Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners’ own terms and conditions.

TITLE: Clopidogrel, Prasugrel and Ticagrelor in Adults with Acute Coronary Syndrome: A Review of the Clinical Effectiveness, Cost Effectiveness and Guidelines

DATE: 06 June 2012 CONTEXT AND POLICY ISSUES Acute coronary syndrome (ACS) is a collective term used to describe the acute onset of myocardial ischemia resulting from the occlusion of coronary arteries and includes the following designations: ST segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (NSTEMI) and unstable angina (UA).1 When patients present with signs and symptoms of ACS, they receive an immediate oral administration of dual antiplatelet therapy consisting of acetylsalicylic acid (aspirin; ASA) and a thienopyridine.2 Thienopyridines are a class of P2Y12 platelet adenosine diphosophate (ADP) receptor antagonists and the one that is most commonly administered to ACS patients is clopidogrel.3 ACS (STEMI, or NSTEMI/UA) is classified based on the characteristics of electrocardiograms (ECG) and the level of cardiac enzymes circulating in the blood.4 STEMI patients receive immediate care, which may include percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), or management by drug alone.5,6 NSTEMI patients receive similar treatment options, but the administration of these treatments are less time-critical than in STEMI patients.6,7 Currently, dual therapy with clopidogrel and ASA is the standard treatment for ACS patients in Canada.6 Clopidogrel has many limitations including a slow onset of action, incomplete platelet inhibition, poor antiplatelet response in some patients, and an irreversible antiplatelet effect.8 A new thienopyridine, prasugrel, has been observed to provide a faster response and better clinical efficacy than clopidogrel, at the expense of an increased risk of major bleeding.9 Like clopidogrel, prasugrel irreversibly inhibits platelet aggregation by binding to the P2Y12 platelet ADP receptor for the entire 8 to 9 day life span of platelets. ACS patients who are on clopidogrel or prasugrel are at a higher risk of bleeding during emergency CABG procedures or other surgical interventions.10,11 Ticagrelor, a cyclopentyltriazolopyridine, has different properties than thienopyridines.3 Since it is not a prodrug requiring metabolic activation, ticagrelor has a faster onset response than clopidogrel.12 In addition, it binds reversibly to P2Y12 platelet ADP receptor, which allows for the restoration of platelet aggregation upon termination of therapy.12 The rapid and reversible effect of ticagrelor makes it a promising option for the treatment of ACS patients including those managed medically or with PCI and/or CABG.13

Antiplatelets for ACS 2

Prasugrel was approved by FDA in 2009 to be co-administered with ASA to prevent ischemic events and stent thrombosis in patients undergoing PCI.14 The newer antiplatelet agent, tricagrelor was recently approved by FDA in 2010 to be used to reduce the risk of thrombotic events in ACS patients.15 This review provides an update to the recent two CADTH reports16,17 on the clinical effectiveness and the clinical guidelines on the use of clopidogrel, prasugrel and ticagrelor for the treatment of adult patients with ACS. This review also provides evidence on the cost-effectiveness of clopidogrel, prasugrel and ticagrelor for treatment of ACS. Relevant FDA reports on prasugrel and ticagrelor are also summarized. RESEARCH QUESTIONS

1. What is the clinical effectiveness of clopidogrel, prasugrel or ticagrelor in adults with ST elevation or non-ST elevation acute coronary syndrome (ACS)?

2. What is the comparative clinical effectiveness of clopidogrel, prasugrel or ticagrelor in

adults with ST-elevation or non-ST elevation ACS? 3. What is the cost-effectiveness of clopidogrel, prasugrel or ticagrelor in adults with ST

elevation or non-ST elevation ACS? 4. What are the evidence-based guidelines and recommendations on the use of

clopidogrel, prasugrel or ticagrelor for ACS? KEY MESSAGE While combination therapy with clopidogrel and ASA remains the basis of antiplatelet therapy in ACS patients, each combined therapy of P2Y12 inhibitors (clopidogrel, prasugrel, or ticagrelor) and ASA can be considered for some groups depending on the clinical presentation and subsequent management for patients with ACS. METHODS Literature Search Strategy A limited literature search was conducted on key resources including PubMed, Ovid Embase, The Cochrane Library (2012, Issue 5), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI (Health Devices Gold), Canadian and major international health technology agencies, as well as a focused Internet search. Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials and guidelines for questions 1, 2 and 4 and to economic studies for question 3. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between May 1, 2011 and May 7, 2012 for questions 1, 2 and 4 and between January 1, 2007 and May 7, 2012 for question 3.

Antiplatelets for ACS 3

Selection Criteria and Methods

One reviewer screened the titles and abstracts of the retrieved publications and evaluated the full-text publications for the final article selection, according to selection criteria presented in Table 1. Table 1: Selection Criteria

Population

Adults (18 or older) with ACS [including NSTEMI and STEMI]

Intervention

Clopidogrel, prasugrel, ticagrelor [with or without acetylsalicylic acid (ASA)]

Comparator

Q1: placebo or ASA

Q2: clopidogrel, prasugrel, ticagrelor [with or without ASA]

Q3, Q4: ASA, clopidogrel, prasugrel, ticagrelor [the latter three are used with or without ASA]

Outcomes

Q1, Q2: Primary outcomes: composite of death, MI, and stroke

Secondary (individual) outcomes: all-cause mortality, cardiovascular mortality, MI, stroke

Harms: major and minor bleeding (as defined in individual studies)

Q3: ICER, cost per QALY

Q4: Guidelines

Study Designs

Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, economic evaluations, guidelines

Exclusion Criteria Studies were excluded if they did not satisfy the selection criteria in Table 1, if they were published prior to 2007, duplicate publications of the same study, or included in a selected health technology assessment or systematic review. Critical Appraisal of Individual Studies Critical appraisal of the included studies was based on study design. The methodological quality of the included randomized controlled trials (RCT) was evaluated using the SIGN50 quality assessment tool.18 The internal validity was assessed with the following components: the adequacy of randomization, allocation concealment, degree of blinding, and use of intention to treat approach for analysis. The Appraisal of Guidelines Research & Evaluation (AGREE) instrument19 was used by two independent reviewers to evaluate the quality of the included guidelines. The domains of scope and purpose, stakeholder involvement, rigour of development, clarity and presentation, applicability, and editorial independence were assessed using 23 key items. Finally, the methodological quality of the included cost-effectiveness studies were assessed using the guidelines for appraisal of economic studies by Drummond et al.20 For the critical appraisal of studies, a numeric score was not calculated. Instead, the strength and limitations of the study were described.

Antiplatelets for ACS 4

SUMMARY OF EVIDENCE Quantity of Research Available The literature search yielded 221 citations. Upon screening titles and abstracts, 192 citations were excluded and 29 potential relevant articles were retrieved for full-text review. Five additional relevant reports were retrieved from other sources. Of the 34 potentially relevant articles, 20 were included in this review. They are three RCTs,21-23 12 economic evaluations24-35 and five guidelines.36-40 The study selection process is outlined in a PRISMA flowchart (Appendix 1). Summary of Study Characteristics Randomized controlled trials:

A summary of study characteristics can be found in Appendix 2.

One RCT (CIPAMI trial)21 conducted in Germany compared a loading dose of 600 mg clopidogrel given in the prehospital phase (n=164) versus clopidogrel administered only after the diagnostic angiogram in patients with STEMI scheduled for primary PCI (n=171). Duration of follow-up was until hospital discharge or day 7, whichever happened first. Clinical outcomes included single and composite endpoint of death, re-myocardial infarction or urgent revascularization, thrombolysis in myocardial infarction (TIMI) major bleeding, and TIMI 2/3 patency of the infarct-related artery in the first diagnostic angiogram immediately prior to PCI.

One RCT (ARMYDA-6 MI)22 compared 600 mg (n=103) and 300 mg clopidogrel (n=98) loading doses in patients with STEMI undergoing PCI. Duration of follow-up was 30 days for major adverse cardiovascular events (MACE) and TIMI major bleeding, and 72 hours for infarct size, TIMI flow grade and left ventricular ejection fraction.

A sub-study23 of the PLATO trial compared ticagrelor (n=2601) versus clopidogrel (n=2615) in patients with ACS intended for non-invasive management. The PLATO trial had been reviewed in the previous CADTH report.16

Economic evaluations:

Twelve economic evaluations were identified.24-35 The characteristics are summarized below and described in Appendix 3. All were cost-effectiveness studies, which can be arranged into five groups based on interventions and patient clinical conditions.

Ticagrelor versus clopidogrel (genotype driven) in ACS patients: One US economic evaluation24 determined the cost-effectiveness of ticagrelor compared with a genotype-driven selection of antiplatelet agents (clopidogrel therapy with no CYP2C19*2 mutation; ticagrelor therapy with mutation). The analysis was conducted from the perspective of US Medicare. Efficacy data comparing the clinical performance of ticagrelor and clopidogrel were taken from the PLATO trial, while the data of the CURE trial were used to adjust the hazard rates in patients with CYP2C19*2 mutation, who received no benefit of clopidogrel. The assumed generic price of clopidogrel was $30/month and the price of ticagrelor was $164/month. All costs were in 2009 US dollars. The study was supported by public funding.

Prasugrel versus clopidogrel in ACS patients undergoing PCI: Two US economic evaluations25,26 estimated the cost-effectiveness of prasugrel compared with clopidogrel using data from TRITON-TIMI 38. One analysis was developed from a managed care organization perspective,25 while the other was evaluated from the perspective of the US health care

Antiplatelets for ACS 5

system;26 both used life time horizon. Drug costs were similar between studies, clopidogrel was $6.08/day25 and $4.62/day,26 prasugrel was $6.07/day25 and $5.45/day.26 One study estimated the cost of generic clopidogrel to be $1/day.26 Both studies received funding from industry.

Clopidogrel + ASA versus ASA in patients with STEMI: Five economic evaluations assessed the cost-effectiveness of clopidogrel + ASA compared with standard therapy (including ASA) in patients with STEMI. The analyses were developed from US medicare perspective,27,30 from the perspective of UK National Health Service,28 from the societal perspective in the Netherlands,29 and from the health care payer perspective for France and Germany and a societal perspective for Sweden.31 Source of efficacy estimate of these economic evaluations was from CLARITY27-

29,31 and COMMIT.28,30,31 All studies used branded cost of clopidogrel and received funding from industries.

