
35.	or/28-34
36.	17 not 35
37.	limit 36 to English language
38.	randomized controlled trial.pt.
39.	controlled clinical trial.pt.
40.	randomi#ed.ti,ab.
41.	placebo.ab.
42.	randomly.ti,ab.
43.	Clinical Trials as topic.sh.
44.	trial.ti.
45.	or/38-44
46.	Meta-Analysis/
47.	exp Meta-Analysis as Topic/
48.	(meta analy* or metanaly* or metaanaly* or meta regression).ti,ab.
49.	((systematic* or evidence) adj3 (review or overview*)).ti,ab.
50.	(reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab.
51.	(search strategy or search criteria or systematic search or study selection or data extraction).ab.
52.	(search* adj4 literature).ab.
53.	(medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation index or bids or cancerlit).ab.
54.	cochrane.jw.
55.	((multiple treatment* or indirect or mixed) adj2 comparison*).ti,ab.
56.	or/46-55
57.	Percutaneous Coronary Intervention/
58.	Percutaneous coronary intervention*.ti,ab.
59.	(PPCI or PCI).ti,ab.
60.	Percutaneous Transluminal Coronary Angioplasty.ti,ab.
61.	PTCA.ti,ab.
62.	Angioplasty, Balloon, Coronary/
63.	exp Angioplasty/
64.	(Balloon adj3 coronary).ti,ab.
65.	((primary or coronary or transluminal or balloon) adj3 angioplasty).ti,ab.
66.	Coronary artery dilat*.ti,ab.
67.	or/57-66
68.	exp *Stents/
69.	drug eluting stent*.ti,ab.
70.	(eluting adj3 stent*).ti,ab.
71.	((paclitaxel or sirolimus or everolimus or biolimus or ridaforolimus or zotarolimus or novolimus) adj3 stent*).ti,ab.
72.	or/68-71
73.	37 and 67 and 72
74.	73 and (45 or 56)

Embase (Ovid) search terms

1.	acute coronary syndrome/ or angina pectoris/ or unstable angina pectoris/ or coronary artery thrombosis/ or exp heart infarction/
2.	heart arrest/
3.	(acute coronary adj2 syndrome*).ti,ab.
4.	((myocardial or heart) adj infarct*).ti,ab.
5.	(heart adj (attack* or event*)).ti,ab.
6.	((heart or cardiac) adj arrest*).ti,ab.
7.	(coronary adj2 thrombos*).ti,ab.
8.	(stemi or st-segment or st segment or st-elevation or st elevation).ti,ab.
9.	“non-ST-segment elevation”.ti,ab.
10.	(non-STEMI or NSTEMI or nonSTEMI).ti,ab.
11.	“Q wave myocardial infarction”.ti,ab.
12.	“non Q wave MI”.ti,ab.
13.	(NSTE-ACS or STE-ACS).ti,ab.
14.	(subendocardial adj3 infarct*).ti,ab.
15.	((unstable or variant) adj2 angina*).ti,ab.
16.	(unstable adj2 coronary).ti,ab.
17.	or/1-16
18.	letter.pt. or letter/
19.	note.pt.
20.	editorial.pt.
21.	Case report/ or Case study/
22.	(letter or comment*).ti.
23.	or/18-22
24.	randomized controlled trial/ or random*.ti,ab.
25.	23 not 24
26.	animal/ not human/
27.	Nonhuman/
28.	exp Animal Experiment/
29.	exp Experimental animal/
30.	Animal model/
31.	exp Rodent/
32.	(rat or rats or mouse or mice).ti.
33.	or/25-32
34.	17 not 33
35.	limit 34 to English language
36.	random*.ti,ab.
37.	factorial*.ti,ab.
38.	(crossover* or cross over*).ti,ab.
39.	((doubl* or singl) adj blind).ti,ab.
40.	(assign* or allocat* or volunteer* or placebo*).ti,ab.
41.	crossover procedure/
42.	single blind procedure/
43.	randomized controlled trial/
44.	double blind procedure/
45.	or/36-44
46.	systematic review/
47.	meta-analysis/
48.	(meta analy* or metanaly* or metaanaly* or meta regression).ti,ab.
49.	((systematic or evidence) adj3 (review* or overview*)).ti,ab.
50.	(reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab.
51.	(search strategy or search criteria or systematic search or study selection or data extraction).ab.
52.	(search* adj4 literature).ab.
53.	(medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation index or bids or cancerlit).ab.
54.	((pool* or combined) adj2 (data or trials or studies or results)).ab.
55.	cochrane.jw.
56.	((multiple treatment* or indirect or mixed) adj2 comparison*).ti,ab.
57.	or/46-56
58.	transluminal coronary angioplasty/ or percutaneous coronary intervention/
59.	Percutaneous coronary intervention*.ti,ab.
60.	(PPCI or PCI).ti,ab.
61.	Percutaneous Transluminal Coronary Angioplasty.ti,ab.
62.	PTCA.ti,ab.
63.	transluminal coronary angioplasty/ or percutaneous transluminal angioplasty/ or angioplasty/ or percutaneous transluminal angioplasty balloon/
64.	(Balloon adj3 coronary).ti,ab.
65.	((primary or coronary or transluminal or balloon) adj3 angioplasty).ti,ab.
66.	Coronary artery dilat*.ti,ab.
67.	or/58-66
68.	stent/ or exp cardiovascular stent/ or exp drug eluting stent/ or exp metal stent/
69.	drug eluting stent*.ti,ab.
70.	(eluting adj3 stent*).ti,ab.
71.	((paclitaxel or sirolimus or everolimus or biolimus or ridaforolimus or zotarolimus or novolimus) adj3 stent*).ti,ab.
72.	or/68-71
73.	35 and 67 and 72
74.	73 and (45 or 57)

Cochrane Library (Wiley) search terms

#1.	MeSH descriptor: [Acute Coronary Syndrome] this term only
#2.	MeSH descriptor: [Angina Pectoris] this term only
#3.	MeSH descriptor: [Angina, Unstable] this term only
#4.	MeSH descriptor: [Coronary Thrombosis] this term only
#5.	MeSH descriptor: [Myocardial Infarction] explode all trees
#6.	(or #1-#5)
#7.	MeSH descriptor: [Heart Arrest] this term only
#8.	(acute coronary near/2 syndrome*):ti,ab
#9.	((myocardial or heart) next infarct*):ti,ab
#10.	(heart next (attack* or event*)):ti,ab
#11.	((heart or cardiac) next arrest*):ti,ab
#12.	(coronary near/2 thrombos*):ti,ab
#13.	(stemi or st-segment or st segment or st-elevation or st elevation):ti,ab
#14.	non-ST-segment elevation:ti,ab
#15.	(non-STEMI or NSTEMI or nonSTEMI):ti,ab
#16.	Q wave myocardial infarction:ti,ab
#17.	non Q wave MI:ti,ab
#18.	NSTE-ACS:ti,ab
#19.	(subendocardial near/3 infarct*):ti,ab
#20.	((unstable or variant) near/2 angina*):ti,ab
#21.	(unstable near/2 coronary):ti,ab
#22.	(or #6-#21)
#23.	MeSH descriptor: [Percutaneous Coronary Intervention] explode all trees
#24.	Percutaneous coronary intervention*:ti,ab
#25.	(PPCI or PCI):ti,ab
#26.	MeSH descriptor: [Angioplasty, Balloon, Coronary] explode all trees
#27.	Percutaneous Transluminal Coronary Angioplasty:ti,ab
#28.	PTCA:ti,ab
#29.	MeSH descriptor: [Angioplasty] explode all trees
#30.	(Balloon near/3 coronary):ti,ab
#31.	((primary or coronary or transluminal or balloon) near/3 angioplasty):ti,ab
#32.	Coronary artery dilat*:ti,ab
#33.	(or #23-#32)
#34.	MeSH descriptor: [Stents] explode all trees
#35.	(drug next eluting next stent*):ti,ab
#36.	(eluting near/3 stent*):ti,ab
#37.	((paclitaxel or sirolimus) near/3 stent*):ti,ab
#38.	(or #34-#37)
#39.	#22 and #33 and #38

B.2. Health Economics literature search strategy

Health economic evidence was identified by conducting a search relating to acute coronary syndromes population combined with terms for interventions in NHS Economic Evaluation Database (NHS EED – this ceased to be updated after March 2015) and the Health Technology Assessment database (HTA) with no date restrictions. NHS EED and HTA databases are hosted by the Centre for Research and Dissemination (CRD). Additional searches were run on Medline and Embase using a filter for health economics studies.

Table 14Database date parameters and filters used

Database

Dates searched

Search filter used

Medline

01 January 2014 – 18 June 2019

Exclusions

Health economics studies

Embase

01 January 2014 – 18 June 2019

Exclusions

Health economics studies

Centre for Research and Dissemination (CRD)

HTA - 2003 – 31 March 2018

NHSEED - 2003 to 31 March 2015

Medline (Ovid) search terms

1.	Acute Coronary Syndrome/ or Angina Pectoris/ or Angina, Unstable/ or Coronary Thrombosis/ or exp Myocardial Infarction/
2.	Heart Arrest/
3.	(acute coronary adj2 syndrome*).ti,ab.
4.	((myocardial or heart) adj infarct*).ti,ab.
5.	(heart adj (attack* or event*)).ti,ab.
6.	((heart or cardiac) adj arrest*).ti,ab.
7.	(coronary adj2 thrombos*).ti,ab.
8.	(stemi or st-segment or st segment or st-elevation or st elevation).ti,ab.
9.	“non-ST-segment elevation”.ti,ab.
10.	(non-STEMI or NSTEMI or nonSTEMI).ti,ab.
11.	“Q wave myocardial infarction”.ti,ab.
12.	“non Q wave MI”.ti,ab.
13.	NSTE-ACS.ti,ab.
14.	(subendocardial adj3 infarct*).ti,ab.
15.	((unstable or variant) adj2 angina*).ti,ab.
16.	(unstable adj2 coronary).ti,ab.
17.	or/1-16
18.	letter/
19.	editorial/
20.	news/
21.	exp historical article/
22.	Anecdotes as Topic/
23.	comment/
24.	case report/
25.	(letter or comment*).ti.
26.	or/18-25
27.	randomized controlled trial/ or random*.ti,ab.
28.	26 not 27
29.	animals/ not humans/
30.	exp Animals, Laboratory/
31.	exp Animal Experimentation/
32.	exp Models, Animal/
33.	exp Rodentia/
34.	(rat or rats or mouse or mice).ti.
35.	or/28-34
36.	17 not 35
37.	limit 36 to English language
38.	Economics/
39.	Value of life/
40.	exp “Costs and Cost Analysis”/
41.	exp Economics, Hospital/
42.	exp Economics, Medical/
43.	Economics, Nursing/
44.	Economics, Pharmaceutical/
45.	exp “Fees and Charges”/
46.	exp Budgets/
47.	budget*.ti,ab.
48.	cost*.ti.
49.	(economic* or pharmaco?economic*).ti.
50.	(price* or pricing*).ti,ab.
51.	(cost* adj2 (effective* or utilit* or benefit* or minimi* or unit* or estimat* or variable*)).ab.
52.	(financ* or fee or fees).ti,ab.
53.	(value adj2 (money or monetary)).ti,ab.
54.	or/38-53
55.	37 and 54
56.	*Angiography/
57.	Angiocardiography/
58.	Coronary Angiography/
59.	Angiograph*.ti.
60.	Arteriograph*.ti.
61.	Angiocardiograph*.ti,ab.
62.	Coronary Angiograph*.ti,ab.
63.	Angiogram*.ti,ab.
64.	Cardioangiograph*.ti,ab.
65.	Angiocardiogram.ti,ab.
66.	Angio Cardiograph*.ti,ab.
67.	Coronary Arteriogra*.ti,ab.
68.	Coronarograph*.ti,ab.
69.	*Myocardial Revascularization/
70.	Angioplasty, Balloon, Coronary/
71.	(Myocardial adj revasculari?ation).ti,ab.
72.	PCI.ti,ab.
73.	Percutaneous coronary intervention.ti,ab.
74.	Percutaneous Transluminal Coronary Angioplasty.ti,ab.
75.	PTCA.ti,ab.
76.	exp Angioplasty/
77.	Blunt microdissection.ti,ab.
78.	((laser or patch) adj angioplasty).ti,ab.
79.	Percutaneous Transluminal Angioplasty.ti,ab.
80.	Transluminal Coronary Angioplasty.ti,ab.
81.	(Balloon adj3 coronary).ti,ab.
82.	(Balloon adj3 angioplasty).ti,ab.
83.	exp STENTS/
84.	stent*.ti,ab.
85.	Or/56-84
86.	aspirin/
87.	(aspirin or acetylsalicylic acid).ti,ab.
88.	(clopidogrel or plavix).ti,ab.
89.	(ticagrelor or brilique).ti,ab.
90.	(prasugrel or efient or effient or prasita).ti,ab.
91.	Prasugrel Hydrochloride/
92.	platelet aggregation inhibitors/
93.	(Glycoproteins IIb-IIIa or GPIIb-IIIa Receptors or Integrin alpha-IIb beta-3 or Integrin alphaIIbbeta3 or GPIIB IIIA).ti,ab.
94.	exp Platelet Glycoprotein GPIIb-IIIa Complex/
95.	exp Receptors, Fibrinogen/
96.	(Abciximab or Reopro or Eptifibatide or Integrelin or Integrilin or Intrifiban or Tirofiban or Aggrastat).ti,ab.
97.	exp adrenergic beta-antagonists/
98.	(propranolol or angilol or inderal-la or half-inderal or inderal or bedranol or prograne or slo-pro or acebutolol or sectral or atenolol or tenormin or bisoprolol or cardicor or emcor or carvedilol or eucardic or celiprolol or celectol or co-tenidone or tenoret or tenoretic or esmolol or brevibloc or labetalol or trandate or metoprolol or betaloc or lopresor or nadolol or corgard or nebivolol or nebilet or hypoloc or oxprenolol or trasicor or slow-trasicor or pindolol or visken or sotalol or beta-cardone or sotacor or timolol or betim).ti,ab.
99.	propranolol/ or acebutolol/ or atenolol/ or bisoprolol/ or celiprolol/ or labetalol/ or metoprolol/ or nadolol/ or nebivolol/ or oxprenolol/ or pindolol/ or sotalol/ or timolol/
100.	(beta adj3 block*).ti,ab.
101.	(b adj3 block*).ti,ab.
102.	(beta adj2 antagonist*).ti,ab.
103.	Antithrombins/
104.	Antithrombin*.ti,ab.
105.	(thrombin adj3 inhibitor*).ti,ab.
106.	Hirudins/
107.	Hirudin*.ti,ab.
108.	Hirulog.ti,ab.
109.	Bivalirudin.ti,ab.
110.	Or/86-109
111.	and (85 or 110)

Embase (Ovid) search terms

1.	acute coronary syndrome/ or angina pectoris/ or unstable angina pectoris/ or coronary artery thrombosis/ or exp heart infarction/
2.	heart arrest/
3.	(acute coronary adj2 syndrome*).ti,ab.
4.	((myocardial or heart) adj infarct*).ti,ab.
5.	(heart adj (attack* or event*)).ti,ab.
6.	((heart or cardiac) adj arrest*).ti,ab.
7.	(coronary adj2 thrombos*).ti,ab.
8.	(stemi or st-segment or st segment or st-elevation or st elevation).ti,ab.
9.	“non-ST-segment elevation”.ti,ab.
10.	(non-STEMI or NSTEMI or nonSTEMI).ti,ab.
11.	“Q wave myocardial infarction”.ti,ab.
12.	“non Q wave MI”.ti,ab.
13.	NSTE-ACS.ti,ab.
14.	(subendocardial adj3 infarct*).ti,ab.
15.	((unstable or variant) adj2 angina*).ti,ab.
16.	(unstable adj2 coronary).ti,ab.
17.	or/1-16
18.	letter.pt. or letter/
19.	note.pt.
20.	editorial.pt.
21.	Case report/ or Case study/
22.	(letter or comment*).ti.
23.	or/18-22
24.	randomized controlled trial/ or random*.ti,ab.
25.	23 not 24
26.	animal/ not human/
27.	Nonhuman/
28.	exp Animal Experiment/
29.	exp Experimental animal/
30.	Animal model/
31.	exp Rodent/
32.	(rat or rats or mouse or mice).ti.
33.	or/25-32
34.	17 not 33
35.	limit 34 to English language
36.	health economics/
37.	exp economic evaluation/
38.	exp health care cost/
39.	exp fee/
40.	budget/
41.	funding/
42.	budget*.ti,ab.
43.	cost*.ti.
44.	(economic* or pharmaco?economic*).ti.
45.	(price* or pricing*).ti,ab.
46.	(cost* adj2 (effective* or utilit* or benefit* or minimi* or unit* or estimat* or variable*)).ab.
47.	(financ* or fee or fees).ti,ab.
48.	(value adj2 (money or monetary)).ti,ab.
49.	or/36-48
50.	35 and 49
51.	angiography/
52.	angiocardiography/
53.	coronary angiography/
54.	Angiograph*.ti.
55.	Arteriograph*.ti.
56.	Angiocardiograph*.ti,ab.
57.	Coronary Angiograph*.ti,ab.
58.	Angiogram*.ti,ab.
59.	Cardioangiograph*.ti,ab.
60.	Angiocardiogram.ti,ab.
61.	Angio Cardiograph*.ti,ab.
62.	Coronary Arteriogra*.ti,ab.
63.	Coronarograph*.ti,ab.
64.	*heart muscle revascularization/
65.	transluminal coronary angioplasty/
66.	(Myocardial adj revasculari?ation).ti,ab.
67.	PCI.ti,ab.
68.	Percutaneous coronary intervention.ti,ab.
69.	Percutaneous Transluminal Coronary Angioplasty.ti,ab.
70.	PTCA.ti,ab.
71.	*angioplasty/
72.	Blunt microdissection.ti,ab.
73.	((laser or patch) adj angioplasty).ti,ab.
74.	Percutaneous Transluminal Angioplasty.ti,ab.
75.	Transluminal Coronary Angioplasty.ti,ab.
76.	(Balloon adj3 coronary).ti,ab.
77.	(Balloon adj3 angioplasty).ti,ab.
78.	exp STENTS/
79.	stent*.ti,ab.
80.	Or/51-79
81.	acetylsalicylic acid/
82.	(aspirin or acetylsalicylic acid).ti,ab.
83.	(clopidogrel or plavix).ti,ab.
84.	(ticagrelor or brilique).ti,ab.
85.	(prasugrel or efient or effient or prasita).ti,ab.
86.	prasugrel/
87.	antithrombocytic agent/
88.	(Glycoproteins IIb-IIIa or GPIIb-IIIa Receptors or Integrin alpha-IIb beta-3 or Integrin alphaIIbbeta3 or GPIIB IIIA).ti,ab.
89.	exp fibrinogen receptor/
90.	(Abciximab or Reopro or Eptifibatide or Integrelin or Integrilin or Intrifiban or Tirofiban or Aggrastat).ti,ab.
91.	abciximab/ or eptifibatide/ or tirofiban/
92.	exp beta adrenergic receptor blocking agent/
93.	(propranolol or angilol or inderal-la or half-inderal or inderal or bedranol or prograne or slo-pro or acebutolol or sectral or atenolol or tenormin or bisoprolol or cardicor or emcor or carvedilol or eucardic or celiprolol or celectol or co-tenidone or tenoret or tenoretic or esmolol or brevibloc or labetalol or trandate or metoprolol or betaloc or lopresor or nadolol or corgard or nebivolol or nebilet or hypoloc or oxprenolol or trasicor or slow-trasicor or pindolol or visken or sotalol or beta-cardone or sotacor or timolol or betim).ti,ab.
94.	propranolol/ or acebutolol/ or atenolol/ or bisoprolol/ or bisoprolol fumarate/ or carvedilol/ or celiprolol/ or esmolol/ or labetalol/ or metoprolol/ or nadolol/ or nebivolol/ or oxprenolol/ or pindolol/ or sotalol/ or timolol/ or timolol maleate/
95.	(beta adj3 block*).ti,ab.
96.	(b adj3 block*).ti,ab.
97.	(beta adj2 antagonist*).ti,ab.
98.	antithrombin/
99.	Antithrombin*.ti,ab.
100.	(thrombin adj3 inhibitor*).ti,ab.
101.	hirudin derivative/
102.	Hirudin*.ti,ab.
103.	Hirulog.ti,ab.
104.	Bivalirudin.ti,ab.
105.	Or/81-104
106.	50 and (80 or 105)

NHS EED and HTA (CRD) search terms

#1.	MeSH DESCRIPTOR Acute Coronary Syndrome
#2.	(MeSH DESCRIPTOR angina pectoris)
#3.	(MeSH DESCRIPTOR Angina, Unstable)
#4.	(MeSH DESCRIPTOR Coronary Thrombosis)
#5.	MeSH DESCRIPTOR Myocardial Infarction EXPLODE ALL TREES
#6.	#1 OR #2 OR #3 OR #4 OR #5
#7.	(MeSH DESCRIPTOR Heart Arrest)
#8.	((acute coronary adj2 syndrome*))
#9.	(((myocardial or heart) adj infarct*))
#10.	((heart adj (attack* or event*)))
#11.	(((heart or cardiac) adj arrest*))
#12.	((coronary adj2 thrombos*))
#13.	((stemi or st-segment or st segment or st-elevation or st elevation))
#14.	(“non-ST-segment elevation”)
#15.	((non-STEMI or NSTEMI or nonSTEMI))
#16.	(“Q wave myocardial infarction”)
#17.	(“non Q wave MI”)
#18.	(NSTE-ACS)
#19.	(STE-ACS)
#20.	(((subendocardial adj3 infarct*)))
#21.	((((unstable or variant) adj2 angina*)))
#22.	(((unstable adj2 coronary)))
#23.	(#6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22)
#24.	(MeSH DESCRIPTOR Angiography)
#25.	(MeSH DESCRIPTOR Angiocardiography)
#26.	((MeSH DESCRIPTOR Coronary Angiography))
#27.	((Angiograph*))
#28.	((Arteriograph*))
#29.	((Angiocardiograph*))
#30.	((Coronary Angiograph*))
#31.	((Angiogram*))
#32.	((Cardioangiograph*))
#33.	((Angiocardiogram))
#34.	((Angio Cardiograph*))
#35.	((Coronary Arteriogra*))
#36.	((Coronarograph*))
#37.	(MeSH DESCRIPTOR Myocardial Revascularization)
#38.	(MeSH DESCRIPTOR Angioplasty, Balloon, Coronary)
#39.	(((Myocardial adj revasculari?ation)))
#40.	((PCI))
#41.	((Percutaneous coronary intervention))
#42.	((Percutaneous Transluminal Coronary Angioplasty))
#43.	((PTCA))
#44.	(MeSH DESCRIPTOR Angioplasty EXPLODE ALL TREES)
#45.	((Blunt microdissection))
#46.	((((laser or patch) adj angioplasty)))
#47.	((Percutaneous Transluminal Angioplasty))
#48.	((Transluminal Coronary Angioplasty))
#49.	(((Balloon adj3 coronary)))
#50.	((Balloon adj3 angioplasty))
#51.	(MeSH DESCRIPTOR Stents EXPLODE ALL TREES)
#52.	((stent*))
#53.	(#24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52)
#54.	(MeSH DESCRIPTOR Aspirin)
#55.	((aspirin or acetylsalicylic acid))
#56.	((clopidogrel or plavix))
#57.	((ticagrelor or brilique))
#58.	((prasugrel or efient or effient or prasita))
#59.	MeSH DESCRIPTOR Prasugrel Hydrochloride
#60.	MeSH DESCRIPTOR Platelet Aggregation Inhibitors
#61.	((Glycoproteins IIb-IIIa or GPIIb-IIIa Receptors or Integrin alpha-IIb beta-3 or Integrin alphaIIbbeta3 or GPIIB IIIA))
#62.	MeSH DESCRIPTOR Platelet Glycoprotein GPIIb-IIIa Complex EXPLODE ALL TREES
#63.	MeSH DESCRIPTOR Receptors, Fibrinogen EXPLODE ALL TREES
#64.	((Abciximab or Reopro or Eptifibatide or Integrelin or Integrilin or Intrifiban or Tirofiban or Aggrastat))
#65.	MeSH DESCRIPTOR Adrenergic beta-Antagonists EXPLODE ALL TREES
#66.	((propranolol or angilol or inderal-la or half-inderal or inderal or bedranol or prograne or slo-pro or acebutolol or sectral or atenolol or tenormin or bisoprolol or cardicor or emcor or carvedilol or eucardic or celiprolol or celectol or co-tenidone or tenoret or tenoretic or esmolol or brevibloc or labetalol or trandate or metoprolol or betaloc or lopresor or nadolol or corgard or nebivolol or nebilet or hypoloc or oxprenolol or trasicor or slow-trasicor or pindolol or visken or sotalol or beta-cardone or sotacor or timolol or betim))
#67.	(MeSH DESCRIPTOR propranolol)
#68.	(MeSH DESCRIPTOR acebutolol)
#69.	(MeSH DESCRIPTOR atenolol)
#70.	(MeSH DESCRIPTOR bisoprolol)
#71.	(MeSH DESCRIPTOR celiprolol)
#72.	(MeSH DESCRIPTOR labetalol)
#73.	(MeSH DESCRIPTOR metoprolol)
#74.	(MeSH DESCRIPTOR nadolol)
#75.	(MeSH DESCRIPTOR nebivolol)
#76.	(MeSH DESCRIPTOR oxprenolol)
#77.	(MeSH DESCRIPTOR pindolol)
#78.	(MeSH DESCRIPTOR sotalol)
#79.	(MeSH DESCRIPTOR timolol)
#80.	((beta adj3 block*))
#81.	((b adj3 block*))
#82.	((beta adj2 antagonist*))
#83.	MeSH DESCRIPTOR Antithrombins
#84.	(Antithrombin*)
#85.	((thrombin adj3 inhibitor*))
#86.	MeSH DESCRIPTOR Hirudins
#87.	(Hirudin*)
#88.	(Hirulog)
#89.	(Bivalirudin)
#90.	#54 OR #55 OR #56 OR #57 OR #58 OR #59 OR #60 OR #61 OR #62 OR #63 OR #64 OR #65 OR #66 OR #67 OR #68 OR #69 OR #70 OR #71 OR #72 OR #73 OR #74 OR #75 OR #76 OR #77 OR #78 OR #79 OR #80 OR #81 OR #82 OR #83 OR #84 OR #85 OR #86 OR #87 OR #88 OR #89
#91.	(#23 AND (#53 OR #90))