Clopidogrel + ASA versus ASA in patients with NSTEMI: Two economic evaluations assessed the cost-effectiveness of clopidogrel + ASA compared with ASA in patients with NSTEMI from the payer’s perspective within the German health care system32 and from the Canadian health care perspective.33 Both used efficacy data from the CURE trial. Only direct costs were incorporated in the analyses of both studies. Daily cost of clopidogrel was €2,2132 or $2.40 (CAD).33 Both studies were funded by industries.

Clopidogrel + ASA versus ASA in ACS patients undergoing PCI: Two economic evaluations assessed the cost-effectiveness of pre-treatment and long-term treatment of clopidogrel in patients undergoing PCI from the health care payer perspective for France and Germany and a societal perspective for Sweden,34 and from the Dutch health care perspective (direct costs only).35 The Dutch study35 compared pre-treatment followed by long-term therapy with only 4 weeks of treatment. The sources of efficacy estimate were PCI-CURE,34,35 CREDO34,35 and PCI-CLARITY.34 All cost were reported for the price year 200634 and 2004,35 where clopidogrel cost was of branded price. Both studies were funded by industries. Guidelines:

Five documents providing recommendations were included in this review, one published in 201236 and four in 2011.37-40

Of the five recommendation statements, one was from Canada,36 one was from Europe,38 one was from US,37 and two were from UK.39,40 The recommendations are from Atlantic Cardiovascular Society (ACS),36 European Society of Cardiology (ESC),38 Institute for Clinical System Improvement (ICSI),37 and National Institute for Health and Clinical Excellence (NICE).39,40

Three guidelines provided recommendations on the use of antiplatelets (clopidogrel, prasugrel, ticagrelor) for ACS patients with UA/NSTEMI and STEMI,36-38 one on the use of ticagrelor for treatment of ACS,39 and one on the use of prasugrel for treatment of ACS with PCI.40 NICE recommendations39,40 were not true evidence-based guidelines, but were based on single technology appraisal.

The characteristics on the grading of recommendations and levels of evidence used to develop the corresponding guidelines are summarized in Appendix 7.

Antiplatelets for ACS 6

Summary of Critical Appraisal

The strengths and limitations of included studies are summarized in Appendix 4.

The investigators of the CIPAMI trial21 and the randomized patients were not blinded to the treatment allocation; in trial ARMYDA-6, only investigators blinding was specified, and in PLATO trial, both investigators and patient were blinded. The participating investigators had perceived beneficial effects of the pre-hospital administration of clopidogrel, and they were unwilling to randomize more patients; therefore the trial was terminated prematurely. In the ARMYDA-6 MI trial,22 the primary outcome (infarct size) was estimated using a mathematical model based on surrogate measures (blood creatine kinase-myocardial band, troponin I and blood hemoglobin). The estimation method might not reflect a real infarct size, and the relation with the clinical outcomes was discussed. Finally in the PLATO trial,23 the article reported a subgroup analysis from the PLATO population; however, it was not reported if this analysis was powered enough to detect the trial outcomes in the analyzed stratum.

The main limitation of all included economic studies was the source of data used to feed the estimation models. The data used was either from historical anterior periods or from countries other than the location where the studies were looking to implement their results. The standards of care and use of resources might differ between countries and through the years; however, these factors were not fully considered in these studies.

Three included guidelines did not report if patients’ preferences and views were taken into consideration at the conception of the guidelines.36-38 Furthermore, the methods used to search and synthesize the evidence were not reported in two guidelines.38,40 Summary of Findings Randomized controlled trials:

The main study findings and authors’ conclusions from the clinical studies can be found in Appendix 5.

Clopidogrel plus ASA versus placebo plus ASA

New information regarding this topic was not identified in this review. This topic had been assessed in the previous CADTH report,16 and the findings from two health technology assessments and four systematic reviews suggest that clopidogrel plus ASA is more effective than placebo plus ASA in ACS patients with UA/NSTEMI, or STEMI, who were clinically managed or underwent PCI.

Clopidogrel pretreatment

The evidence of clopidogrel pre-treatment has not been assessed in the previous CADTH report.16

In the CIPAMI trial,21 600-mg loading dose clopidogrel given in the pre-hospital phase was found to be associated with a trend towards reduction in clinical events compared to clopidogrel given after diagnostic angiogram in patients with STEMI scheduled for primary PCI. The overall combined endpoint of death, re-infarction, and urgent revascularization occurred in 3.0% and 7.0% (P = 0.09; OR 0.42, 95% CI 0.14 to 1.20). Upon removal of two patients in the pre-hospital group, who did not receive clopidogrel before angiography, and five patients in the control group, who received clopidogrel in the pre-hospital phase, the difference of the combined endpoint was statistically significant (2.5% vs. 7.5%, P < 0.05; OR 0.38, 95% CI 0.12 to 0.98). There were no significant differences between treatment groups in TIMI major bleeding (9.1%

Antiplatelets for ACS 7

vs. 8.2%, P = 0.80; OR 1.1, 95% CI 0.5 to 2.4), and TIMI 2/3 patency of infarct-related before PCI (49.3% vs. 45.1%, P = 0.5; OR 1.18, 95% CI 0.75 to 1.87). It was concluded that “early inhibition of platelet ADP-receptor with a high loading dose of 600 mg clopidogrel given in the pre-hospital phase in patients with STEMI scheduled for primary PCI is safe, did not increase pre-PCI patency of the infarct vessel, but was associated with a trend towards a reduction in clinical events”.

Clopidogrel loading dose (600 mg versus 300 mg)

In the previous CADTH report,16 the systematic review by Siller-Matula (2010) was included to assess the efficacy and safety of two clopidogrel loading doses (600 mg vs. 300 mg) in ACS patients (STEMI, NSTEMI) undergoing PCI. The results of the meta-analysis suggest that intensified loading dose of clopidogrel reduced the incidence of major cardiovascular events without an increase in major bleeding.

The ARMYDA-6 MI trial, conducted in Italy, Hungary, Serbia, and Belgium, evaluated the impact of pre-treatment with a 600-mg versus a 300-mg clopidogrel loading dose on efficacy and safety outcomes in the setting of urgent PCI for ACS patients with STEMI. Both arms had similar symptoms-to-balloon time (600 mg: 283 ± 183 min vs. 300 mg: 288 ± 223 min; P = 0.86) and clopidogrel load-to-balloon time (35 ± 34 min vs. 39 ± 41 min; P = 0.45). The incidence of 30-day MACE was lower in the 600-mg group (5.8%, 6/103) compared with 300-mg group (15.0%, 15/98). The difference was statistically significant (p=0.049). There was a trend in the reduction of death (3.9% vs. 7.1%), re-infarction (0.98% vs. 5.1%), and target vessel re-vascularization (0.98% vs. 7.1%) in the 600-mg group compared with the 300-mg group, although the differences were not statistically significant. The safety endpoint in terms major bleeding (1.9% vs. 2.0%) minor bleeding (7.8% vs. 6.1%) and entry-site complications (2.9% vs. 3.1%) did not differ in the 600-mg and 300-mg groups. Infarct size was significantly lower in the high loading dose regimen, measured by area under curve of cardiac markers: median creatine kinase –myocardial band (2,070 ng/ml vs. 3,049 ng/ml, P = 0.0001); troponin I (255 ng/ml vs. 380 ng/ml, P < 0.0001). Overall, TIMI flow grade <3 after PCI was less frequent in the 600-mg arm (6% vs. 16%, P = 0.031), whereas left ventricular fraction at discharge was improved (52.1 ± 9.5% vs. 48.8 ± 11.3%, P = 0.026). It was concluded that 600-mg clopidogrel loading dose is safe and more effective than 300-mg in ACS patients with STEMI undergoing PCI.

New P2Y12 inhibitors (prasugrel or ticagrelor) versus clopidogrel

The overall conclusion derived from three systematic reviews assessed in the previous CADTH report16 is that both prasugrel and ticagrelor are more efficacious than clopidogrel in ACS patients with STEMI and UA/NSTEMI. Indirect comparison suggests that prasugrel and ticagrelor have similar efficacy, except prasugrel is more protective for stent thrombosis, but causes more bleeding.

A sub-study of the PLATO trial was identified in this review, and was not available in the previous CADTH report. This study evaluated the efficacy and safety outcomes in patients in the PLATO trial who at randomization were planned for a non-invasive treatment strategy. All patients received ASA, unless intolerant of it, though no range of ASA dose received was indicated for this sub-study group. The incidence of primary endpoint (CV death, MI, stroke) was significantly lower with ticagrelor than with clopidogrel (12.0% vs. 14.3%; HR 0.85, 95% CI 0.73, 1.00; P = 0.04). The result was mainly driven by the reduction in CV death (5.5% vs. 7.2%; HR 0.76, 95% CI 0.61, 0.96; P = 0.019) without any significant difference in MI or stroke. Overall mortality was also lower with ticagrelor (6.1% vs. 8.2%; HR 0.75, 95% CI 0.61, 0.93; P = 0.010). There was numerical increase in major bleeding (11.9% vs. 10.3%; HR 1.17, 95% CI 0.89 to 1.39; P = 0.079), non-CABG related major bleeding (4.0% vs. 3.1%; HR 1.30, 95% CI 0.95 to

Antiplatelets for ACS 8

1.77; P = 0.103), and intracranial bleeding (0.5% vs. 0.2%; HR 2.83, 95% CI 0.90 to 8.90; P = 0.075), but these differences were not statistically significant. It was concluded that, in ACS patients initially intended for non-invasive management, the benefits of ticagrelor over clopidogrel were consistent with those derived from the overall population of PLATO. Economic evaluations: The main economic study findings and authors’ conclusions can be found in Appendix 6.

Ticagrelor versus clopidogrel (genotype driven) in ACS patients

A US economic evaluation (2011)24 determined the cost-effectiveness of universal ticagrelor compared with genotype driven selection of either clopidogrel or ticagrelor based the presence or absence of CYP2C19*2 mutation. The 5-year medical costs (in 2009 US$) was estimated using a hybrid decision tree/Markov model. Under a base-case scenario, the incremental cost-effectiveness ratio (ICER) for universal ticagrelor after 5 year was $10,059 per QALY compared to genotype driven treatment. One-way sensitivity analysis showed that the result was most sensitive to the price of ticagrelor and hazard ratio for death; ICERs remained below the common threshold of $50,000 per QALY until a monthly ticagrelor price of $693 or a 0.93 hazard ratio for death. Probabilistic sensitivity analysis using Monte Carlo simulation estimated that the ICER for universal ticagrelor was below $50,000 per QALY in 97.7% of simulations. It was concluded that universal ticagrelor increased QALY for ACS patients at a cost below a typically accepted threshold.