Appendix C. Clinical evidence selection

Figure 1Flow chart of clinical study selection for the review of drug-eluting stents in adults with acute coronary syndromes, including those with unstable angina or NSTEMI undergoing percutaneous coronary intervention and those with STEMI undergoing primary percutaneous coronary intervention

Appendix D. Clinical evidence tables

Download PDF (966K)

Appendix E. Forest plots

E.1. Drug-eluting stents (DES) versus bare metal stents (BMS)

Figure 2All-cause mortality (≤1 year)

Figure 3All-cause mortality (>1-3 years)

Figure 4Cardiac mortality (≤1 year)

Figure 5Cardiac mortality (>1-3 years)

Figure 6Target vessel failure (≤1 year)

Figure 7Target vessel failure (>1-3 years)

Figure 8Target vessel revascularisation (≤1 year)

Di Lorenzo - data is TLR

Laarman 2006 - data is TLR

Bonna - data is TLR

Strozzi - data is TLR

Figure 9Target vessel revascularisation (>1-3 years)

Di Lorenzo - data is TLR

Laarman 2006 - data is TLR

Figure 10Stent thrombosis – definite or probable (≤1 year)

Figure 11Stent thrombosis – definite or probable (>1-3 years)

Figure 12Myocardial infarction (≤1 year)

Figure 13Myocardial infarction (>1-3 years)

Figure 14Bleeding(≤1 year)

Figure 15Bleeding (major) (>1-3 years)

Figure 16Bleeding (minor) (>1-3 years)

Figure 17Minimal luminal diameter (≤1 year)

Figure 18Minimal luminal diameter – unspecified (≤1 year)

E.1.1. Minimal important differences for continuous outcomes

The MID values reported in Table 15 were used to assess imprecision for the various continuous outcomes included in this evidence review.

Table 15Minimal important difference: DES versus BMS

Outcomes	Minimal important difference (MID)
Minimal luminal diameter (≤1 year) (in-segment)	0.35
Minimal luminal diameter (≤1 year) (in-stent)	0.40
Minimal luminal diameter (≤1 year) (in-lesion)	0.35
Minimal luminal diameter (≤1 year) (proximal edge)	0.33
Minimal luminal diameter (≤1 year) (distal edge)	0.36
Minimal luminal diameter - unspecified (≤1 year)	0.33

Appendix F. GRADE tables

Table 16Clinical evidence profile: Drug eluting stents (DES) versus bare metal stents (BMS)

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	DES	BMS	Relative (95% CI)	Absolute	Quality	Importance
All-cause mortality (follow-up up to1 year)
22	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious³	none	349/7800 (4.5%)	309/6249 (4.9%)	see comment⁵	2 fewer per 1000 (from 9 fewer to 5 more)	⨁⨁◯◯ LOW	CRITICAL
All-cause mortality (follow-up 1-3 years)
12	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	386/8032 (4.8%)	284/4967 (5.7%)	RR 0.87 (0.75 to 1.01)	7 fewer per 1000 (from 14 fewer to 1 more)	⨁⨁◯◯ LOW	CRITICAL
Cardiac mortality (follow-up up to 1 year)
14	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	242/6786 (3.6%)	210/5331 (3.9%)	RR 0.98 (0.82 to 1.17)	1 fewer per 1000 (from 7 fewer to 7 more)	⨁⨁⨁◯ MODERATE	CRITICAL
Cardiac mortality (follow-up 1-3 years)
10	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	222/7695 (2.9%)	176/4721 (3.7%)	RR 0.85 (0.70 to 1.03)	6 fewer per 1000 (from 11 fewer to 1 more)	⨁⨁◯◯ LOW	CRITICAL
Target vessel failure (follow-up up to 1 year)
4	randomised trials	serious¹	serious⁴	no serious indirectness	serious²	none	108/1016 (10.6%)	168/1025 (16.4%)	RR 0.62 (0.44 to 0.88)	62 fewer per 1000 (from 20 fewer to 92 fewer)	⨁◯◯◯ VERY LOW	CRITICAL
Target vessel failure (follow-up 1-3 years)
3	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	51/356 (14.3%)	90/347 (25.9%)	RR 0.55 (0.41 to 0.74)	117 fewer per 1000 (from 67 fewer to 153 fewer)	⨁⨁⨁◯ MODERATE	CRITICAL
Target vessel revascularisation (follow-up up to 1 year)
18	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	378/7205 (5.2%)	565/5653 (10%)	RR 0.52 (0.46 to 0.59)	48 fewer per 1000 (from 41 fewer to 54 fewer)	⨁⨁⨁◯ MODERATE	CRITICAL
Target vessel revascularisation (follow-up 1-3 years)
13	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	703/9602 (7.3%)	713/5539 (12.9%)	RR 0.52 (0.47 to 0.57)	62 fewer per 1000 (from 55 fewer to 68 fewer)	⨁⨁⨁◯ MODERATE	CRITICAL
Stent thrombosis – Definite or probable (follow-up up to 1 year)
12	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	163/6466 (2.5%)	168/4939 (3.4%)	RR 0.71 (0.57 to 0.89)	10 fewer per 1000 (from 4 fewer to 15 fewer)	⨁⨁◯◯ LOW	CRITICAL
Stent thrombosis - Definite or probable (follow-up 1-3 years)
12	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	218/9228 (2.4%)	147/5162 (2.8%)	RR 0.80 (0.64 to 0.99)	6 fewer per 1000 (from 0 fewer to 10 fewer)	⨁⨁◯◯ LOW	CRITICAL
Myocardial infarction (follow-up up to 1 year)
20	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	148/5438 (2.7%)	244/5342 (4.6%)	see comment⁵	18 fewer per 1000 (from 12 fewer to 23 fewer)	⨁⨁⨁◯ MODERATE	CRITICAL
Myocardial infarction (follow-up 1-3 years)
10	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	143/5552 (2.6%)	161/3904 (4.1%)	RR 0.66 (0.53 to 0.83)	14 fewer per 1000 (from 7 fewer to 19 fewer)	⨁⨁◯◯ LOW	CRITICAL
Bleeding - Unspecified (follow-up up to 1 year)
2	randomised trials	serious¹	no serious inconsistency	no serious indirectness	very serious²	none	18/716 (2.5%)	26/751 (3.5%)	RR 0.73 (0.41 to 1.31)	9 fewer per 1000 (from 20 fewer to 11 more)	⨁◯◯◯ VERY LOW	IMPORTANT
Bleeding - Major (follow-up up to 1 year)
6	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	66/4090 (1.6%)	67/3305 (2%)	RR 0.79 (0.56 to 1.11)	4 fewer per 1000 (from 9 fewer to 2 more)	⨁⨁◯◯ LOW	IMPORTANT
Bleeding - Minor (follow-up up to 1 year)
5	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	85/3691 (2.3%)	92/2904 (3.2%)	RR 0.84 (0.63 to 1.12)	5 fewer per 1000 (from 12 fewer to 4 more)	⨁⨁◯◯ LOW	IMPORTANT
Bleeding - Major (follow-up 1-3 years)
2	randomised trials	serious¹	serious⁴	no serious indirectness	very serious²	none	238/3652 (6.5%)	78/1452 (5.4%)	RR 0.99 (0.63 to 1.57)	1 fewer per 1000 (from 20 fewer to 31 more)	⨁◯◯◯ VERY LOW	CRITICAL
Bleeding - Minor (follow-up 1-3 years)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	very serious²	none	24/1549 (1.5%)	13/765 (1.7%)	RR 0.91 (0.47 to 1.78)	2 fewer per 1000 (from 9 fewer to 13 more)	⨁◯◯◯ VERY LOW	IMPORTANT
Minimal luminal diameter - In-segment (follow-up up to 1 year; Better indicated by lower values)
2	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	177	169	-	MD 0.53 higher (0.4 to 0.65 higher)	⨁⨁⨁◯ MODERATE	IMPORTANT
Minimal luminal diameter - In-stent (follow-up up to 1 year; Better indicated by lower values)
5	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	554	549	-	MD 0.68 higher (0.6 to 0.77 higher)	⨁⨁⨁◯ MODERATE	IMPORTANT
Minimal luminal diameter - In-lesion (follow-up up to 1 year; Better indicated by lower values)
2	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	345	350	-	MD 0.43 higher (0.32 to 0.53 higher)	⨁⨁◯◯ LOW	IMPORTANT
Minimal luminal diameter - Proximal edge (follow-up up to 1 year; Better indicated by lower values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	19	18	-	MD 0.12 lower (0.21 lower to 0.45 higher)	⨁⨁◯◯ LOW	IMPORTANT
Minimal luminal diameter - Distal edge (follow-up up to 1 year; Better indicated by lower values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	very serious²	none	20	20	-	MD 0.05 lower (0.39 lower to 0.29 higher)	⨁◯◯◯ VERY LOW	IMPORTANT
Minimal luminal diameter - Unspecified (follow-up up to 1 year; Better indicated by lower values)
7	randomised trials	serious¹	very serious⁴	no serious indirectness	serious²	none	3369	1904	-	MD 0.18 higher (0.05 to 0.32 higher)	⨁◯◯◯ VERY LOW	IMPORTANT

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias
2: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs.
3: Imprecision was assessed by calculating the optimal information size and graded as follows: <80% - very serious imprecision, 80-90%- serious imprecision, >90%– no imprecision
4: Downgraded by 1 or 2 increments because heterogeneity, I2= > 50%, p= > 0.04, unexplained by subgroup analysis
: No relative effect due to 0 events. Risk difference calculated in Review Manager

Appendix G. Health economic evidence selection

Figure 19Flow chart of health economic study selection for the guideline

* Non-relevant population, intervention, comparison, design or setting; non-English language

Review A = dual-antiplatelet therapy; Review B = early invasive investigation for UA/NSTEMI; Review C = antithrombins in UA/NSTEMI; Review D = bivalirudin in STEMI; Review E = multi-vessel PCI; Review F = drugeluting stents; Review G = combination of antiplatelets and anticoagulants; Review H = beta-blocker therapy.

Appendix H. Health economic evidence tables

Download PDF (317K)

Appendix I. Excluded studies

I.1. Excluded clinical studies

Table 17Studies excluded from the clinical review

Study	Exclusion reason
Ardissino 2004⁴	Incorrect population (<50% ACS)
Ahmed 2012¹	Incorrect study design
Alfonso 2008²	Incorrect study design (pooled analysis)
Aoki 2009³	Incorrect comparison
Ariotti 2016⁵	Incorrect study design (subgroup analysis)
Arroyo 2014⁶	Study protocol
Belkacemi 2012¹¹	Incorrect intervention
Belkacemi 2012¹²	Incorrect intervention
Bonaa 2016¹⁵	No extractable outcome data
Brener 2015¹⁶	Incorrect comparison
Brugaletta 2013²³	No extractable outcome data
Carrier 2017²⁵	Incorrect study design (subgroup analysis)
Chacko 2009²⁶	No relevant extractable outcome data
Costa 2015²⁹	Incorrect comparison
Crimi 2016³⁰	Incorrect study design (subgroup analysis)
Darkahian 2014³¹	Incorrect intervention
Dominguez Franco 2008³⁷	Incorrect study design
Dudek 2013³⁸	Incorrect study design (subgroup analysis)
Ellis 2009⁴⁰	No relevant extractable outcome data
Erglis 2007⁴¹	Incorrect population
Garg 2011⁴³	Incorrect study design (subgroup analysis)
Garot 2017⁴⁴	Incorrect population
Holmvang 2013⁴⁹	No relevant extractable outcome data
Ielasi 2015⁵⁰	Incorrect comparison (subgroup analysis for age)
Ischinger 2006⁵¹	No relevant extractable outcome data
Jimenez-Quevedo, 2013⁵³	No relevant extractable outcome data
Kaiser 2005⁵⁴	Incorrect population
Kandzari 2013⁵⁸	Incorrect study design (pooled analysis)
Kaul 2015⁵⁹	Incorrect comparison
Kelbaek 2008⁶⁰	Incorrect population
Kim 2010⁶²	Incorrect intervention
Konig 2007⁶³	Incorrect intervention
Kurz 2015⁶⁴	Incorrect study design (subgroup analysis)
La Manna 2011⁶⁶	Incorrect comparison
Ledwoch 2017⁶⁸	Incorrect study design
Lemos 2012⁷⁰	Incorrect population
Lemos 2009⁷¹	Incorrect population
Li 2004⁷²	Abstract only
Mehilli 2011⁷⁴	Incorrect population
Menozzi 2009⁷⁷	Incorrect population
Morice 2017⁷⁸	Incorrect study design (subgroup analysis)
Musto 2013⁷⁹	No relevant extractable outcome data
Park 2013⁸⁴	Study protocol
Pedersen 2014⁸⁵	Incorrect study design (subgroup analysis)
Pitt 2007⁸⁶	Abstract only
Raber 2016 ⁸⁸	Abstract only
Rebeiz 2009⁹²	No relevant extractable outcome data
Ribichini 2009⁹⁷	Study protocol
Ribichini, 2013⁹⁸	No relevant extractable outcome data
Rodriguez 2009⁹⁹	Incorrect intervention
Rubartelli 2010¹⁰¹	Incorrect population
Silber 2011¹⁰⁷	Incorrect population
Sinning 2012¹⁰⁸	No relevant extractable outcome data
Spaulding 2011¹¹⁰	No relevant extractable outcome data
Storger 2004¹¹⁵	Incorrect population
Tierala 2006¹¹⁹	Abstract only
Tomai 2014¹²⁰	No relevant extractable outcome data
Van den Branden 2012¹²⁷	No relevant extractable outcome data
Vink 2011¹³⁰	No relevant extractable outcome data
Wiemer, 2010¹³²	No relevant extractable outcome data
Wijnbergen 2014¹³⁴	No relevant extractable outcome data
Witzenbichler 2011¹³⁶	Incorrect study design (subgroup analysis)
Zellweger 2012¹³⁹	Incorrect comparison
Zellweger 2008¹³⁸	Incorrect comparison

I.2. Excluded health economic studies

Published health economic studies that met the inclusion criteria (relevant population, comparators, economic study design, published 2003 or later and not from non-OECD country or USA) but that were excluded following appraisal of applicability and methodological quality are listed below. See the health economic protocol for more details.

Table 18Studies excluded from the health economic review

Reference	Reason for exclusion
Bagust 2006⁸	This study was assessed as partially applicable with potentially serious limitations. However, a more applicable UK analysis⁴⁸ was available that updated this analysis with more evidence therefore this study was selectively excluded.
Baschet 2006⁹	This study was rated as partially applicable with potentially serious limitations. However, given that a more applicable analysis¹³⁵ comparing drug-eluting with bare metal stents that included the same RCTs was available this study was selectively excluded.
Baumler 2012¹⁰	Excluded as rated very serious limitations due to being a model where treatment effects are based on a study that does not meet clinical review inclusion criteria. Also partially applicable, reasons include: German setting may not reflect current NHS context.
Brophy 2004²⁰	This study was assessed as partially applicable with potentially serious limitations. However, given that a more applicable UK analysis⁴⁸ comparing drug-eluting stents with bare-metal stents based on the same RCTs was available, this study was selectively excluded.
Brophy 2005²¹	This study was assessed as partially applicable with potentially serious limitations. However, given that a more applicable UK analysis⁴⁸ comparing drug-eluting stents with bare-metal stents based on the same RCTs was available, this study was selectively excluded.
Ekman 2006³⁹	This study was assessed as partially applicable with potentially serious limitations. However, a more applicable UK analysis⁴⁸ was available that included the same RCT; therefore this study was selectively excluded.
Goeree 2009⁴⁵	Excluded as rated very serious limitations due to being a model where treatment effects are based on a study that does not meet clinical review inclusion criteria. Also partially applicable, reasons include: Canadian setting may not reflect current NHS context.
Jahn 2010⁵²	Excluded as rated very serious limitations due to being a model where treatment effects are based on studies that do not meet clinical review inclusion criteria. Also partially applicable, reasons include: Austrian perspective may not reflect current NHS context.
Kaiser 2005⁵⁴	This study was assessed as partially applicable with potentially serious limitations. However, a more applicable UK analysis was available that incorporated the same RCT;⁴⁸ therefore this study was selectively excluded.
Kuukasjarvi 2007⁶⁵	This study was assessed as partially applicable with potentially serious limitations. However, given that a more applicable UK analysis comparing drug-eluting stents with bare-metal stents based on the same RCTs⁴⁸ was available, this study was selectively excluded.
Lee 2014⁶⁹	Excluded as rated very serious limitations due to being a model where treatment effects are based on a study that does not meet clinical review inclusion criteria. Also partially applicable, reasons include: Korean setting may not reflect current NHS context.
Poder 2017⁸⁷	This study was assessed as partially applicable with potentially serious limitations. However, given there were more applicable analyses comparing drug-eluting stents with bare-metal stents with the relevant health outcomes this study was selectively excluded. The analysis was a cost-benefit analysis and did not use QALYs as the health outcome.
Suh 2013¹¹⁷	This study was assessed as partially applicable with potentially serious limitations. However, given there were more applicable analyses comparing drug-eluting stents with bare-metal stents with the relevant health outcomes this study was selectively excluded. The analysis was a cost-comparison and did not use QALYs as the health outcome.
Tarricone 2004¹¹⁸	This study was assessed as partially applicable with potentially serious limitations. However, given that a more applicable UK analysis comparing drug-eluting stents with bare-metal stents based on the same RCTs⁴⁸ was available, this study was selectively excluded.
Van Hout 2005¹²⁹	This study was assessed as partially applicable with potentially serious limitations. However, a more applicable UK analysis was available that incorporated the same RCT;⁴⁸ therefore this study was selectively excluded.

Tables

Table 1PICO characteristics of review question

Population	Patients with UA/NSTEMI and those with STEMI intended for treatment with a stent
Intervention(s)	Drug eluting stents including: Sirolimus Everolimus Paclitaxel Rapamycin Paclitaxel & Cilostazol Ridaforolimus Novolimus Zotarolimus
Comparison(s)	Bare metal stents including: Cobalt Chronium Platinium Chronium Stainless Steel
Outcomes	CRITICAL Time points: early ≤1 and later >1-3 year All-cause mortality Cardiac mortality TVF- target vessel failure TLR and TVR – target lesion and target vessel revascularisation Stent thrombosis (definite and/or probable) (record if assessed using optical coherence tomography (OCT), Intravascular ultrasound (IVUS) or angiography) Myocardial infarction Health-related quality of life including EQ5D and SF-36. MPORTANT Bleeding- Where possible, bleeding outcomes will be categorised into: Major bleeding (including BARC 3-5 and as reported by author) Minor bleeding (including BARC 2, TIMI and as reported by author). The following hierarchy of bleeding scales will be used: BARC Author’s definition TIMI GUSTO MLD - Minimal lumen diameter (measuring how much restenosis there is)-surrogate marker for TLR and TVR
Study design	Randomised Controlled Trials (RCT) Systematic Reviews (SR) of RCTs

Table 2Summary of evaluated outcomes in included studies

Study	No. of participa nts	Country	All-cause mortality		Cardiac mortality		TVF		TLR/TVR		MI		Stent thrombosis		MLD		Bleeding
Study	No. of participa nts	Country	1 yr	+1 yr	1 yr	+1 yr	1 yr	+1 yr	1 yr	+1 yr	1 yr	+1 yr	1 yr	+1 yr	1 yr	+1 yr	1 yr	+1 yr
Brilakis 2009¹⁹: SOS	80	USA, Greece	Y	Y	N	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	N	N
Brilakis 2018¹⁷: DIVA	597	USA	Y	Y	Y	Y	N	N	Y	Y	Y	Y	Y	Y	N	N	Y	Y
Chechi 2007 ²⁷	80	Italy	Y	N	N	N	N	N	Y	N	Y	N	Y	N	Y	N	N	N
de Belder 2014³²: XIMA	800	UK, Spain	Y	N	Y	N	N	N	Y	N	Y	N	N	N	N	N	Y	N
Di Lorenzo 2009³⁴: PASEO	270	Italy	Y	Y	N	N	N	N	Y	Y	Y	Y	Y	Y	N	N	N	N
Diaz de la Llera 2007 ³⁵	120	Spain	Y	N	N	N	N	N	Y	N	N	N	Y	N	N	N	N	N
Guagliumi 2010⁴⁶: OCTAMI	44	USA, Italy	Y	N	N	N	N	N	Y	N	Y	N	Y	N	N	N	N	N
Han 2007 ⁴⁷	200	Chile	N	N	Y	N	N	N	N	N	Y	N	Y	N	N	N	N	N
Kaiser 2010⁵⁵: BASKETPROVE	2314	Multinational	N	Y	N	Y	N	N	N	Y	N	N	N	Y	N	N	N	N
Kaiser 2015⁵⁶: BASKETPROVE II	2291	Multinational	N	Y	N	Y	N	N	N	Y	N	Y	N	Y	N	N	N	N
Kelbaek 2008⁶¹: DEDICATION	626	Denmark	Y	Y	Y	Y	N	N	Y	Y	Y	Y	N	N	Y	N	N	N
Laarman 2006⁶⁷: PASSION	619	Netherlands	Y	Y	Y	Y	N	N	Y	Y	Y	Y	Y	Y	N	N	N	N
Menichelli 2007⁷⁶: SESAMI	320	Italy	Y	Y	N	N	N	N	Y	Y	Y	Y	Y	Y	N	N	N	N
Raber 2012⁹⁰: COMFORTABLE	1161	Multinational	Y	Y	Y	Y	N	N	N	Y	N	N	Y	Y	Y	Y	N	N
Remkes 2016⁹⁴: ELISA 3 trial	474	Netherlands	N	N	N	N	N	N	N	Y	N	N	N	N	N	N	N	N
Ribamar Costa 2012 ⁹⁵	40	Brazil	Y	N	N	N	N	N	N	N	Y	N	Y	N	Y	N	N	N
Ribichini 2011⁹⁶: CEREADES	250	Italy	Y	N	Y	N	N	N	Y	N	Y	N	N	N	N	N	N	N
Rodriguez 2011¹⁰⁰: EUCATAX	422	Argentina	Y	N	Y	N	Y	N	Y	N	Y	N	Y	N	N	N	N	N
Sabate 2012¹⁰⁴ EXAMINATION	1498	Spain, Italy, Netherlands	Y	Y	Y	Y	N	N	Y	Y	N	N	Y	Y	N	N	Y	Y
Sanchez 2010¹⁰⁵: GRACIA-3	433	Spain	N	N	Y	N	N	N	N	N	Y	N	Y	N	Y	N	Y	N
Spaulding 2006¹⁰⁹: TYPHOON	715	Multinational	Y	N	Y	N	Y	N	N	N	Y	N	Y	N	Y	N	N	N
Steinwender 2008 ¹¹¹	16	Austria	Y	N	N	N	N	N	N	N	N	N	Y	N	Y	N	N	N
Stone 2009¹¹²: HORIZONSAMI	3006	Multinational	Y	Y	Y	Y	N	N	Y	Y	N	N	Y		Y	N	N	Y
Strozzi 2007 ¹¹⁶	119	Croatia	Y	N	N	N	N	N	Y	N	Y	N	N	N	Y	N	N	N
Valgimigli 2008¹²²: MULTISTRATEGY trial	744	Multinational	Y	Y	Y	Y	N	N	Y	Y	Y	N	N	Y	N	N	Y	N
Valgimigli 2014¹²⁶: PRODIGY	2013	Italy	N	N	N	N	N	Y	N	N	N	N	N	Y	N	N	N	N
Valgimigli 2015¹²⁵: ZEUS trial	1606	Multinational	Y	N	Y	N	N	N	Y	N	Y	N	Y	N	N	N	Y	N
van der Hoeven 2008¹²⁸: MISSION	310	Netherlands	Y	Y	Y	Y	Y	Y	N	N	Y	Y	N	Y	Y	N	N	N
Wijnbergen 2012¹³³: DEBATER	907	Netherlands	Y	N	N	N	N	N	Y	N	N	N	Y	N	N	N	Y	N

: Green boxes = study evaluated outcome; Grey boxes = study did not evaluate outcome; Y= yes (evaluated) N=no (not evaluated)

Table 3Summary of studies included in the evidence review

Study

Intervention and comparison

Population

Outcomes

Comments

Brilakis 2009¹⁹: SOS trial

Brilakis, 2011¹⁸

Intervention (n=39):

Drug-eluting stents: paclitaxel-eluting stents

Comparison (n=41):

Bare metal stents (type of bare metal stent used was unspecified in study)

n=80

People with 1 or more 50% to 99% de novo or re-stenotic lesions in an SVG that were between 2.5 and 4.0 mm in diameter and need for percutaneous coronary intervention (PCI)