Prasugrel versus clopidogrel in ACS patients undergoing PCI

A US economic evaluation (2012),25 using a disease-progression model, estimated the cost-effectiveness of prasugrel in relation to clopidogrel from a US payer perspective for treatment of ACS patients undergoing PCI. All costs were adjusted to 2009 US dollars. The average total cost (median follow-up 15 months) was $97,090 per 100 patients lower with prasugrel due to reduced hospitalization rate. Under a base-case scenario, prasugrel-based therapy was associated with cost-savings and fewer clinical events in patients subgroups, in alternative time horizons (30 days, 1 year), in a US cohort and a North American cohort, and with generic clopidogrel at $3 per day less than prasugrel. The cost was higher for prasugrel when clopidogrel cost was at $4 per day less than prasugrel. In lifetime analysis based on clopidogrel generic prices ($3 or $4 per day less than prasugrel), the ICERs were $6,643 or $13,906 per life year gained (LYG), respectively. One-way sensitivity analyses showed that the results were most sensitive to the relative costs of the two treatments and the cost for hospital stays. Probabilistic sensitivity analyses showed that, at the clopidogrel branded price, prasugrel-based therapy was dominant in 97.6% of the 10,000 simulations. With clopidogrel prices of $3 and $4 less per day than prasugrel, the probability that prasugrel is cost-effective using a threshold value of $50,000 per LYG was 99.5% and 98.2%, respectively. It was concluded that the use of prasugrel-based therapy in ACS patients undergoing PCI resulted in cost-savings under branded price of clopidogrel and favorable cost-effective ratios at generic prices due to offsetting savings in the cost of rehospitalization.

A US economic evaluation (2010),26 evaluated the cost-effectiveness of prasugrel versus clopidogrel from the perspective of US healthcare system. All costs were in 2005 US dollars. Cumulative medical care costs (median follow-up 14.7 months), including study drug and the initial and follow-up hospitalizations were $221 per patient lower with prasugrel (95% CI -759 to 299) due to lower rate of re-hospitalization. Prasugrel was associated with 0.102 years of life expectancy gained (95% CI 0.030 to 0.180), due to decreased in non-fatal MI. Under base-case assumptions, treatment with prasugrel was a dominant strategy in 79.7% of bootstrap

Antiplatelets for ACS 9

replicates, and the ICER was <$50,000 per life-year gained in 99.8%. If the generic clopidogrel cost was $1/day, the incremental cost with prasugrel was $996 per patient with an associated ICER of $9,727 per life-year gained, and 98.2% of bootstrap estimates were <$50,000 per life-year gained. It was concluded that treatment of ACS patients undergoing PCI with prasugrel for up to 15 months was an attractive strategy compared with clopidogrel.

Clopidogrel + ASA versus ASA in patients with STEMI

A US economic evaluation (2010),27 calculated the cost-effectiveness of short-term clopidogrel therapy (30 days) in STEMI patients treated with fibrinolysis. Total costs and resource use were not significantly different for the clopidogrel and placebo groups ($8,128 vs. $8,134). All costs were in 2008 US dollars. Clopidogrel remained economically dominant in terms of cost per LYG, or cost per event prevented. In a sensitivity analysis accounting for higher long-term medical costs due to greater life expectancy, clopidogrel remained under $6000 per LYG. Clopidogrel price changes had little effect on cost-effectiveness ratios. Clopidogrel therapy was dominant in 35% of the bootstrap simulations and cost less than $50,000 per LYG in 67% of simulations. It was concluded that short-term clopidogrel therapy was a highly economically attractive strategy, because it improved clinical outcomes at no increase in costs.

An economic evaluation (2010)28 carried out from the perspective of the UK NHS assessed the long-term cost effectiveness of treatment for 1 month, and for 1 year with clopidogrel in addition to ASA compared with ASA in patients with STEMI. Costs were reported as 2006 values. Under a base-case scenario, the ICERs after 1 month and 1 year therapy were £2284 and £3891 per QALY, respectively. Univariate sensitivity analysis showed no variation of the included parameters resulted in an ICER greater than £10,000 (COMMIT/CCS-2 data) or £6000 (CLARITY-TIMI 28). Probabilistic sensitivity analyses, presented as cost-effectiveness acceptability curves, demonstrated the probability that treatment with clopidogrel has higher net benefits than treatment with standard therapy alone for a range of monetary values that a decision-maker may consider the maximum acceptable to gain one QALY. Both cost-effectiveness acceptability curves for 1 month and 1 year showed that the probability of clopidogrel plus standard therapy being cost-effective was around 0.95 at current willingness to pay thresholds. It was concluded that clopidogrel plus standard therapy treatment of STEMI patients undergoing fibrinolytic intervention was cost-effective in the UK setting.

An economic evaluation (2010)29 assessed the costs and effects of clopidogrel plus ASA compared with ASA in patients with STEMI in a societal perspective in the Netherlands. All costs were in euros at 2006 values. For a cohort similar to that of CLARITY protocol and with the 28-day efficacy, treatment with clopidogrel plus ASA resulted in 0.05 LYG and 0.062 QALYs gained for a cost that was €1929 lower than ASA therapy, indicating that combined treatment was economically dominant. Sensitivity analyses showed that ICERs were insensitive to variation in all listed factors except the upper margin of the 95% CI of risk reduction of CV mortality. Continuation of treatment outside the trial period (2 to 12 months) was expected to result in ICERs of below €20,000 per QALY as long as the real risk reduction (product of risk and risk reduction) of combination treatment is greater than 0.487% per year. It was concluded that combined therapy of clopidogrel and ASA was cost-effective according to the regimen as in CLARITY trial.

A US economic evaluation (2009)30 used a decision tree model to estimate the long-term cost-effectiveness of clopidogrel in STEMI patients in the COMMIT trial from the US Medicare perspective. All costs were in 2003 US dollars. Within 28 days, clopidogrel plus ASA was a dominant strategy because total event rate was decreased (9.2% vs. 10.1%) without an increase in cost ($7791 vs. $7797). Over life-year time, 1-year treatment of clopidogrel plus ASA produced an ICER of $10,691 per LYG. Sensitivity analyses, using event rate and LYG as

Antiplatelets for ACS 10

parameters, showed that ICERs for clopidogrel plus ASA were well below the common benchmark ceiling ratio of $50,000 per LYG. It was concluded that addition of clopidogrel to ASA, up to 1 year of therapy, was a highly cost-effective strategy in STEMI patients.

An economic evaluation (2007)31 assessed the cost-effectiveness of clopidogrel in short- and long-term treatment of STEMI with the use of data from two trials in Sweden, Germany and France (CLARITY and COMMIT). The analyses were conducted from a healthcare perspective for France and Germany, and a societal perspective for Sweden. All costs were reported for the price year 2005. Under base-case scenario and as for CLARITY and COMMIT populations, the ICERs in Sweden were €2100/LYG and €2772/LYG, respectively; the ICERs in Germany were €92/LYG and €4144/LYG, respectively; and the ICERs in France were dominant and €2786/LYG, respectively. One-way sensitivity analyses regarding variations in treatment effects, costs and discount factors for the two studies showed that the results in all three countries were most sensitive to the cost of added LYGs and the exclusion of costs after the first year from the analysis. For Sweden at the commonly quoted willingness-to-pay threshold of €50,000/QALY, the probabilistic sensitivity analyses showed that the clopidogrel strategy was cost-effective in around 90% of the simulations (CLARITY cohort) and 84% when applying COMMIT results. It was concluded that treatment of STEMI patients with clopidogrel was cost-effective in all three European countries, with the predicted ICERs well below the accepted threshold values.

Clopidogrel + ASA versus ASA in patients with NSTEMI

An economic evaluation (2007)32 conducted in Germany assessed the long-term cost-effectiveness of clopidogrel in ACS patients with NSTEMI from the payer’s perspective within the German healthcare system. A Markov model was used to evaluate the incremental cost-effectiveness of clopidogrel in addition to ASA using data from the CURE trial. Costs were adjusted to 2004 value. Direct medical costs per patient in 1 year of treatment with clopidogrel plus ASA and ASA alone were €8,953 and €8,548, respectively. The model predicted a survival of 9.02 years in clopidogrel plus ASA group and 8.89 years in ASA group, yielding an ICER of €3,113 per LYG. In sensitivity analyses, variations of key parameters did not alter the overall results of the base-case scenario, resulting in a range of ICERs from €1,338 to €9,322. It was concluded that adding clopidogrel to ASA for ACS patients with NSTEMI generated an additional life year saved at a relatively low cost of €3,113.

An economic evaluation (2007)33 assessed the long-term cost-effectiveness of clopidogrel in ACS patients with NSTEMI in the Canadian health care system. The analysis was based on the CURE trial. All costs were reported for the price year 2004 Canadian dollars. Clopidogrel was shown to be cost-effective, with ICERs less than $10,000 per event prevented and less than $4,000 per LYG. The probability of clopidogrel resulting in cost/LYG of less than $20,000 was 0.975 for CURE patients and 0.904 for PCI-CURE patients. It was concluded that combination therapy of clopidogrel and ASA for ACS patients with NSTEMI was cost-effective.

Clopidogrel + ASA versus ASA in ACS patients undergoing PCI

An economic evaluation (2008)34 conducted a cost-effectiveness analysis of pre-treatment and long-term treatment with clopidogrel in ACS patients undergoing PCI in three European countries based on meta-analysis of PCI-CURE, CREDO and CLARITY trials. The analyses were conducted from a healthcare perspective for France and German, and a societal perspective for Sweden. All costs were reported for the price year 2006. Under base-case scenario, the ICER in Sweden was €4,225 per QALY; the ICER in Germany was €7,871 per QALY; and the ICER in France was €5,226 per QALY. The one-way sensitivity analyses showed that costs of added years of life had highest impact on the overall results. Clopidogrel is cost saving across all countries when assessing pre-treatment only. The results were relatively

Antiplatelets for ACS 11

stable when key parameters were varied. In probabilistic sensitivity analyses, using the commonly quoted willingness-to-pay threshold of €50,000 per QALY, at least 99% of simulations can be considered cost-effective in three countries. At a lower threshold of €10,000 per QALY, 91% of simulations would be cost-effective in Sweden, 87% in France and 59% in Germany (mainly due to higher unit cost of clopidogrel). It was concluded that pre-treatment and long-term treatment with clopidogrel for up to one year in a PCI setting were cost-effective.