Unstable angina: 37.5%

Non-STEMI: 22.5%

Age (mean): 66.5 years

Gender (male to female ratio): 80:0

Ethnicity: White 94%, Black 2.5%, Hispanic 1.5%

USA and Greece

All-cause mortality at 1 year and 35 months

Myocardial infarction at 1 year and 35 months

Target vessel revascularisation at 1 year and 35 months

Target lesion revascularisation at 1 year and 35 months

Target vessel failure at 1 year and 35 months

Stent thrombosis (definite or probable) at 1 year and 35 months

Minimal luminal diameter (in-segment, proximal edge, in-stent, distal edge) at 1 year and 35 months

Brilakis 2018¹⁷: DIVA trial

Intervention (n=292):

Drug-eluting stents: Any drug-eluting stent that was approved by the US Food and Drug Administration and clinically available at the time of enrolment could be used

Comparison (n=305):

Bare metal stents: Any bare metal stent that was approved by the US Food and Drug Administration and clinically available at the time of enrolment could be used

n=597

People with at least one significant de-novo SVG lesion (50–99% stenosis of a 2∙25–4∙5 mm diameter SVG) requiring percutaneous coronary intervention

Unstable angina: 31%

NSTEMI: 23.5%

Age (mean): 68.6 years

Gender (male to female ratio):

Ethnicity: White 88.5%, Black 8.5%, Hispanic 5.5%

USA

All-cause mortality at 1 year

Cardiac mortality at 1 year

Myocardial infarction at 1 year

Target vessel revascularisation at 1 year

Target lesion revascularisation at 1 year

Stent thrombosis (definite and definite or probable) at 1 year

Post-procedural bleeding at 1 year

Chechi 2007²⁷

Intervention (n=40):

Drug-eluting stents: paclitaxel-eluting stents

Comparison (n=40):

Bare metal stents (type of bare metal stent used was unspecified in study)

n=80

People with chest pain persisting for ≥30 minutes associated with ST elevation

Age (mean): 60.7 years

Gender (male to female ratio): 66:14

Ethnicity: Not reported

Italy

All-cause mortality at 7 months

Target lesion revascularisation at 7 months

Target vessel revascularisation at 7 months

Myocardial infarction at 7 months

Minimal lumen diameter at 7 months

Included in Cochrane Review (STEMI patients)

de Belder 2014³²: XIMA trial

Intervention (n=399):

Drug-eluting stents: everolimus-eluting stents

Comparison (n=401):

Bare metal stents (type of bare metal stent used was unspecified in study)

n=800

People with non–ST-segment elevation myocardial, infarction, unstable angina, and stable angina

Age (mean): 83.5 years

Gender (male to female ratio): 480:320

Ethnicity: Not reported

Multinational (United Kingdom and Spain)

All-cause mortality at 1 year

Cardiac mortality at 1 year

Target vessel revascularisation at 1 year

Myocardial infarction at 1 year

Major bleeding at 1 year

Included in Cochrane Review (STEMI patients)

Di Lorenzo 2009³⁴: PASEO trial

Di Lorenzo 2009³³

Intervention 1 (n=90):

Drug-eluting stents: paclitaxel-eluting stents

Intervention 2 (n=90):

Drug-eluting stents: sirolimus-eluting stents

Comparison (n=90):

Bare metal stents (type of bare metal stent used was unspecified in study)

n=270

People with chest pain for more than 30 minutes and ST-segment elevation

Age (mean): 62.5 years

Gender (male to female ratio): 190:80

Ethnicity: Not reported

Italy

All-cause mortality at 1 year, 2 years

Target lesion vascularisation at 1 year and 2 years

Myocardial infarction (re-infarction) at 1 year and 2 years

Stent thrombosis (definite, probable and possible) at one1 year, 2 years

Included in Cochrane Review (STEMI patients)

Diaz de la Llera 2007³⁵

Intervention (n=60):

Drug-eluting stents: sirolimus-eluting stents

Comparison (n=60):

Bare metal stents (type of bare metal stent used was unspecified in the study)

n=120

People with STEMI who were candidates for primary angioplasty

Age (mean): 64.5 years

Gender (male to female ratio): 95:19

Ethnicity: Not reported

Spain

All-cause mortality at 1 year

Target vessel revascularisation at 1 year

Stent thrombosis (late and acute or subacute) at 1 year

Included in Cochrane Review (STEMI patients)

Guagliumi 2010⁴⁶: OCTAMI trial

Intervention (n=33):

Drug-eluting stents: zotarolimus-eluting stents

Comparison (n=11):

Bare metal stents (type of bare metal stent used was unspecified in the study)

n=44

People presented with STEMI <12 h after symptom onset (prolonged chest pain for more than 20 min, unresponsive to nitroglycerin, and ST-segment elevation

Age (mean): 61.1 years

Gender (male to female ratio): 34:10

Ethnicity: Not reported

Italy and USA

All-cause mortality at 1 year

Target lesion revascularisation at 1 year

Target vessel revascularisation at 1 year

Myocardial infarction at 1 year

Included in Cochrane Review (STEMI patients)

Han 2007⁴⁷

Intervention (n=100):

Drug-eluting stents: tacrolimus-eluting stents

Comparison (n=100):

Bare metal stents (type of bare metal stent used was unspecified in the study)

n=200

People with symptomatic or documented myocardial ischemia, including acute myocardial infarction

Age (mean): 58.4 years

Gender (male to female ratio): 153:47

Ethnicity: Not reported

Chile

Cardiac mortality at 8 months

Myocardial infarction at 8 months

Included in Cochrane Review (STEMI patients)

Kaiser 2010⁵⁵: BASKET-PROVE trial

Intervention 1 (n=775):

Drug-eluting stents: first-generation sirolimus-eluting stents

Intervention 2 (n=774):

Drug-eluting stents: second-generation everolimus-eluting stent

Comparison (n=765):

Bare metal stents – cobalt chromium

n=2314

People who presented with chronic or acute coronary disease, who underwent angioplasty with stenting

Unstable angina/NSTEMI: 32.3%

NSTEMI: 32%

Age (mean): 66.5 years

Gender (male to female ratio): 1759: 555

Ethnicity: Not reported

Switzerland, Denmark, Austria, and Italy

All-cause mortality at 2 years

Cardiac mortality at 2 years

Myocardial infarction at 2 years

Target vessel revascularisation at 2 years

Stent thrombosis (definite; definite or possible) at 2 years

Major bleeding at 2 years

Minor bleeding at 2 years

Included in Cochrane Review (STEMI patients)

Kaiser 2015⁵⁶: BASKET-PROVE II trial

Intervention 1 (n=765):

Drug-eluting stents: second-generation biolimus-A9–eluting biodegradable-polymer stainlesssteel stents

Intervention 2 (n=765)

Drug-eluting stents: second-generation everolimus-eluting durable-polymer cobalt-chromium stents

Comparison (n=761):

Bare metal stents: newest-generation thin-strut BMS coated with a biocompatible siliconecarbide layer

n=2291

People presenting with chronic or acute coronary artery disease requiring angioplasty and stenting

STEMI: 29%

NSTEMI: 34%

Age (mean): 62.5 years

Gender (male to female ratio):

Ethnicity: 1787: 504

Switzerland, Denmark, Germany, and Austria

All-cause mortality at 2 years

Cardiac mortality at 2 years

Myocardial infarction at 2 years

Target vessel revascularisation at 2 years

Stent thrombosis (definite; definite or possible at 2 years

Included in Cochrane Review (STEMI patients)

Kelbaek 2008⁶¹: DEDICATION trial Kaltoft 2010⁵⁷

Intervention (n=313):

Drug-eluting stents: mixed use of drug eluting stents (47% were sirolimus-eluting, 40% were paclitaxel-eluting, and 13% were zotarolimus-eluting stents

Comparison (n=313):

Mixed use of bare metal stents (38% were made of cobalt alloy, 39% were stainless steel stents, and 23% were miscellaneous stainless steel stents

n=626

People with chest pain of >30 minute duration who had a cumulated ST-segment elevation

Age (mean): 62.05 years

Gender (male to female ratio): 458:168

Ethnicity: Not reported

Denmark

All-cause mortality at 1 year and 3 years

Cardiac mortality at 1 year and 3 years

Target lesion revascularisation at 1 year and 3 years

Target vessel revascularisation at 1 year and 3 years

Myocardial infarction at 1 year and 3 years

Minimal lumen diameter (in-lesion zone and in-stent zone) at 8 months

Included in Cochrane Review (STEMI patients)

Laarman 2006⁶⁷: PASSION trial

Dirksen 2008³⁶

Intervention (n=310):

Drug-eluting stents: paclitaxel-eluting stents

Comparison (n=309):

Bare metal stents (type of bare metal stent used was unspecified in the study)

n=619

People who had an acute myocardial infarction with ST-segment elevation (>20 minutes of chest pain and ST-segment elevation

Age (mean): 61 years

Gender (male to female ratio): 470:149

Ethnicity: Not reported

Netherlands

All-cause mortality at 1 year and 2 years

Cardiac mortality at 1 year and 2 years

Target lesion revascularisation at 1 year and 2 years

Myocardial infarction (re-current) at 1 year and 2 years

Included in Cochrane Review (STEMI patients)

Menichelli 2007⁷⁶: SESAMI trial

Violini 2010¹³¹

Intervention (n=160):

Drug-eluting stents: sirolimus-eluting stents

Comparison (n=160):

Bare metal stents (type of bare metal stent used was unspecified in the study)

n=320

People who had symptoms of acute MI for ≥30 minutes but ≤12 hours, and had ≥1 mm ST-segment elevation

Age (median): 62.5 years

Gender (male to female ratio): 128:32

Ethnicity: Not reported

Italy

All-cause mortality at 1 year and 3 years

Target lesion revascularisation at 1 year and 3 years

Target vessel revascularisation at 1 year and 3 years

Myocardial infarction (re-infarction) at 1 year and 3 years

Stent thrombosis (definite) at 1 year and 3 years

Included in Cochrane Review (STEMI patients)

Raber 2012⁹⁰: COMFORTABLE trial

Magro 2014⁷³

Raber 2016⁸⁸

Raber 2014⁹¹, Raber 2012⁸⁹

Intervention (n=578):

Drug-eluting stents: eluting biolimus from a biodegradable polylactic acid polymer

Comparison (n=583):

Bare metal stents (type of bare metal stent used was unspecified in the study)

n=1161

People with symptom onset within 24 hours and ST segment elevation

Age (mean): 60.6 years

Gender (male to female ratio): 918:243

Ethnicity: Not reported

Multinational (11 centres across: Denmark, Israel, Netherlands, Serbia, Switzerland, United Kingdom)

All-cause mortality at 1 year and 2 years

Cardiac mortality at 1 year and 2 years

Target lesion revascularisation at 1 year and 2 years

Target vessel revascularisation at 2 years

Stent thrombosis (definite and probable) at 1 year and 2 years

Minimal lumen diameter (in stent, in segment) at 12 months

Included in Cochrane Review (STEMI patients)

Remkes 2016⁹⁴: ELISA 3 trial

Intervention (n=234):

Drug-eluting stents: everolimus-eluting stents

Comparison (n=240):

Bare metal stents (type of bare metal stent used was unspecified in the study)

n=474

People with NSTEMI hospitalised with ischaemic chest pain or dyspnoea at rest, with the last episode occurring 24 hours or less

Age (mean): 65.27 years

Gender (male to female ratio): 351:123

Ethnicity: Not reported

Netherlands

Target vessel revascularisation at 2 years

Minimal lumen diameter at 9 months

Included in Cochrane Review (STEMI patients)

Ribamar Costa 2012⁹⁵

Intervention (n=20):

Drug-eluting stent (unspecified), study reports Cypher Select.