An economic evaluation (2007)35 examined the cost-effectiveness, from the Dutch healthcare perspective, of clopidogrel in patients undergoing PCI. The analysis compared pre-treatment followed by long-term therapy (9-12 months) with only 4 weeks of treatment based on data of PCI-CURE and CREDO trials. All costs were reported for the price year 2004. Based on PCI-CURE or CREDO population, long-term therapy was found to be dominant (more effective, less costly) over short-term therapy. The results were robust over the entire range of the univariate sensitivity analyses. With PCI-CURE population, long-term clopidogrel had 0.98 probability of being cost-saving and a 0.65 probability of being more effective, with additional life-years saved and QALYs gained, and the probability that long-term clopidogrel was cost-effective was 87% at €20,000 per LYG threshold. With CREDO population, long-term clopidogrel therapy was more effective in 99% and cost saving in 99% of the 1000 simulations; and the probability that long-term clopidogrel was cost-effective was 99% at €20,000 per LYG threshold. It was concluded that in the Netherlands a loading dose of clopidogrel before PCI followed by long-term therapy is dominant for the prevention of subsequent ischemic events in patients undergoing either elective procedures or in patients undergoing primary PCI compared with short-term treatment with clopidogrel without a pre-treatment dose. Guidelines:

The previous CADTH report17 reviewed the recommendations from eleven guidelines on the use of antiplatelet agents for ACS. The conclusions drawn at that time were that: 1) clopidogrel in combination with ASA is used to prevent ischemic events and stent thrombosis in NSTEMI and STEMI patients; 2) prasugrel in combination with ASA is used to prevent stent thrombosis in patients undergoing PCI; 3) ticagrelor may be used to reduce risk of thrombotic events in ACS patients, though its place in therapy with respect to other antiplatelet agents is not clear.

Of the five additional guidelines identified in this review,36-40 the Atlantic Anti-platelet Initiative (AAPI) guidelines by Love et al., 201236 developed in collaboration with the Atlantic Cardiovascular Society was the most up-to-date and was based on the Canadian setting. Details of the recommendations of five guidelines are presented in Appendix 8. An overview of recommendations of AAPI is provided in Table 2. ASA was recommended for all patients with definite or suspected ACS who do not have contraindications to therapy.

Table 2: Summary of recommendations of AAPI Clinical Presentations Recommendations

STEMI receiving thrombolytic therapy

1. Clopidogrel should continue to be the preferred P2Y12 inhibitor (300 mg LD, 75 mg od; omit LD in patients > 75 years) [Strong recommendation, high-quality evidence]

STEMI undergoing primary PCI

1. Clopidogrel should be the preferred P2Y12 inhibitor administered prior to cardiac catheterization laboratory arrival (300-600 mg LD, 75 mg od) [Strong recommendation, high-quality evidence]

2. Prasugrel or ticagrelor is not recommended for pre-hospital of emergency department administration [Conditional recommendation, very low-quality evidence]

3. Prasugrel (60 mg LD, 10 mg od) or ticagrelor (180 mg LD, 90 mg bid) is recommended if first administered in the cardiac

Antiplatelets for ACS 12

Clinical Presentations Recommendations

catheterization laboratory and there are no contraindication [Strong recommendation, moderate-quality evidence]

4. Switching from clopidogrel to prasugrel [Conditional recommendation, very low-quality evidence] or ticagrelor [Strong recommendation, moderate-quality evidence] during or after cardiac catheterization can be considered if higher degree of platelet inhibition is required.

STEMI with planned medical management

1. Clopidogrel should be the preferred P2Y12 inhibitor (300 mg LD, 75 mg od; omit LD in patients > 75 years) [Strong recommendation, high-quality evidence]

NSTE-ACS requiring urgent invasive assessment

1. Clopidogrel should be the preferred agent (300-600 mg LD, 75 mg od) [Strong recommendation, high-quality evidence]

2. Prasugrel or ticagrelor should not administered prior to cardiac catheterization [Conditional recommendation, very low-quality evidence]

3. Switching from clopidogrel to prasugrel [Conditional recommendation, very low-quality evidence] or ticagrelor [Strong recommendation, moderate-quality evidence] during or after cardiac catheterization can be considered in patients with high risk of NSTE-ACS in the absence of contraindications

NSTE-ACS with planned invasive management

1. Clopidogrel should be the preferred P2Y12 inhibitor (300 mg LD, 75 mg od) [Strong recommendation, high-quality evidence]

2. Ticagrelor (180 mg LD, 90 mg bid) can be considered for high risk patients in the absence of contraindications [Conditional recommendation, moderate-quality evidence]

3. Switching from initially treated clopidogrel to ticagrelor in high risk patients should be considered once more is known about patient characteristics and coronary anatomy [Strong recommendation, moderate-quality evidence]

4. Switching from initially treated clopidogrel to prasugrel is generally not recommended [Conditional recommendation, very low-quality evidence]

NSTE-ACS with planned medical management

1. Clopidogrel should be the preferred P2Y12 inhibitor (300 mg LD, 75 mg od) [Strong recommendation, high-quality evidence]

2. Ticagrelor (180 mg LD, 90 mg bid) can be considered for high risk patients in the absence of contraindications [Conditional recommendation, moderate-quality evidence]

3. Switching from initially treated clopidogrel to ticagrelor in high risk patients should be considered once more is known about patient characteristics and coronary anatomy (if cardiac catheterization performed) [Strong recommendation, moderate-quality evidence]

4. Prasugrel is currently not recommended [Conditional recommendation, very low-quality evidence]

Patients with ACS undergoing early CABG

1. P2Y12 inhibitor should generally not be administered prior to cardiac catheterization [Conditional recommendation, low-quality evidence]

2. In patients who received a P2Y12 inhibitor, clopidogrel and ticagrelor should be discontinued 5 days before surgery, or prasugrel 7 days before surgery [Strong recommendation, moderate-quality evidence]

3. Same P2Y12 inhibitor administered pre-operatively should be restarted after surgery [Conditional recommendation, low-quality

Antiplatelets for ACS 13

Clinical Presentations Recommendations

evidence] ACS=acute coronary syndrome; bid=twice daily; CABG=coronary artery bypass grafting; LD=loading dose; NSTE=non ST-segment elevation; od=once daily; PCI=percutaneous coronary intervention; STEMI=ST-segment

elevation myocardial infarction

The European Society of Cardiology (ESC) provided recommendations on the use oral antiplatelet agents for the management of NSTE-ACS.38

Ticagrelor (180 mg LD, 90 mg bid) is recommended for all patients at moderate-to-high risk of ischemic events [Class I, Level B]

Prasugrel (60 mg LD, 10 mg od) is recommended for P2Y12 inhibitor-naïve patients (especially diabetics) undergoing PCI with known coronary anatomy and no contraindications [Class I, Level B]

Clopidogrel (300 mg LD, 75 mg od) is recommended for patients who cannot receive ticagrelor or prasugrel [Class I, Level A]

A 600-mg LD clopidogrel is recommended for patients undergoing invasive strategy when ticagrelor or prasugrel is not an option [Class I, Level B]

A 150-mg maintenance dose of clopidogrel should be considered for the first 7 days in patients managed with PCI [Class IIa, Level B]

In patients pretreated with P2Y12 inhibitors who need to undergo non-urgent major surgery (including CABG), clopidogrel and ticagrelor should be discontinued 5 days before surgery, or prasugrel 7 days before surgery [Class IIa, Level C]

Ticagrelor or clopidogrel should be re-started after CABG surgery [Class IIa, Level B] The Institute for Clinical System Improvement (ICSI) had recommendations on the use of P2Y12

inhibitors for invasive and non-invasive management of ACS.37

For patients with planned non-invasive management strategy, a loading dose of clopidogrel of ticagrelor should be given in addition to ASA as soon as possible. treatment should be continued for at least 1 month and up to 12 months.

For STEMI and primary PCI, a loading dose of a P2Y12 inhibitor should be given as soon as possible or before PCI. Prasugrel is not recommended in patients with history of stroke or transient ischemic attack, or who are >75 years, except high risk situations (diabetes or prior MI history).

Clopidogrel is recommended in STEMI patients receiving fibrinolytic therapy and undergoing non-primary PCI.

Clopidogrel or ticagrelor is recommended in STEMI patients receiving no fibrinolytic therapy and undergoing non-primary PCI.

Prasugrel should be given to STEMI patients once the coronary anatomy is known and PCI is planned.

When revascularization is required and CABG is planned, clopidogrel or ticagrelor should be discontinued for 5 days and prasugrel for 7 days before surgery.

The National Institute for Health and Clinical Excellence (NICE) recommended ticagrelor in combination with low-dose ASA for up to 12 months as treatment option in ACS patients with STEMI, NSTEMI or UA.39 NICE also recommended prasugrel in combination with ASA as treatment option in ACS patients with STEMI undergoing primary PCI, when stent thrombosis has occurred during clopidogrel treatment, or in ACS patients having diabetes.40

Antiplatelets for ACS 14

FDA approval:

Prasugrel

The FDA Action Package for prasugrel revealed the timing of loading in TRITON-TIMI 38 trial.41 The FDA found that the loading dose of study drugs was not administered immediately in TRITON, as was the case in previous clopidogrel trials and in recommended guidelines, but was delayed by protocol until after angiography was performed for UA/NSTEMI patients and not specified as immediate for STEMI patients. This aspect, together with excess bleeding with prasugrel, precluded the FDA from deeming prasugrel superior to clopidogrel.

Prasugrel was approved by FDA on July 10, 200942 for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with ACS who are to be managed with PCI as followed:

Patients with unstable UA or NSTEMI

Patients with STEMI when managed with either primary or delayed PCI

Latest approval of the Full Prescription Information was on September 27, 2011,43 with box warnings for bleeding risk. A Risk Evaluation and Mitigation Strategy44 has been put in place and a Medication Guide45 is now available for distribution with each prescription to inform patients about the serious risks associated with prasugrel, particularly risk of bleeding. The manufacturer has also implemented a communication plan to healthcare providers to convey information regarding serious risk of bleeding associated with prasugrel, and appropriate patient selection.46 Prasugrel can cause significant, sometimes fatal, bleeding. Risk factors for bleeding include age ≥75 years, body weight <60 kg, propensity to bleed, and concomitant use of medications that increase the risk of bleeding. Prasugrel should not be started in patients likely to undergo urgent CABG and when possible, prasugrel should be discontinued at least 7 days prior to any surgery. Ticagrelor

In the Complete Response Letter,47 the FDA expressed concern that the North American results are not a chance finding. In the US population, there was a statistically non-significant trend towards a higher incidence the composite outcome with ticagrelor compared to clopidogrel. The effect of ASA dose is an alternative explanation for the difference in treatment effect between US and outside of US (OUS). US patients received higher ASA dose (median 325 mg/day) than OUS patients (median 100 mg/day). In light of this aspect, the FDA recommended the manufacturer provide further detailed analyses of ASA dose on US/OUS findings based on a number of methods to categorize ASA dose. The effect of ASA dose should be analyzed on the primary composite endpoint and its components, as well as on major subgroups. FDA also required the manufacturer to submit draft labeling and A Risk Evaluation and Mitigation Strategy (REMS), which contains a Medication Guide, Communication Plan and a timetable for submission of assessments of the REMS. FDA also required a safety update.