Comparison (n=20):

Bare metal stents (type of bare metal stent used was unspecified in the study)

n=40

People with ST-segment elevation myocardial infarction (MI) treated in the very early phase (primary or rescue percutaneous coronary intervention [PCI]), restenotic lesions, lesions located at grafts and at the left main stem

Age (mean): 56.3 years

Gender (male to female ratio): 28:12

Ethnicity: Not reported

Brazil

All-cause mortality at 1 year

Myocardial infarction at 1 year

Stent thrombosis at 1 year

Minimal lumen diameter (proximal edge and distal edge) at 1 year

Included in Cochrane Review (STEMI patients)

Ribichini 2011⁹⁶: CEREA-DES trial

Intervention (n=125):

Drug-eluting stents: paclitaxel-eluting stents or the sirolimus-eluting stents

Comparison (n=125):

Bare metal stents (type of bare metal stent used was unspecified in the study)

n=250

People showing significant coronary artery disease (either single or multi-vessel involvement), with signs or symptoms of myocardial ischemia, amenable for PCI

Unstable angina: 30.8%

NSTEMI: 26.8%

Age (mean): 63.99 years

Gender (male to female ratio): 210:40

Ethnicity: Not reported

Italy

All-cause mortality at 1 year

Cardiac mortality at 1 year

Myocardial infarction (non–Q-wave and Q-wave) at 1 year

Target lesion revascularisation at 1 year

Target vessel revascularisation at 1 year

Rodriguez 2011¹⁰⁰: EUCATAX trial

Intervention (n=211):

Drug-eluting stents: paclitaxel-eluting stents coated with a biodegradable polymer and glycocalyx

Comparison (n=211):

Bare metal stents (type of bare metal stent used was unspecified in the study)

n=422

People with a de novo stenosis in a major coronary artery

Unstable angina: 63.3%

Age (mean): 64.3 years

Gender (male to female ratio): 343:79

Ethnicity: Not reported

Argentina

All-cause mortality at 1 year

Cardiac mortality at 1 year

Myocardial infarction (acute) at 1 year

Target vessel revascularisation at 1 year

Target vessel failure at 1 year

Sabate 2012¹⁰⁴

EXAMINATION trial

Sabate 2011¹⁰³

Sabate, 2014¹⁰² (2 year results)

Brugaletta 2012²²:

Intervention (n=751):

Drug-eluting stents: everolimus-eluting stents

Comparison (n=747):

Bare metal stents – cobalt chromium balloon expandable bare metal stent

n=1498

People with STEMI within the first 48 hours after symptom onset, requiring emergent percutaneous coronary intervention

Age (mean): 61.2 years

Gender (male to female ratio): 1244:254

Ethnicity: Not reported

Spain, Italy, Netherlands

All-cause mortality at 1 year and 2 years

Cardiac mortality at 1 year and 2 years

Target lesion revascularisation at 1 year and 2 years

Target vessel revascularisation at 1 year and 2 years

Myocardial infarction at 1 year and 2 years

Stent thrombosis (definite/definite and probable) at 1 year and 2 years

Major bleeding at 1 year and 2 years

Minor bleeding at 1 year and 2 years

Included in Cochrane Review (STEMI patients)

Sanchez 2010¹⁰⁵: GRACIA-3 trial

Intervention (n=217):

Drug-eluting stents: paclitaxel-eluting stent with or without tirofiban.

Comparison (n=216):

Bare metal stents (type of bare metal stent used was unspecified in the study) - with or without tirofiban.

n=433

People with symptom onset within 12 hours, chest pain lasting more than 20 minutes and ST-segment elevation.

Age (mean): 61 years

Gender (male to female ratio): 358/75

Ethnicity: Not reported

Spain

Cardiac mortality at 1 year

Myocardial infarction at 1 year

Stent thrombosis (definite and probable) at 1 year

Minor bleeding at 1 year

Minimal lumen diameter at 1 year

Major bleeding at 1 year

Included in Cochrane Review (STEMI patients)

Spaulding 2006¹⁰⁹: TYPHOON 2006 trial

Intervention (n=356):

Drug-eluting stents: sirolimus-eluting stent

Comparison (n=359):

Bare metal stents (type of bare metal stent used was unspecified in the study)

n=715

People with symptoms which began less than 12 hours before catheterization and if the electrocardiogram showed ST segment elevation

Age (mean): 59.3 years

Gender (male to female ratio): 558:157

Ethnicity: Not reported

Multinational (Australia, Czech Republic, Denmark, France, Germany, Hungary, Israel, Italy, Latvia, Netherlands, Poland, Portugal, Spain, Switzerland, United Kingdom)

All-cause mortality at 1 year

Cardiac mortality at 1 year

Target vessel failure at 1 year

Myocardial infarction (re-current) at 1 year

Stent thrombosis at 1 years

Minimal lumen diameter (in stent and in lesion) at 8 months

Included in Cochrane Review (STEMI patients)

Steinwender 2008¹¹¹

Intervention (n=8):

Drug-eluting stents: sirolimus-eluting stents

Comparison (n=8):

Bare metal stents (type of bare metal stent used was unspecified in the study)

n=16

People with a first ST-elevation anterior myocardial infarction

Age (mean): 55.5 years

Gender (male to female ratio):12:4

Ethnicity: Not reported

Austria

All-cause mortality at 6 months

Minimal lumen diameter at 6 months

Included in Cochrane Review (STEMI patients)

Stone 2009¹¹²: HORIZONS-AMI trial

Mehran 2008⁷⁵

Stone 2010¹¹³

Stone 2011¹¹⁴

Intervention (n=2257):

Drug-eluting stents: paclitaxel-eluting stents

Comparison (n=749):

Bare metal stents (type of bare metal stent used was unspecified in the study)

n=3006

People presenting with ST-segment elevation myocardial infarction

Age (mean): 59.6 years

Gender (male to female ratio):

Ethnicity: Not reported

Multinational (Argentina, Austria, Germany, Israel, Italy, Netherlands, Norway, Poland, Spain, United Kingdom, USA)

All-cause mortality at 1 year and 3 years

Cardiac mortality at 1 year and 3 years

Target lesion revascularisation at 1 year and 3 years

Target vessel revascularisation (ischemia-driven) at 1 year and 3 years

Stent thrombosis at 1 year and 3 years

Major bleeding (including CABG) at 3 years

Minimal lumen diameter at 1 year

Included in Cochrane Review (STEMI patients)

Strozzi 2007¹¹⁶

Intervention (n=39):

Drug-eluting stents: sirolimus-eluting stents

Comparison (n=40):

Bare metal stents (type of bare metal stent used was unspecified in the study)

n=119

People with a diagnosis of acute coronary syndrome included acute myocardial infarction with ST elevation, prolonged angina for more than 20 minutes, or recurrent episodes at rest with indicators of cardiac ischemia or injury

Age (mean): 57.8 years

Gender (male to female ratio): 95:24

Ethnicity: Not reported

Croatia

All-cause mortality at 6 months

Target lesion revascularisation at 6 months

Myocardial infarction at 6 months

Minimal lumen diameter at 6 months

Included in Cochrane Review (STEMI patients)

Valgimigli 2008¹²²: MULTISTRATEGY trial

Valgimigli 2013¹²¹

Intervention (n=372):

Drug-eluting stents: sirolimus-eluting stents

Comparison (n=372):

Bare metal stents (type of bare metal stent used was unspecified in the study)

n=744

People with chest pain for longer than 30 minutes with an electrocardiographic ST-segment elevation

Age (mean): 63.9 years

Gender (male to female ratio): 565:179

Ethnicity: Not reported

Multinational (16 centres in: Italy, Argentina and Spain)

All-cause mortality at 8 months and 3 years

Cardiac mortality at 3 years

Target vessel revascularisation at 8 months and 3 years

Myocardial infarction at 8 months

Stent thrombosis (definite and/or probable) at 3 years

Major bleeding at 30 days

Minor bleeding at 30 days

Included in Cochrane Review (STEMI patients)

Valgimigli 2014¹²⁶: PRODIGY trial

Valgimigli 2010¹²³

Intervention 1 (n=1508):

Drug-eluting stents: everolimus-eluting stents, paclitaxel-eluting stents or zotarolimus eluting stents

Intervention 2 (n=505):

Drug-eluting stents: paclitaxel-eluting stents

Intervention 3 (n=502):

Drug-eluting stents: zotarolimus-eluting stents

Comparison (n=505):

Third-generation thin-strut bare metal stents(metal not specified in the study)

n=2013

People with chronic stable coronary artery disease or acute coronary syndromes, including non–ST-segment elevation myocardial infarction (MI) and ST-segment elevation MI

ACS: 73%

NSTEMI:22.5%

STEMI:32.3%

Unstable angina:18.5%

Age (mean): 68.5 years

Gender (male to female ratio): 1538:465

Ethnicity: Not reported

Italy

Target lesion revascularisation at 2 years

Target vessel revascularisation at 2 years

Stent thrombosis (definite or probable) at 2 years

Included in Cochrane Review (STEMI patients)

Valgimigli 2015¹²⁵: ZEUS trial

Valgimigli 2013¹²⁴

Intervention (n=802):

Drug-eluting stents: zotarolimus-eluting stents

Comparison (n=804):

Bare metal stents (type of bare metal stent used was unspecified in the study)

n=1606

People who underwent elective, urgent, or emergent percutaneous coronary intervention with intended stent implantation 63.3% ACS, 16% unstable angina, 27.5% NSTEMI, 19% STEMI

Age (median): 71.8 years

Gender (male to female ratio): 1133:473

Ethnicity: Not reported

Multinational (Netherlands, Italy, Greece, Hungary, Ireland, Switzerland, Portugal, Belgium)

All-cause mortality at 1 year

Cardiac mortality at 1 year

Target vessel revascularisation at 1 year

Target lesion revascularisation at 1 year

Myocardial infarction at 1 year

Stent thrombosis (definite and possible) at 1 year

Bleeding at 1 year

Included in Cochrane Review (STEMI patients)

van der Hoeven 2008¹²⁸: MISSION trial

Atary 2010⁷ Boden 2011¹³

Boden 2012¹⁴

Intervention (n=158):

Drug-eluting stents: sirolimus-eluting stents

Comparison (n=152):

Bare metal stents (type of bare metal stent used was unspecified in the study)

n=310

People with STEMI symptoms which started 9 hours before primary percutaneous coronary intervention

Age (mean): 59.2 years

Gender (male to female ratio): 241:69

Ethnicity: Not reported

Netherlands

All-cause mortality (cardiac and non-cardiac) at 1 year and 3 years

Cardiac mortality at 1 year and 3 years

Target vessel failure at 1 years and 3 years

Myocardial infarction (re-current MI spontaneous and procedure related) at 1 year and 3 years

Stent thrombosis (definite) at 3 years

Minimal lumen diameter (in-stent and in-segment) at 1 year

Included in Cochrane Review (STEMI patients)

Wijnbergen 2012¹³³: DEBATER trial

Intervention (n=441):

Drug-eluting stents: sirolimus-eluting stent

Comparison (n=466):

Bare metal stent (type of bare metal stent used was unspecified in the study – choice of the bare metal stent was left to the discretion of the operator)

n=907

People with STEMI, who resented within 12 hours of onset of symptoms

Age (mean): 61 years

Gender (male to female ratio): 668:202

Ethnicity: Not reported

Netherlands

All-cause mortality at 1 year

Target vessel revascularisation at 1 year

Stent thrombosis (definite and probable) at 1 year

Bleeding at 1 year

Included in Cochrane Review (STEMI patients)

Table 4Clinical evidence summary: Drug eluting stents (DES) versus bare metal stents (BMS)

Outcomes

No of Participants (studies) Follow up

Quality of the evidence (GRADE)

Relative effect (95% CI)

Anticipated absolute effects

Risk with BMS

Risk difference with DES (95% CI)

All-cause mortality

14049

(22 studies)

up to 1 year

⊕⊕⊝⊝

LOW¹^,³

due to risk of bias, imprecision

N/A⁵

49 per 1000

2 fewer per 1000

(from 9 fewer to 5 more)

All-cause mortality

12999

(12 studies)

1-3 years

⊕⊕⊝⊝

LOW¹^,²

due to risk of bias, imprecision

RR 0.87

(0.75 to 1.01)

57 per 1000

7 fewer per 1000

(from 14 fewer to 1 more)

Cardiac mortality

12117

(14 studies)

up to 1 year

⊕⊕⊕⊝

MODERATE¹

due to risk of bias

RR 0.98

(0.82 to 1.17)

39 per 1000

1 fewer per 1000

(from 7 fewer to 7 more)

Cardiac mortality

12416

(10 studies)

1-3 years

⊕⊕⊝⊝

LOW¹^,²

due to risk of bias, imprecision

RR 0.85

(0.70 to 1.03)

37 per 1000

6 fewer per 1000

(from 11 fewer to 1 more)

Target vessel failure

2041

(4 studies)

up to 1 year

⊕⊝⊝⊝

VERY LOW¹^,²^,⁴

due to risk of bias, inconsistency, imprecision

RR 0.62

(0.44 to 0.88)

164 per 1000

62 fewer per 1000

(from 20 fewer to 92 fewer)

Target vessel failure

703

(3 studies)

1-3 years

⊕⊕⊕⊝

MODERATE¹

due to risk of bias

RR 0.55

(0.41 to 0.74)

259 per 1000

117 fewer per 1000

(from 67 fewer to 153 fewer)

Target vessel revascularisation

12858

(18 studies)

up to 1 year

⊕⊕⊕⊝

MODERATE¹

due to risk of bias

RR 0.52

(0.46 to 0.59)

100 per 1000

48 fewer per 1000

(from 41 fewer to 54 fewer)

Target vessel revascularisation

15141

(13 studies)

1-3 years

⊕⊕⊕⊝

MODERATE¹

due to risk of bias

RR 0.52

(0.47 to 0.57)

129 per 1000

62 fewer per 1000

(from 55 fewer to 68 fewer)

Stent thrombosis - definite or probable

11405

(12 studies)

up to 1 year

⊕⊕⊝⊝

LOW¹^,²

due to risk of bias, imprecision

RR 0.71

(0.57 to 0.89)

34 per 1000

10 fewer per 1000

(from 4 fewer to 15 more)

Stent thrombosis - definite or probable

14390

(12 studies)

1-3 years

⊕⊕⊝⊝

LOW¹^,²

due to risk of bias, imprecision

RR 0.80

(0.64 to 0.99)

28 per 1000

6 fewer per 1000

(from 0 fewer to 10 fewer)