Ticagrelor received approval from FDA on July 20, 201148 for the reduction of thrombotic cardiovascular events in patients with ACS (UA, NSTEMI or STEMI). The FDA indicated that maintenance doses of ASA above 100 mg daily should be avoided. The Full Prescription Information was approved in July, 2011,49 which contains a box warning for bleeding risk and ASA dose. The REMS50 has been approved by FDA, and the Medication Guide51 is now available for distribution with each prescription.

Antiplatelets for ACS 15

Limitations

Clinical

The CIPAMI trial21 was not powered to show significant differences for clinical endpoints. The duration of follow-up was relatively short, until hospital discharge or day seven, whichever happened first. Treatment allocation was not blinded to patients or investigators.

The ARMYDA-6 MI trial22 was also not powered for the evaluation of clinical endpoints. Surrogate outcome measures of infarct size were chosen as primary outcome. The method used to measure infarct size was mathematical modeling based on surrogate outcome measures and may not be an true measurement of actual infarct size.

In the PLATO sub-study,23 despite an intended non-invasive strategy at the time of randomization, about half of patients had coronary angiography, one third had PCI, and one tenth had CABG during follow-up. The results could be therefore confounded by invasive treatment when intention-to-treat analysis was applied.

The CIPAMI and the ARMYDA-6 trials were not conducted in Canada. Although PLATO was multi-national trial, patients from Canada represented only 401 out of 18,624 randomized patients (2.15%). Hence the applicability of the findings from those trials to Canadian setting is uncertain.

There were no head-to-head comparison of prasugrel and ticagrelor for treatment efficacy in ACS, limiting the ability to draw conclusions about their relative effectiveness.

Economic

There were no economic evaluations which evaluated the cost-effectiveness of prasugrel or ticagrelor from the Canadian healthcare perspective. Among the economic evaluations for clopidogrel, there was only one cost-effectiveness analysis of clopidogrel for NSTEMI in the Canadian healthcare system. Most of the economic evaluations (11 out of 12) were financially sponsored by industry. The branded prices of clopidogrel, instead of the generic price, were used in 10 out of 12 economic evaluations. These evaluations may be losing relevance as new generic products are introduced in Canada.

Guidelines

Of the five included guidelines, only one was published by a Canadian professional society.36 The ICSI guidelines37 did not provide grading for the recommendations and levels of evidence. The NICE guidelines for ticagrelor39 and prasugrel40 used the single technology appraisal process developed by NICE, in which the grading of recommendations and levels of evidence were not clearly specified. They may not be classified as complete guidelines. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING Both clinical and economic evaluations showed that clopidogrel plus ASA was associated with a reduced risk of cardiovascular events and was cost-effective compared with ASA alone in ACS patients with UA/NSTEMI or STEMI, who were clinically managed or underwent PCI. In STEMI patients scheduled for primary PCI, a 600-mg loading dose of clopidogrel given to patients before arrival to cardiac catheterization laboratory was associated with a trend towards reduction in clinical events than a loading dose given after diagnostic angiography. Moreover, an intensified loading dose of clopidogrel (600 mg) was found to be safe and more effective than 300-mg in ACS patients with STEMI or NSTEMI undergoing PCI.

Antiplatelets for ACS 16

Results from pivotal studies, TRITON-TIMI 38 and PLATO, have shown that prasugrel and ticagrelor were more effective, but associated with higher risk of bleeding compared with standard clopidogrel therapy. However the PLATO trial found that in a North American subpopulation, there was no significant difference in the primary composite outcome, which has led to the formation of an aspirin hypothesis, due to higher median ASA doses used in the North American group. This hypothesis regarding the importance of ASA dose remains to be proven clinically. Prasugrel is indicated for prevention of thrombotic events in ACS patients who are to be managed with PCI, while ticagrelor is indicated for prevention of thrombotic events in ACS patients who are planned for PCI or non-invasive management. An indirect comparison (from the previous CADTH report)16 of prasugrel and ticagrelor showed similar efficacy of the two agents with prasugrel having an increased efficacy in preventing stent thrombosis but with an accompanying increase in the incidence of bleeding. Economic evaluations showed that prasugrel- and ticagrelor-based therapy was economically attractive compared with clopidogrel, although evidence specific to the Canadian healthcare context is lacking. Additionally, some aspects of the TRITON-TIMI 38 design may not be in line with current Canadian practice, weakening the claim that prasugrel is superior to clopidogrel. These include 1) the use of a 300mg clopidogrel loading dose and 2) the timing of clopidogrel pretreatment. Among the evidence-based clinical guidelines, the Atlantic Canadian Guidelines36 for the acute use of oral anti-platelet therapy in patients with ACS is the most up-to-date and based on the Canadian setting. In this guideline, the use of anti-platelet therapy is recommended based on the clinical presentation and subsequent management for patients with ACS. While clopidogrel and ASA combination therapy remains the basis for antiplatelet therapy in patients with ACS, the use of ticagrelor or prasugrel may be considered for some groups, such as STEMI patients who have not received antiplatelet therapy prior to arrival in the catheterization lab or high risk NSTE-ACS patients. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca

Antiplatelets for ACS 17

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38. Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011 Dec;32(23):2999-3054.

39. Ticagrelor for the treatment of acute coronary syndromes [Internet]. London: National Institute for Health and Clinical Excellence (NICE); 2011 Oct. [cited 2012 May 10]. (NICE technology appraisal guidance 236). Available from: http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf

40. Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention [Internet]. London: National Institute for Health and Clinical Excellence (NICE); 2009 Oct. [cited 2012 May 10]. (NICE technology appraisal guidance 182). Available from: http://www.nice.org.uk/nicemedia/live/12324/45849/45849.pdf

41. Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Medical review(s) [Internet]. In: Effient (prasugrel) tablets. Company: Eli Lilly and Company. Application No.: 22-307. Approval Date: 7/10/09. Silver Spring (MD): The Center; 2009 [cited 2012 May 10]. (FDA drug approval package). Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022307s000TOC.cfm.

42. Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Approval letter [Internet]. In: Effient (prasugrel) tablets. Company: Eli Lilly and Company. Application

Antiplatelets for ACS 21

No.: 22-307. Approval Date: 7/10/09. Silver Spring (MD): The Center; 2009 Jul 10 [cited 2012 May 10]. (FDA drug approval package). Available from: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/022307s000_ltr.pdf.

43. Full prescribing information: Effient (prasugrel) tablets [Internet]. Toronto: Elli Lilly Canada Inc; 2011 Sep. [cited 2012 May 10]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022307s003lbl.pdf

44. Risk evaluation and mitigation strategy [Internet]. Silver Spring (MD): Center for Drug Evaluation and Research, U.S. Food and Drug Administration (FDA); 2011 Sep. [cited 2012 May 10]. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM187493.pdf

45. Medication guide: Effient (prasugrel) tablets [Internet]. Toronto: Eli Lilly Canada Inc; 2011. [cited 2012 May 10]. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM238428.pdf

46. Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Risk assessment and risk mitigation review(s) [Internet]. In: Effient (prasugrel) tablets. Company: Eli Lilly and Company. Application No.: 22-307. Approval Date: 7/10/09. Silver Spring (MD): The Center; 2009 [cited 2012 May 10]. (FDA drug approval package). Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022307s000TOC.cfm.

47. Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Other action letters [Internet]. In: Brilinta (ticagrelor) tablets. Company: AstraZeneca Canada Inc. Application No.: 022411Orig1s000. Approval Date: 7/20/2011. Silver Spring (MD): The Center; 2010 Dec 16 [cited 2012 May 10]. (FDA drug approval package). Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022433Orig1s000OtherActionLtrs.pdf.

48. Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Approval letter [Internet]. In: Brilinta (ticagrelor) tablets. Company: AstraZeneca Canada Inc. Application No.: 022411Orig1s000. Approval Date: 7/20/2011. Silver Spring (MD): The Center; 2011 Jul 20 [cited 2012 May 10]. (FDA drug approval package). Available from: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/022433Orig1s000ltr.pdf.

49. Full prescribing information: Brilinta (ticagrelor) tablets, for oral use [Internet]. Mississauga (ON): AstraZeneca; 2011 Jul 20. [cited 2012 May 10]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022433Orig1s000Lbl.pdf

50. Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Risk evaluation and mitigation strategy (REMS) [Internet]. In: Brilinta (ticagrelor) tablets. Company: AstraZeneca Canada Inc. Application No.: 022411Orig1s000. Approval Date: 7/20/2011. Silver Spring (MD): The Center; 2011 Jul 20 [cited 2012 May 10]. (FDA drug approval package). Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022433Orig1s000REMS.pdf.