Myocardial infarction

10780

(20 studies)

up to 1 year

⊕⊕⊝⊝

⊕⊕⊕⊝

MODERATE¹

due to risk of bias

N/A⁵

46 per 1000

18 fewer per 1000

(from 12 fewer to 23 fewer)

Myocardial infarction

9456

(10 studies)

1-3 years

⊕⊕⊝⊝

LOW¹^,²

due to risk of bias, imprecision

RR 0.66

(0.53 to 0.83)

41 per 1000

14 fewer per 1000

(from 7 fewer to 19 fewer)

Bleeding - Unspecified

1467

(2 studies)

up to 1 year

⊕⊝⊝⊝

VERY LOW¹^,²

due to risk of bias, imprecision

RR 0.73

(0.41 to 1.31)

35 per 1000

9 fewer per 1000

(from 20 fewer to 11 more)

Bleeding - Major

7395

(6 studies)

up to 1 year

⊕⊕⊝⊝

LOW¹^,²

due to risk of bias, imprecision

RR 0.79

(0.56 to 1.11)

20 per 1000

4 fewer per 1000

(from 9 fewer to 2 more)

Bleeding - Minor

6595

(5 studies)

up to 1 year

⊕⊕⊝⊝

LOW¹^,²

due to risk of bias, imprecision

RR 0.84

(0.63 to 1.12)

32 per 1000

5 fewer per 1000

(from 12 fewer to 4 more)

Bleeding - Major

5104

(2 studies)

1-3 years

⊕⊝⊝⊝

VERY LOW¹^,²^,⁴

due to risk of bias, inconsistency, imprecision

RR 0.99

(0.63 to 1.57)

54 per 1000

1 fewer per 1000

(from 20 fewer to 31 more)

Bleeding - Minor

2314

(1 study)

1-3 years

⊕⊝⊝⊝

VERY LOW¹^,²

due to risk of bias, imprecision

RR 0.91

(0.47 to 1.78)

17 per 1000

2 fewer per 1000

(from 9 fewer to 13 more)

Minimal luminal diameter - In-segment

346

(2 studies)

up to 1 year

⊕⊕⊕⊝

MODERATE¹

due to risk of bias

The mean minimal luminal diameter - in-segment in the control groups was

1.745 mm

The mean minimal luminal diameter - in-segment in the intervention groups was

0.53 higher

(0.4 to 0.65 higher)

Minimal luminal diameter - In-stent

1103

(5 studies)

up to 1 year

⊕⊕⊕⊝

MODERATE¹

due to risk of bias

The mean minimal luminal diameter - in-stent in the control groups was

1.75 mm

The mean minimal luminal diameter - in-stent in the intervention groups was

0.68 higher

(0.60 to 0.77 higher)

Minimal luminal diameter - In-lesion

695

(2 studies)

up to 1 year

⊕⊕⊝⊝

LOW¹^,²

due to risk of bias, imprecision

The mean minimal luminal diameter - in-lesion in the control groups was

1.84 mm

The mean minimal luminal diameter - in-lesion in the intervention groups was

0.43 higher

(0.32 to 0.53 higher)

Minimal luminal diameter - Proximal edge

(1 study)

up to 1 year

⊕⊕⊝⊝

LOW¹^,²

due to risk of bias, imprecision

The mean minimal luminal diameter - proximal edge in the control groups was

2.86 mm

The mean minimal luminal diameter - proximal edge in the intervention groups was

0.12 lower

(0.45 lower to 0.21 higher)

Minimal luminal diameter - Distal edge

(1 study)

up to 1 year

⊕⊝⊝⊝

VERY LOW¹^,²

due to risk of bias, imprecision

The mean minimal luminal diameter - distal edge in the control groups was

2.85 mm

The mean minimal luminal diameter - distal edge in the intervention groups was

0.05 lower

(0.39 lower to 0.29 higher)

Minimal luminal diameter - Unspecified

5273

(7 studies)

up to 1 year

⊕⊝⊝⊝

VERY LOW¹^,²^,⁴

due to risk of bias, inconsistency, imprecision

The mean minimal luminal diameter - unspecified in the control groups was

2.25 mm

The mean minimal luminal diameter - unspecified in the intervention groups was

0.18 higher

(0.05 to 0.32 higher)

1: Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias
2: Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs
3: Imprecision was assessed by calculating the optimal information size and graded as follows: <80% - very serious imprecision, 80-90%- serious imprecision, >90%– no imprecision
4: Downgraded by 1 or 2 increments because heterogeneity, I2= > 50%, p= > 0.04, unexplained by subgroup analysis
5: No relative effect due to 0 events. Risk difference calculated in Review Manager

Table 5Health economic evidence profile: drug-eluting stents versus bare metal stents

Study	Applicability	Limitations	Other comments	Incremental cost	Incremental effects	Cost effectiveness	Uncertainty
Canoui-Poitrine 2009²⁴ (France)	Partially applicable^(a)	Potentially serious limitations^(b)	Within-trial analysis of French subgroup of the TYPHOON RCT with probabilistic analysis. QALYs estimated by attributing a QALY loss to all adverse events that occurred during follow-up.^(c) Cost-utility analysis (QALYs) / cost-effectiveness analysis (TVR avoided) Population: people presenting with STEMI less than 12 hours after the onset of chest pain, undergoing PCI. Comparators: Bare metal stents Drug eluting stents (sirolimus) Follow-up: 1 year	£911^(d)	−0.0006 QALYs −15.6% TVR	BMS dominates DES (lower cost and higher QALYs) £5,842 per repeat TVR avoided	No probabilistic analysis for QALY analysis. 54.9% of ICERs estimated remain under the threshold of £7,980 per repeat TVR avoided. One person in the DES arm had a heart transplant which considerably increased costs of the DES arm. Removing this incident resulted in an ICER of £4,635 per TVR avoided.
Hill 2007⁴⁸ (UK) ERG analysis for NICE TA152	Partially applicable^(e)	Potentially serious limitations^(f)	Decision analytic model based around differences in repeat revascularisation within 12 months. QALY differences arise due to lower QOL weights being attributed to those that have a repeat revascularisation. Mortality and long-term morbidity assumed to be unaffected. Cost-utility analysis (QALYs) Population: people with coronary artery disease revascularised in NHS hospitals - non-elective index PCI results presented here (assumed to equate to ACS) Comparators: Bare metal stents Drug eluting stents (Taxus, Cypher) Time horizon: 1 year	Narrow effectiveness ^(g) Taxus = £852^(h) Cypher = £919^(h) Broad effectiveness ^(g) Taxus = £795^(h) Cypher = £861^(h)	Narrow effectiveness ^(g) 0.002444 QALYs Broad effectiveness ^(g) 0.003251 QALYs	Narrow effectiveness ^(g) Taxus = £348,700 Cypher = £376,100 Broad effectiveness ^(g) Taxus = £244,400 Cypher = £264,800	No probabilistic analysis. A wide range of sensitivity analyses around baseline risks, relative risks, costs, utilities and other inputs were undertaken. The ICERs ranged from £185,300 to £702,200 per QALY gained. Additional results are presented after this table. A scenario exploring the absolute risk and difference in the costs of BMS and DES was undertaken. This showed that for nonelective patients with an absolute risk of 18% or more and a price difference of £300 the ICER ranged from DES being dominant to £24,000. This led to the previous recommendation in NICE TA152. A breakdown of these results is demonstrated in Table 7.
Schur 2018¹⁰⁶ (Spain)	Partially applicable⁽ⁱ⁾	Potentially serious limitations^(j)	Within-trial analysis of the EXAMINATION RCT 5 year data with modelled extrapolation and probabilistic analysis; incorporates mortality, MI, stent thrombosis and revascularisation. Cost-utility analysis (QALYs) Population: STEMI within the first 48 hours requiring emergent PCI (with vessel sizes of 2.25 to 4.00mm); 85% PPCI. Comparators: Bare metal stents Drug eluting stents (everolimus) Time horizon: lifetime (with treatment effect duration 5 years)	£455^(k)	0.10 QALYs	£4,180 per QALY gained	86.9% of simulations were below a threshold of £26,467 per QALY gained. ICERs in sensitivity analyses ranged from ~£3000 to ~£8000 per QALY gained. Analyses varying the different in stent costs found that if this was £116 there was no difference in lifetime costs.
Wisloff 2013¹³⁵ (Norway)	Partially applicable^(l)	Potentially serious limitations^(m)	Decision analytic model with treatment effects obtained from a published network meta-analysis, this included mortality, myocardial infarction and revascularisation. Cost-effectiveness analysis (life years) Population: people with STEMI, NSTEMI, unstable or stable angina undergoing PCI with stent Comparators: Bare metal stents Drug-eluting stents (sirolimus) Drug-eluting stents (paclitaxel) Time horizon: lifetime (with treatment effect for 5 years)	2−1: -£1,473⁽ⁿ⁾ 3-1: -£223⁽ⁿ⁾ 3−2: £1,250⁽ⁿ⁾	2−1: 0.003 life years 3-1: 0.151 life years 3−2: 0.148 life years	DES dominates (lower costs and higher life years) BMS 3 vs 2: £9,553 per life year gained	With a cost effectiveness threshold of <£8,571per life year gained SES had highest probability of being cost-effective. With a cost effectiveness threshold of >£8,571per life year gained PES had the highest probability of being cost-effective. An analysis was conducted assuming lifetime treatment effectiveness of DES demonstrated that PES was the most cost-effective option.
Zbinden 2017¹³⁷ (Switzerland)	Partially applicable^(o)	Potentially serious limitations^(p)	Within-trial analysis of a subgroup of BASKET-PROVE RCT with probabilistic analysis Cost-utility analysis (QALYs) based on within-trial analysis of EQ-5D data; also cost-effectiveness analysis (target lesion revascularisations avoided) Population: people with stable CAD or ACS undergoing PCI with at least one stent with a diameter ≥3mm and ≤15 mm lesion Comparators: Bare metal stents Drug eluting stents (Cypher, Xience) Follow-up: 2 years	£75^(q)	0.005 QALYs 0.083 TLRs avoided	£15,105 per QALY gained £1,986 per TLR avoided	QALY analysis Probability DES cost effective (£26,486 threshold): 52.0% TLR avoided analysis Probability DES cost effective (£5,297 threshold): 88.2% No deterministic sensitivity analysis.