Antiplatelets for ACS 22

51. Medication guide: Brilinta (ticagrelor) tablets [Internet]. Mississauga (ON): AstraZeneca; 2011 Jul. [cited 2012 May 10]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022433s000MedG.pdf

52. Guide to the single technology appraisal process [Internet]. London: National Institute for Clinical Excellence (NICE); 2009 Oct. [cited 2012 May 22]. Available from: http://www.nice.org.uk/media/913/06/Guide_to_the_STA-proof_6-26-10-09.pdf

Antiplatelets for ACS 23

APPENDIX 1: Selection of Included Studies

192 citations excluded

29 potentially relevant articles retrieved for scrutiny (full text, if

available)

5 potentially relevant reports retrieved from other sources (grey

literature, hand search)

34 potentially relevant reports

14 reports excluded:

irrelevant population (1)

published in language other than English (1)

other (review articles, editorials)(12)

20 reports included in review

3 RCTs

12 Economic evaluations

5 guidelines

221 citations identified from electronic literature search and

screened

Antiplatelets for ACS 24

APPENDIX 2: Characteristics of Included Clinical Studies First Author, Publication Year, Country

Study Design, Length of Follow-up

Patient characteristics, sample Size (n)

Intervention Comparators Clinical Outcomes

Zeymer,21

2012 Germany

CIPAMI: Multi-center, prospective, randomized, open study Follow-up: until hospital discharge or day 7 (whichever happened first)

Adult patients (N=335) with acute STEMI, candidates for primary PCI. Inclusion: acute STEMI ≤6h Exclusion: thrombolytic therapy within 24 h before randomization, oral anticoagulation, stroke or TIA, active bleeding, contraindication to clopidogrel, currently treated with clopidogrel or ticlopidine

Prehospital clopidogrel (n=164): 600-mg loading dose of clopidogrel as early as possible in the prehospital phase Prior PCI: 500 mg ASA, heparin or enoxaparin After PCI: low dose ASA and clopidogrel 75 mg/day for at least 30 days

Standard therapy (n=171): 600-mg loading dose of clopidogrel immediately prior to PCI Prior PCI: 500 mg ASA, heparin or enoxaparin After PCI: low dose ASA and clopidogrel 75 mg/day for at least 30 days

Single and composite endpoint of death, re-myocardial infarction, urgent revascularization until 48 h and until hospital discharge

TIMI major bleeding

TIMI 2/3 patency of the infarct-related artery in the first diagnostic angiogram immediately prior to PCI

Patti,22

2011 Italy, Hungary, Serbia, Belgium

ARMYDA-6 MI: International, multicenter, prospective, double-blinded, randomized trial Follow-up:

30 days for MACE, and TIMI major and minor bleeding

72 hours for infarct size, TIMI flow grade, and left ventricular ejection fraction

Adult patients (N=201) with STEMI undergoing PCI Inclusion: STEMI Exclusion: thrombolysis, cardiogenic shock, platelet count <70 x 10

9/L, or

treatment with clopidogrel within 10 days from randomization

600-mg clopidogrel (n=103) at the time of first medical contact in emergency department before sending to catheterization laboratory Prior PCI: 500 mg ASA, 70 IU/kg heparin After PCI: ASA 100 mg/day and clopidogrel 75 mg/day for up to 1 year

300-mg clopidogrel (n=98) at the time of first medical contact in emergency department before sending to catheterization laboratory Prior PCI: 500 mg ASA, 70 IU/kg heparin After PCI: ASA 100 mg/day and clopidogrel 75 mg/day for up to 1 year

30-day MACE

Stent thrombosis

Bleeding

Infarct size

TIMI flow grade

Left ventricular ejection fraction

James,23

2011 Multiple countries

Substudy of PLATO (for non-invasive management): international, multicenter, prospective, double-blinded, randomized trial Follow-up: 6 – 12 months

Adult ACS patients (N=5216) intended for non-invasive management

Ticagrelor (LD 180 mg, 90 mg MD bid) (n=2601) All patients received ASA 75-100 mg/day

Clopidogrel (LD 300 mg, 75 mg/day MD) (n=2615) All patients received ASA 75-100 mg/day

Single and composite endpoint of CV death, MI and stroke

Bleeding

CIPAMI: the clopidogrel to improve primary percutaneous coronary intervention in acute myocardial infarction; CV=cardiovascular; LD=loading dose; MACE=major adverse cardiovascular events; MD=maintenance dose; MI=myocardial infarction;

Antiplatelets for ACS 25

APPENDIX 3: Characteristics of Included Economic Evaluations First Author, Publication Year, Country

Type of Economic Evaluation, Study Perspective

Patient Population

Interventions Comments

Ticagrelor vs. clopidogrel (genotype driven) in ACS patients

Crespin,24

2011 USA

Cost-effectiveness analysis Medicare perspective (primary health insurance provider for virtually all US citizens >65 years old)

A cohort of 100,000 Medicare beneficiaries of age 66 or older hospitalized for ACS

Universal ticagrelor vs. genotype-driven treatment (no mutation: treat with clopidogrel, mutation: treat with ticagrelor)

Hybrid decision tree/Markov model

Source of efficacy estimate: PLATO, CURE

Time horizon = 5 years

Antiplatelet medication treatment = 12 months

Annual rate discounted = 3%, sensitivity analysis for rates of 0% to 5%

All costs were in 2009 US dollars

Assumption of pricing for generic clopidogrel was $30/month and ticagrelor (same as prasugrel) was $164/month

Reported outcomes in terms of QALYs and life years gained

Sensitivity analysis: one-way analysis

Probabilistic sensitivity analysis using Monte Carlo simulation (1000 iterations)

Used the typical accepted US threshold of $50,000 per QALY as cost effective

Source of funding: Public

Prasugrel vs clopidogrel in ACS patients undergoing PCI

Mauskopf,25

2012 USA

Cost-effectiveness analysis US managed care organization perspective

ACS patients undergoing PCI

Prasugrel vs. clopidogrel

Disease progression model

Treatment duration: 30 days, 1 year, 15 months

Time horizon: life time

Life expectancy discount rate: 3%

Base-case estimates were taken from the TRITON TIMI 38 eight-country economic cohort data

Drug costs: LD clopidogrel $24.32, LD prasugrel $36.42, MD clopidogrel $6.08/day, MD prasugrel $6.07/day

One-way sensitivity analyses

Probabilistic sensitivity analyses (10,000 iterations)

Antiplatelets for ACS 26

First Author, Publication Year, Country

Type of Economic Evaluation, Study Perspective

Patient Population

Interventions Comments

Source of funding: Industry

Mahoney,26

2010 USA

Cost-effectiveness analysis Perspective of US health care system

Patients from TRITON-TIMI 38 (ACS patients with planned PCI from 8 countries, (N=6705)

Prasugrel vs. clopidogrel

All costs, except drug cost, were in 2005 US dollars

Drug costs: net whole sale prize as of August 2009 (clopidogrel, $4.62/day for base case; prasugrel, $5.45/day)

Generic clopidogrel ($1/day)

Follow-up: ranged from <1 to 15 years (average, 3.35 years)

Time horizon: life time

Primary economic endpoint = total in-trial costs; ICER per life-year gained

Model was not specified

Discount rates: 0%, 5%

Subgroups: sex, diabetes, STEMI vs. NSTEMI, stents vs. no stents, history of stroke/TIA, age ≥75 years, body weight <60 kg

Bootstrap methods (5000 replicates)

Source of funding: Industry

Clopidogrel + ASA vs. ASA in ACS patients with STEMI

Gibler,27

2010 USA

Cost-effectiveness analysis US Medicare perspective

A cohort of 3491 STEMI patients treated with fibrinolysis and either clopidogrel or placebo in CLARITY-TIMI 38 trial

Clopidogrel (300 mg LD, 75 mg/day MD) vs. placebo Standard treatment: fibrinolytic agent, ASA, and heparin

Short term clopidogrel therapy = 30 days

Source of efficacy estimate: CLARITY-TIMI 38

All costs were in 2008 US dollars

Model was not specified

Cost-effectiveness ratios, cost per life year gained

Bootstrap method used to estimate bias-corrected 95% confidence intervals for differences in cost and efficacy as well as the cost per LYG ratio

Sensitivity analyses: increase or decrease in life expectancy; change in price of clopidogrel (increased or decreased by 50%)

Used the typical accepted US threshold of $50,000 per LYG as cost effective

Antiplatelets for ACS 27

First Author, Publication Year, Country

Type of Economic Evaluation, Study Perspective

Patient Population

Interventions Comments

Source of funding: Industries

Karnon,28

2010 UK

Cost-utility analysis Health care perspective: Perspective of UK National Health Service (NHS)

A representative cohort of 1000 UK patients aged 60 years, with STEMI

Clopidogrel (± 300 mg LD, 75 mg/day MD) vs. placebo Standard therapy: 75-325 mg/day ASA

Markov model

Source of efficacy estimate: COMMIT/CCS-2, CLARITY-TIMI 28, CURE

Time horizon = 1 month, 1 year, life time

Costs are reported as 2006 values

Monte Carlo analyses were undertaken to estimate the patient level variation in costs

Incremental cost per QALY gained

Univariate sensitivity analyses

Discount rate: 6% for costs and 1.5% for QALYs

Probabilistic sensitivity analyses using Monte Carlo simulation

Source of funding: Industry

Thurston,29

2010 UK

Cost-effectiveness analysis Societal perspective in the Netherlands

STEMI patients in CLARITY trial (N=3491)

Clopidogrel + ASA vs. ASA for 1-month treatment

Decision tree model

Source of efficacy estimate: CLARITY, CURE

Time horizon = life time

All costs were in euros at 2006 values

Included both direct and indirect costs

Base-case analysis: according to CLARITY 28-day efficacy data; simulations were run until patients rich 100 years

Discount rates for cost and effects were 4% and 1.5%, respectively

Deterministic sensitivity analyses (efficacy rates, discount factors, and all estimates of the first year costs)

Probabilistic sensitivity analyses: use Monte Carlo simulation

Scenario analyses: assessed the cost-effectiveness of clopidogrel therapy at different patient risk levels and different levels of risk reductions

Source of funding: industry

Antiplatelets for ACS 28

First Author, Publication Year, Country

Type of Economic Evaluation, Study Perspective

Patient Population

Interventions Comments

Zhang,30

2009 USA

Cost-effectiveness analysis US Medicare perspective

STEMI patients in COMMIT trial (N=45,852)

Clopidogrel + ASA vs. ASA for 28 days

Decision tree model

Source of efficacy estimate: COMMIT, CURE

Time horizon = life time

Clopidogrel given for 1 year at $4.22/day (2003 values)

Life years lost was discounted at 3% annually

ICER per LYG

Sensitivity analyses (variation of incidence of death, MI or stroke; variation of LYG; one month use of clopidogrel vs. 15 days)

Source of funding: industries

Berg,31

2007 France, Sweden and Germany

Cost-effectiveness analysis Health care payer perspective for France and Germany, and a societal perspective for Sweden

STEMI patients in CLARITY and COMMIT trials (Sweden, Germany and France)

Clopidogrel + ASA vs. ASA for up to 1 year

Decision tree and Markov model

Source of efficacy estimate: CLARITY, COMMIT, CURE

All costs were reported for the price year 2005

Measured of benefits: LYG and QALY

Discount rate for costs: 3%

One-way sensitivity analyses (treatment effects, costs and discount factor)

Probabilistic sensitivity analyses (bootstrap with 1,000 replicates)

Source of funding: industries

Clopidogrel + ASA vs. ASA in ACS patients with NSTEMI

Bruggenjurgen,32

2007 Germany

Cost-effectiveness analysis Payer’s perspective within the German health-care system

ACS patients with NSTEMI in the CURE trial

Clopidogrel + ASA vs. ASA for up to 9 months

Markov model with 6 states (at risk, 1

st year with stroke, following

years with stroke, 1st year with

new MI, following years with MI, and death)

Source of efficacy estimate: CURE

Time horizon = life time

Model outcome: LYG

Direct costs: drugs, physician visits, hospitalization, rehabilitation, reintergration, and nursing

No indirect costs

Annual costs for clopidogrel = €807 (daily costs €2.21)

Antiplatelets for ACS 29

First Author, Publication Year, Country

Type of Economic Evaluation, Study Perspective

Patient Population

Interventions Comments

Discount rate for both cost and effects was 3%

Sensitivity analyses (parameters = drug prices, effect sizes)

Source of funding: industry

Kolm,33

2007 Canada

Cost-effectiveness analysis Canadian health care perspective

ACS patients with NSTEMI in the CURE and PCI-CURE trials

Clopidogrel + ASA vs. ASA for up to 9 months

Model was not specified

Costs = direct medical costs for hospitalization and drug costs; no indirect costs.