: Abbreviations: BMS = bare-metal stent; DES = drug-eluting stent; ERG = evidence review group; ICER = incremental cost-effectiveness ratio; PCI = percutaneous coronary intervention; PES = paclitaxel-eluting stent; QALY = quality-adjusted life years; RCT = randomised controlled trial; SES = sirolimus-eluting stent; STEMI = ST segment elevation myocardial infarction; TLR = target lesion revascularisation; TVR = target vessel revascularisation
(a): 2007 French healthcare perspective may not reflect current UK context. Some methods used to derive quality of life weights are not in line with NICE reference case and where EQ5D has been used it is unclear if with the UK tariff.
(b): Within-trial analysis based on a French subgroup of a single trial (TYPHOON RCT) and so does not reflect full body of available evidence for this area and may not reflect real world UK context.. Time horizon of 1 year may not fully capture differences in costs and health outcomes as NGC review suggests effects continue beyond 1 year. It is unclear what is driving lower QALYs in the DES group as most outcomes favour DES; the only outcomes that are numerically worse in the DES group are ‘Other cardiac events’ which authors’ state includes things such as such as hospitalizations for chest pain without proof of ischaemia, acute pulmonary oedema or heart failure and stroke where 1 event occurred with DES and 0 with BMS. Utility scores are reported for the following events suggesting they were incorporated: angioplasty, CABG, MI, congestive heart failure, severe chest pain, stroke, implantable cardioverter defibrillator, carotid thromboendarterectomy, infrainguinal surgery, insulin-dependent diabetes mellitus, medulloblastoma tumour – non-metastatic, stomach ulcer, hip fracture, catheter ablation in patients with ventricular tachycardia.
(c): Utility scores are reported for angioplasty, CABG, MI, congestive heart failure, severe chest pain, stroke, implantable cardioverter defibrillator, carotid thromboendarterectomy, infrainguinal surgery, insulin dependent diabetes mellitus, medulloblastoma tumour – non-metastatic, stomach ulcer, hip fracture, catheter ablation in patients with ventricular tachycardia.
(d): 2007 French Euros converted to UK pounds.⁸³ Cost components included: index admission costs (stent costs, procedure cost, drug costs, ICU cost, ward costs, rehabilitation) and follow-up including medication and all repeat hospitalisation costs. (Cost of stents included in analysis (mean, median): BMS = £544, £439; DES = £1,587, £1,237).
(e): Resource use from 2000-2002 and 2004/05 UK unit costs may not reflect current UK practice. The analysis does not include the variety of drug-eluting stents currently available in the NHS as it only focuses on two types of stents (CYPHER and TAXUS) which dominated the market at the time.
(f): Analysis based on 7 RCTS (TAXUS I, TAXUS II, TAXUS IV, E-SIRIUS, RAVEL, SIRIUS and Pache) and so does not reflect full body of available evidence for this area and also includes studies stable patients that have been excluded from the clinical review for this guideline. Time horizon of 1 year may not fully capture differences in costs and health outcomes as NGC review suggests effects continue beyond 1 year and there may be benefits other than revascularisation that are not captured in the analysis..
(g): Different relative risks were applied based on ‘broad’ and ‘narrow’ estimates. ‘Broad’ estimates are based on cases involved any TLR/TVR irrespective of any other lesions/vessels revascularised (0.369) and ‘narrow’ estimates are based on cases involving TLR/TVR only (0.492).
(h): Cost components: stent costs, cost of angiography, follow-up appointments and repeat revascularisation cost. Stent costs: BMS = £291.95; DES effective list price Taxus = £997.50, Cypher = £1044.75; DES actual cost Taxus = £855.43, Cypher = £983.51.
(i): Spanish healthcare perspective and international resource use may not reflect current UK context. STEMI only. Discounting at 3% and use of Spanish EQ5D tariff not fully in line with NICE reference case.
(j): Within-trial analysis of a single RCT and so does not reflect full body of available evidence for this area. Baseline risks based on multinational RCT (Spain, Italy, Netherlands) and so may not be reflective of real world UK risk; although authors note that “The EXAMINATION trial had broad inclusion and few exclusion criteria to ensure an all-comers population of adult STEMI patients which is representative of routine clinical practice”.
(k): 2016 Spanish Euros converted to UK pounds.⁸³ Cost components included: type and number of stents; clinical events up to 5 years: MIs, stent thrombosis events, revascularisation procedures (PCI and CABG); annual CV outpatient treatment and drug costs during first 5 years (when clinical events accounted for explicitly); long-term annual CV treatment costs after year 5; 12 months antiplatelet therapy after revascularisation events. Cost of stents: BMS = £466; DES = £897.
(l): 2008 Norwegian healthcare perspective may not reflect current UK context. Analysis includes patients with stable coronary artery disease as well as ACS. 4% discount rate and measure of effect (life years) not in line with NICE reference case methods.
(m): Baseline risks are based on the overall CAD population in Scandinavia and so may differ from a UK ACS population. Treatment effects were based on both ACS and stable patients and so studies excluded from our review have been incorporated; additional studies have also been identified by the review undertaken for this guideline. The price of stents used in the model was not official prices and were obtained through personal communication with a cardiologist.
(n): 2008 Norwegian Kroner converted to UK pounds.⁸³ Cost components included: stent costs, costs of procedures and cost of medication. Cost of stents: BMS = £107; SES = £515; PES = £419.
(o): 2013 Swiss healthcare payer perspective and international resource use from 2007-2008 may not reflect the current UK context. Analysis includes patients with stable coronary artery disease as well as ACS (proportion not reported for analysis subgroups but for overall BASKET-PROVE RCT was 64% ACS). QALYs were derived using EQ-5D German population utility value set instead of the UK population value set.
(p): Within-trial analysis of subgroup of one RCT (BASKET-PROVE subgroup with stents >3mm and <15mm lesion length) and so does not reflect full body of available evidence for this area. Analysis was conducted on a retrospective subgroup. Incremental cost data is not numerically reported. Time horizon of 2 years may not fully capture differences in costs and health outcomes as NGC review suggests effects on revascularisations for ACS overall maintained at 1-3 year time point and approach to modelling may not fully capture benefits to patients e.g. if QALY losses are generally short-term following revascularisation. Unclear if survival incorporated when calculating QALYs per patient.
(q): Incremental cost data not reported numerically, but was calculated using reported incremental QALYs and ICER. 2013 Swiss Francs converted to UK pounds.⁸³ Cost components: stent costs, inpatient and outpatient procedures, only included costs of follow-up if it involved revascularisation. Cost of stents: BMS = £610; DES = £761.

Table 6Hill 2007 cost-effectiveness results for non-elective PCI patients

Prices	Effectiveness	Brand	Incremental cost	Incremental QALYs	ICER
Overall
Effective list	Narrow	Taxus	£852	0.002444	£348,700
		Cypher	£919	0.002444	£376,100
	Broad	Taxus	£795	0.003251	£244,400
		Cypher	£861	0.003251	£264,800
Actual	Narrow	Taxus	£651	0.002444	£266,200
		Cypher	£832	0.002444	£340,500
	Broad	Taxus	£595	0.003251	£182,900
		Cypher	£775	0.003251	£238,300
No risk factors
Effective list	Narrow	Taxus	£844	0.002155	£391,600
		Cypher	£909	0.002155	£421,900
	Broad	Taxus	£793	0.002867	£276,600
		Cypher	£858	0.002867	£299,200
Actual	Narrow	Taxus	£648	0.002155	£300,500
		Cypher	£825	0.002155	£382,600
	Broad	Taxus	£598	0.002867	£208,700
		Cypher	£774	0.002867	£269,900
1 risk factor
Effective list	Narrow	Taxus	£947	0.005332	£177,500
		Cypher	£1,032	0.005332	£193,500
	Broad	Taxus	£821	0.007095	£115,700
		Cypher	£905	0.007095	£127,600
Actual	Narrow	Taxus	£691	0.005332	£129,500
		Cypher	£921	0.005332	£172,800
	Broad	Taxus	£569	0.007095	£80,200
		Cypher	£796	0.007095	£112,200
2 risk factors
Effective list	Narrow	Taxus	£627	0.009716	£64.600
		Cypher	£709	0.009716	£73,000
	Broad	Taxus	£399	0.012928	£30,800
		Cypher	£478	0.012928	£37,000
Actual	Narrow	Taxus	£382	0.009716	£39,300
		Cypher	£603	0.009716	£62,100
	Broad	Taxus	£160	0.012928	£12,400
		Cypher	£375	0.012928	£29,000

(a): ICERs in bold indicate where drug-eluting stents are cost-effective at a threshold of £20,000.

Table 7Hill 2007 cost–effectiveness results for all non-elective patients (using mean number of stents implanted, 1.46 stents) by absolute risk of TVR and level of price premium for DES

Absolute risk (%)	Incremental cost per QALY by levels of price premium
	£100	£200	£300	£400	£500	£600	£700	£800
6	£18,000	£87,400	£156,800	£226,100	£295,500	£364,900	£434,200	£503,600
8	£2,100	£57,500	£112,800	£168,200	£223,600	£279,000	£334,300	£389,700
10	DES dominant	£37,400	£83,400	£129,400	£175,400	£221,400	£267,400	£313,400
10.04	DES dominant	£37,100	£83,000	£128,800	£174,700	£220,500	£266,400	£312,200
12	DES dominant	£23,000	£62,300	£101,600	£140,800	£180,100	£219,400	£258,600
14	DES dominant	£12,200	£46,400	£80,700	£114,900	£149,100	£183,300	£217,500
16	DES dominant	£3,800	£34,100	£64,300	£94,600	£124,900	£155,200	£185,400
18	DES dominant	DES dominant	£24,200	£51,300	£78,400	£105,500	£132,600	£159,700
20	DES dominant	DES dominant	£16,100	£40,600	£65,100	£89,600	£114,200	£138,700
22	DES dominant	DES dominant	£9,300	£31,700	£54,000	£76,400	£98,800	£121,100
24	DES dominant	DES dominant	£3,500	£24,100	£44,600	£65,200	£85,700	£106,300
26	DES dominant	DES dominant	DES dominant	£17,600	£36,600	£55,600	£74,500	£93,500
28	DES dominant	DES dominant	DES dominant	£12,000	£29,600	£47,200	£64,800	£82,400
30	DES dominant	DES dominant	DES dominant	£7,100	£23,500	£39,900	£56,300	£72,800
32	DES dominant	DES dominant	DES dominant	£2,700	£18,100	£33,500	£48,800	£64,200
34	DES dominant	DES dominant	DES dominant	DES dominant	£13,300	£27,700	£42,200	£56,600
36	DES dominant	DES dominant	DES dominant	DES dominant	£9,000	£22,600	£36,200	£49,800
38	DES dominant	DES dominant	DES dominant	DES dominant	£5,100	£18,000	£30,800	£43,700
40	DES dominant	DES dominant	DES dominant	DES dominant	£1,600	£13,800	£26,000	£38,100
42	DES dominant	DES dominant	DES dominant	DES dominant	-£1,600	£10,000	£21,500	£33,100
44	DES dominant	DES dominant	DES dominant	DES dominant	-£4,500	£6,500	£17,500	£28,500
46	DES dominant	DES dominant	DES dominant	DES dominant	-£7,100	£3,300	£13,800	£24,300

(b): ICERs in bold indicate where drug-eluting stents are cost-effective at a threshold of £20,000

Table 8Stent costs used in studies

Study	BMS cost	DES cost	Difference
Canoui-Poitrine 2009²⁴ (France)	£439	£1,237	£798
Hill 2007⁴⁸ (UK)	£292	Taxus = £997, Cypher = £1,045	£705 (Taxus), £753 (Cypher)
Schur 2018¹⁰⁶ (Spain)	£466	£897	£431
Wisloff 2013¹³⁵ (Norway)	£107	SES = £515, PES = £419	£408 (SES), £312 (PES)
Zbinden 2017¹³⁷ (Switzerland)	£610	£761	£151

Table 9Comparison of NGC meta-analysis results and treatment effects in economic studies

	NGC meta-analysis				Canoui-Poitrine 2009 (Typhoon trial - French subgroup)^(a)		Schur 2018 (Examination trial)^(b)				Zbinden 2017 (Basket prove trial)^(c)		Hill 2007 (model)^(d)		Wisloff 2013 (model)^(e)
	</= 12 months		1-3 years		1yr		2 year		5 year		1-3 yrs		1 year		6 month probabilities		Applied for 5 years
	BMS	RR DES	BMS	RR DES	BR BMS	RR DES	BR BMS	RR DES	BR BMS	HR DES	BR BMS	RR DES	BR BMS	RR DES	BR BMS first 6 months	BR BMS after 6 months	RR PES	RR SES
All-cause mortality	5%	0.95	6%	0.87	4%	0.69	5%	0.86	12%	0.72	4%	0.77			uncle ar	1%	0.89	1.0 5
TVR	10%	0.51	13%	0.52	22%	0.30	8%	0.61	10%	0.62	10%	0.39		0.43
Stent thrombosis	3%	0.71	3%	0.81	5%	0.90	3%	0.47	3%	0.64	1%	0.60
MI	5%	0.60	4%	0.66	2%	1.03	2%	0.77	4%	1.27	3%	0.49			6%	2%	1.05	0.8 1
All revasc					29%	0.39			16%	0.77			7% 11%	0.59 0.45	2%	2%	0.46	0.2 9

(a): Economic analysis was a within-trial analysis; data here is as reported in paper for the French subgroup of the Typhoon RCT used for the economic analysis
(b): Economic analysis was a within-trial analysis; 2 year data here is as reported in NGC met- analysis (to facilitate comparison with estimate from same timepoint); 5 year data is as reported in economic paper
(c): Economic analysis was a within-trial analysis of a subgroup of the Basket Prove RCT with >15mm lesion (a people in Basket prove had stent >3mm diameter); data for these outcomes was not reported for the subgroup and the results for the overall population are presented here.
(d): Economic analysis was a model. The all revascularisation data is what is reported as the model inputs; the TVR RR was used to estimate the all revasc effect by combining with real world data about repeat revascularisations. The first figures were what were calculated for the basecase initially; the second figures were the agreed best estimates following TA committee discussion.
(e): Economic analysis was a model; data here is as reported in the paper

Table 10UK unit costs of coronary stents: local costs and equivalent NHS supply chain costs

	Using local costs	Using NHS supply chain costs 1^(a)	Using NHS supply chain costs 2^(b)
Average DES cost (weighted by stent type usage)	£250^(c)	£348	£380
Typical BMS cost^(d)	£75	£87	£87
Difference	£175	£261	£293

: Source: Stent type usage from BCIS audit for 1st April 2017 to 31st March 2018 on people undergoing PCI for
: ACS; local stent costs provided by committee members; NHS Supply Chain 2018⁸²
(a): Where there were two costs listed for one stent in the NHS Supply Chain Catalogue, this estimate uses the lower cost that was listed.
(b): Where there were two costs listed for one stent in the NHS Supply Chain Catalogue, this estimate uses the higher cost that was listed.
(c): Two types of drug-eluting stents did not have local costs available therefore the cost listed in the NHS supply chain catalogue was used. These two types of stents had low usage and it is not thought to impact estimates significantly.
(d): Audit data does not report a breakdown of bare metal stent use as their use is low. Therefore, the cost of bare metal stents was based on the cost of the Integrity bare metal stent which was the last available BMS at one of the committee member’s local hospital. Please note that this was the cheapest BMS listed on the NHS Supply Chain catalogue and therefore estimates are considered conservative towards drug-eluting stents.

Final

Intervention evidence review

This evidence review was developed by the National Guideline Centre based at the Royal College of Physicians

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, where appropriate, their carer or guardian.

Local commissioners and 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: NBK565358PMID: 33301274