All costs were reported for the price year 2004 Canadian dollars

Cost of clopidogrel = $2.40 per 75 mg dose

Discount rate for cost and life expectancy was 3%

ICER per event or ICER per LYG

Bootstrap method (5000 replicates) used to estimate distribution of costs and ICERs

Cost-effective threshold = $20,000

Sensitivity analyses (parameters = life expectancy reduction by 50% and by 80%, and higher cost of ASA)

Source of funding: industry

Clopidogrel + ASA vs. ASA in ACS patients undergoing PCI

Berg,34

2008 Sweden, Germany and France

Cost-effectiveness analysis Health care payer perspective for France and Germany, and a societal perspective for Sweden

ACS patients undergoing PCI in the PCI-CURE, CREDO, PCI-CLARITY trials

Clopidogrel + ASA vs. ASA for up to 1 year

Combined decision tree and Markov model

Source of efficacy estimate: PCI-CURE, CREDO, PCI-CLARITY

All costs were reported for the price year 2006

Main outcome = QALYs

Time horizon = life time

Discount rate for both cost and effects was 3%

Sensitivity analyses (parameters = different costs and outcomes, variation in 1

st year costs, age

limits for the use of life tables, discount factor and treatment effect)

Probabilistic sensitivity analyses (Monte Carlo 1000 simulations)

Antiplatelets for ACS 30

First Author, Publication Year, Country

Type of Economic Evaluation, Study Perspective

Patient Population

Interventions Comments

Source of funding: industries

Heeg,35

2007 The Netherlands

Cost-effectiveness analysis Dutch healthcare perspective (direct costs only)

ACS patients undergoing PCI in the PCI-CURE, CREDO trials

Clopidogrel + ASA for nine to 12 months vs. 4 weeks treatment

Markov model

Source of efficacy estimate: PCI-CURE, CREDO

Time horizon = life time

All costs were reported for the price year 2004

Main outcome = QALYs

Discount rate for both cost and effects was 4%

One-way sensitivity analysis (parameters = all cost estimates, treatment effects, and utility values)

Probabilistic sensitivity analyses (Monte Carlo 1000 simulations)

Source of funding: industry ASA=acetylsalicylic acid; LD=loading dose; MD=maintenance dose; NSTEMI=non ST-segment elevation myocardial infarction; PCI=percutaneous coronary intervention; STEMI= ST-segment elevation myocardial infarction;

Antiplatelets for ACS 31

APPENDIX 4: Summary of Study Strengths and Limitations First Author, Publication Year

Strengths Limitations

Clinical Studies

Zeymer,21

2012

Allocation of the trial treatments was randomized; allocation concealment was ensured using sealed envelopes.

Intention to treat analysis was reported.

Treatment allocation was not blinded for the patients and investigators. The participating emergency physicians had the perception, during the trial, that the pre-hospital administration of clopidogrel had beneficial effects on the patients’ outcomes. For this reason, the trial was terminated prematurely.

Patti,22

2011

Physicians who performed the follow-up assessment were not aware of the randomization assignment. However, Patients’ blinding for treatment allocation was not specified.

Results were analysed using the intention to treat concept.

The trial was not supported by any industry sponsorship.

Surrogate outcome measures (CK-MB, T-1, and blood hemoglobin) were chosen for the trial primary outcome (infarct size). The infarct size was calculated using an estimation model which might not reflect the real infarct size.

This was a multicentre trial; however, it was not reported if the results were consistent across the enrolling centres.

James,23

2011

Allocation of the trial treatments was randomized.

Both investigators and patients were blinded for treatment allocation.

Intention to treat analysis was conducted.

This is was a protocol defined stratum analysis from the PLATO trial. However, it was not reported if the trial was powered enough to detect differences in the trial outcomes in this stratum.

Despite the initial intent for a non-invasive treatment, 40% of the stratified patients were managed by invasive treatment. However, results were analysed with the intention to treat method; therefore, the results could be cofounded by patients who received invasive treatment instead of the intended non-invasive treatment.

The comparator in this trial (clopidogrel) was used at a loading dose of 300mg; however, some guidelines suggested that a loading dose of 600mg would be more beneficial. This would potentially have amplified the efficacy of the trial intervention (ticagrelor).

Economic Evaluations

Crespin,24

2011 The research question was clearly stated

The source of effectiveness data was reported (PLATO trial)

The primary outcome for the economic evaluation was clearly reported (QALY and life years gained).

Prices were adjusted for inflation, when needed.

The price for ticagrelor (or generic clopidogrel) was not available at the time of the study analysis. Instead the study assumed that the price of ticagrelor will be the same as the net wholesale price of prasugrel.

Mauskopf,25

2012

The study objective and assumptions were clearly identified.

The type of analysis (cost-effectiveness), the type of model (disease-progression), and the measurements of benefit (cost and health outcomes) were clearly defined.

Aggregated and disaggregated costs

Justifications for the type of model and assumptions used were not reported.

The study reported the source of data; however, the time period presented in this data was not defined. Furthermore, adjustment for inflation (or evaluating the need for this adjustment) was not reported.

Methods to value health states and health

Antiplatelets for ACS 32

First Author, Publication Year

Strengths Limitations

were reported. benefits were not reported.

Mahoney,26

2010

The research question was clearly stated

The source of effectiveness data was reported (TRITON-TIMI 38 trial)

The primary outcome for the economic evaluation was clearly reported (in trial cost, and if one drug proved to be both more effective and more costly than the other an incremental cost-effectiveness would be performed).

The cost analysis was based on patient-level data from the trial; however, healthcare cost data were not collected directly from the patients.

The study applied the UD DRG-based cost estimates to multinational hospitalizations, and that did not necessarily account for possible differences in treatment practices and resource use in different countries.

Gibler,27

2010

The research question was clearly stated

The source of effectiveness data was reported (CLARITY-TIMI 28 trial)

The primary outcome for the economic evaluation was clearly reported (cost per event prevented and cost per life year gained).

Data used in the analysis did not assign costs for the diagnosis, resource use form re-hospitalizations, nursing home care, and rehabilitation. These factors constitute the motor of the long-term cost.

The study applied the US DRG-based cost estimates to a multinational trial data, and that did not necessarily account for possible differences in treatment practices and resource use in different countries.

Karnon,28

2010

The research question was clearly stated.

The source of effectiveness data was reported.

The Markov model transition probabilities, utilities values estimation and health states cost were defined and the data sources were reported.

The costs used in the model were obtained from a health care perspective (in UK) and reported as 2006 values. The study was reported in 2010 and did not include any inflation adjustment.

The effectiveness estimates were obtained from multinational clinical trials and observational studies; however, the study did not account for possible differences in treatment practices and resource use in different countries.

Thurston,29

2010

The research question was clearly

stated.

The source of effectiveness data was reported.

The study used a decision tree model, but the model was described in an anterior publication.

Sources for survival estimates, cost and utilities values were reported.

Health states values were arbitrary and were not justified in the report.

This was a Dutch study but the used data for the risk of events and survival estimates were obtained the Swedish registry. Furthermore, effectiveness estimates were obtained from multinational clinical trials. For these reasons, some uncertainty about the generalizability of the study findings on the Dutch population might be raised.

Zhang,30

2009

The research question was clearly

stated.

The source of effectiveness data was reported (COMMIT and CURE trials).

The hospitalisation and unit costs were based on the US DRG 2003 costs. However, the study did not adjust for inflation from 2003 until 2009.

Berg,31

2007

The research question was clearly stated.

The source of effectiveness data was reported (CLARITY, COMMIT, and CURE trials).

The study employed a combination of decision tree and Markov model.

The costs used in the analysis were converted to the local currency and adjusted for inflation.

Estimates for effectiveness and baseline risks were captured form multinational sources, and the population considered in each source might not match the other sources. Therefore, there might be some concerns about the generalizability of these data to the study countries (France, Germany, and Sweden)

Bruggenjurgen,32

2007 The research question was clearly The baseline risk data were obtained from a

Antiplatelets for ACS 33

First Author, Publication Year

Strengths Limitations

stated.

The source of effectiveness data was reported ( the CURE trial)

The study used a Markov model; model the primary outcome was life-years saved

Costs for resource use were obtained from published data; data sources were reported.

national Swedish registry, and the effectiveness data were obtained from the CURE trial; the application of these estimates to the Dutch population might raise questions about the generalizability of findings.

Kolm,33

2007

The research question was clearly stated.

The source of effectiveness data was reported ( the CURE trial)

The primary outcome was clearly identified (incremental cost-effectiveness ratio)

Effectiveness data were based on a multinational clinical trial, while costing was based the Canadian health care system. However, the analysis did not fully account for possible differences in treatment practices and resource use between countries.

Berg,34

2008

The research question was clearly

stated.

The source of effectiveness data was reported (a meta-analysis of three clinical trials; CURE, CREDO and CLARITY)

The study employed a combination of decision tree and Markov model.

The costs used in the analysis were converted to the local currency and adjusted for inflation.

Information on the baseline event rates and long-term survival were obtained from a national registry for a time period from 1995 to 2003. However, data from the period might not be reflective to the current clinical practice in cardiology.

Heeg,35

2007

The research question was clearly stated.

The source of effectiveness data was reported ( the CURE and CREDO trials)

The study employed a lifetime Markov model.

The model simulated all events of long-term therapy during the first and second 6-month periods individually; however, it did not consider any potential correlations that may naturally exist between individual events during these periods and between different events (stroke and MI).

Guidelines

Atlantic Cardiovascular Society, Canada Love et al.,

36 2012

The guidelines had a clear overall objectives and a specified patients population

The development panel represented key stakeholders.

Key recommendations are easily identified

Recommendations were rated according to the GRADE system of evaluation.

Patient’s preferences and views were not explicitly taken into consideration.

The guidelines are not supported with application tools

Methods used for searching the evidence were not reported.

The cost implication of applying these guidelines was not evaluated or reported.

The editorial independence of the guidelines was not reported or specified.

European Society of Cardiology (ESC), Europe Hamm et al.,

38 2011

The guidelines are supported with clinically accessible tools to facilitate their implementation.

Key recommendations are clearly reported and easily identified.

Objectives and target patients populations were not clearly identified.

Patient’s preferences and views were not taken into consideration.

Methods used for the search, selection and synthesis of evidence were not reported.

Institute for Clinical System Improvement (ICSI), USA, 2011

37

Objectives and target patients population are clearly defined.

Methods used for the searching and evaluating the Evidence were clearly reported.

The guidelines are supported with

Key recommendations are not clearly identified.

It was not reported if patient’s preferences and views were taken into consideration.

Antiplatelets for ACS 34

First Author, Publication Year

Strengths Limitations

clinical evaluation algorithms that help the clinical implementation.

Potential organizational barriers in applying the recommendations were discussed

National Institute for Health and Clinical Excellence (NICE), UK, 2011

39

Use the single technology appraisal process developed by NICE52

National Institute for Health and Clinical Excellence (NICE), UK, 2011

40

Use the single technology appraisal process developed by NICE52

Antiplatelets for ACS 35

APPENDIX 5: Main Study Findings and Authors’ Conclusions – Clinical First Author, Publication Year, Country

Main Findings

Zeymer,21

2012 Germany

Composite endpoint of death, re-infarction, and urgent target vessel revascularization (overall)

Pre-hospital (n=164) vs. standard (n=171): 3% vs. 7%, p=0.09; OR 0.42, 95% CI 0.14 – 1.20 Composite endpoint of death, re-infarction, and urgent target vessel revascularization (for treated patients)

Pre-hospital (n=161) vs. standard (n=174): 2.5% vs. 7.5%, p<0.05; OR 0.38, 95% CI 0.12 – 0.98 TIMI major bleeding

9.1% vs. 8.2%, p=0.8; OR 1.1, 95% CI 0.5 – 2.4 TIMI 2/3 patency of infarct-related before PCI

49.3% vs. 45.1%, p=0.5; OR 1.18, 95% CI 0.75 – 1.87

Authors’ Conclusions: “Early inhibition of platelet ADP-receptor with a high loading dose of 600 mg clopidogrel

given in the pre-hospital phase in patients with STEMI scheduled for primary PCI is safe, did not increase pre-PCI patency of the infarct vessel, but was associated with a trend towards a reduction in clinical events” (p.305)

Patti,22

2011 Italy, Hungary, Serbia, Belgium

600-mg Clopidogrel

(n=103)

300-mg Clopidogrel

(n=98)

p Value

30-day MACE 6 (5.8) 15 (15.0) 0.049 Individual components

Death 4 (3.9) 7 (7.1) 0.48 Re-infarction 1 (0.98) 5 (5.1) 0.19 TVR 1 (0.98) 7 (7.1) 0.06 Stroke 0 1 (1.0) 0.98 Death + re-infarction 5 (4.9) 12 (12.2) 0.10 Death + re-infarction + stroke 5 (4.9) 13 (13.2) 0.07 Death + re-infarction + TVR 6 (5.8) 14 (14.2) 0.08

Define or probable stent thrombosis 1 (0.98) 4 (4.1) 0.34 Safety endpoint

30-day major bleeding 2 (1.9) 2 (2.0) 0.65 30-day minor bleeding 8 (7.8) 6 (6.1) 0.86 Entry-site complications 3 (2.9) 3 (3.1) 0.72

Infarct size (ng/ml) Median CK-MB 2,070 3,049 0.0001 Troponin-I 255 380 <0.0001

TIMI flow grade pre-PCI >1 22 (21) 12 (12) 0.12 post-PCI <3 6 (6) 16 (16) 0.031

Left ventricular ejection fraction at discharge 52.1 ± 9.5% 48.8 ± 11.3% 0.026 MACE=major adverse cardiovascular events; TIMI=Thrombolysis in myocardial infarction; TVR=target vessel revascularization

Values are n (%) or mean ± SD

Authors’ Conclusions: “In STEMI patients, pre-treatment with a 600-mg clopidogrel loading dose before primary

PCI was associated with a reduction of the infarct size compared with a 300-mg loading dose, as well as with improvement of angiographic results, residual cardiac function, and 30-day major adverse cardiovascular events; further studies are warranted to evaluate impact of such strategy on survival” (p.1592)

James, 23

2011 PLATO’s substudy

Ticagrelor (n=2601)

Clopidogrel (n=2615)

HR (95% CI) P value

1o outcome (CV death, MI,

stroke) 295 (12.0) 346 (14.3) 0.85 (0.73, 1.00) 0.045

Antiplatelets for ACS 36

First Author, Publication Year, Country

Main Findings

Multi countries CV death 132 (5.5) 173 (7.2) 0.76 (0.61, 0.96) 0.019

All cause death 147 (6.1) 185 (8.2) 0.75 (0.61, 0.93) 0.010

MI 176 (7.2) 187 (7.8) 0.94 (0.77, 1.15) 0.555

Stroke 50 (2.1) 37 (1.7) 1.35 (0.89, 2.07) 0.162

Total major bleeding 272 (11.9) 238 (10.3) 1.17 (0.98, 1.39) 0.079

TIMI major bleeding 181 (7.9) 164 (7.2) 1.13 (0.91, 1.39) 0.270

Non-CABG bleeding 90 (4.0) 71 (3.1) 1.30 (0.95, 1.77) 0.103

Intracranial bleeding 11 (0.5) 4 (0.2) 2.83 (0.90, 8.90) 0.075

Life threatening bleeding 125 (5.5) 129 (5.6) 0.99 (0.77, 1.26) 0.911 CV=cardiovascular; MI=myocardial infarction; TIMI=Thrombolysis in myocardial infarction

Values are n (%)

Authors’ Conclusions: “In a population of patients with acute coronary syndrome managed with a planned non-

invasive treatment strategy, more intense P2Y12 receptor inhibition with ticagrelor achieved a clinically important reduction in ischemic events and mortality, but without increasing major bleeding, compared with clopidogrel. These results indicate the broad benefits of P2Y12 inhibition for patients with acute coronary syndrome across management strategies” (p.4)

Antiplatelets for ACS 37

APPENDIX 6: Main Study Findings and Authors’ Conclusions - Economic First Author, Publication Year, Country

Main Findings Authors’ Conclusions

Ticagrelor vs. clopidogrel (genotype driven) in ACS patients

Crespin,24

2011 USA

Base Case

Universal ticagrelor vs. Genotype-driven ICER after 1 year: $42,546/QALY ICER after 5 year: $10,059/QALY One-way sensitivity analyses

The ICER remained below $50,000 per QALY until a monthly ticagrelor price of $693 or a 0.93 hazard ratio for death Probabilistic analyses

Universal ticagrelor was below $50,000 per QALY in 97.7% of simulation

“Prescribing ticagrelor universally increases quality-adjusted life years for ACS patients at a cost below a typically accepted threshold” (p.483)

Prasugrel vs clopidogrel in ACS patients undergoing PCI

Mauskopf,25

2012 USA

Average total costs (median follow-up 15 months)

$97,090 per 100 patients lower with prasugrel due to reduced hospitalization rate Prasugrel-based therapy was associated with cost-savings and fewer clinical events in patients subgroups, in alternative time horizon (30 days, 1 year), in US cohort and north American cohort, with generic clopidogrel at $3 per day less than prasugrel. The cost was higher for prasugrel when clopidogrel cost was at $4 per day less than prasugrel ICER based on lower clopidogrel prices were $6,643 and $13,906 per LYG, respectively One-way sensitivity analysis

The results were most sensitive to the relative costs of the two treatments and the cost for hospital stays. Probabilistic sensitivity analyses

At current prices, prasugrel-based therapy was dominant in 97.6% of the 10,000 simulations. With clopidogrel prices of $3 and $4 less per day than prasugrel, the probability that prasugrel is cost-effective using a threshold value of $50,000 per LYG was 99.5% and 98.2%, respectively.

“Use of prasugrel-based therapy compared with clopidogrel-based therapy in ACS patients having a PCI resulted in cost-savings at current prices and favorable cost-effective ratios at likely generic prices for clopidogrel-based therapy because of offsetting savings in the costs of rehospitalization. In addition, the results in the managed care population were similar to estimated results based on the clinical trial population” (p.173)

Mahoney,26

2010 USA

Average total costs (median follow-up 14.7 months)

Prasugrel, $26,067; clopidogrel, $26,288 $221 per patient lower with prasugrel (95% CI -759, 299) due to lower rate of rehospitalization Life expectancy from CV death, MI or stroke

Prasugrel, 0.428; clopidogrel 0.530 life-years lost Prasugrel was associated with life expectancy gained 1.102 years (95% CI 0.030, 0.180), due to decreased in non-fatal MI Base case

Treatment with prasugrel was a dominant strategy in

“For patients undergoing PCI in the ACS setting, treatment with prasugrel compared with clopidogrel is highly cost-effective, and under many circumstances cost saving, over both the subacute and long-term phases of treatment. further studies are necessary to understand the optimal duration of treatment and the cost-effectiveness in other non-ACS setting” (p.78)

Antiplatelets for ACS 38

First Author, Publication Year, Country

Main Findings Authors’ Conclusions

79.7% of bootstrap replicates, and the ICER was <$50,000 per life-year gained in 99.8% Prasugrel remained an economically dominant strategy for both the initial 30 days of treatment and the extension of treatment from 31 days to 14.7 months If generic clopidogrel cost was $1/day, the incremental cost with prasugrel was $996 per patient with an associated ICER of $9727 per life-year gained, and 98.2% of bootstrap estimates were <$50,000 per life-year gained Prasugrel was a dominant treatment strategy in an analysis of costs and effectiveness based on US patients only, and in other subgroups including men, with or without diabetes, , NTEMI or NSTEMI, bare metal stents, no history of stroke or TIA.

Clopidogrel + ASA vs. ASA in ACS patients with STEMI

Gibler,27

2010 USA

Total costs and resource use were not significantly different for the clopidogrel and placebo groups ($8128 vs. $8134) Clopidogrel remained economically dominant in terms of cost per LYG, or cost per event prevented In a sensitivity analysis accounting for higher long-term medical costs due to greater life expectancy, clopidogrel remained under $6000 per LYG Clopidogrel price changes had little effect on cost-effectiveness ratios Clopidogrel therapy was dominant in 35% of the bootstrap simulation and cost less than $50,000 per LYG in 67% of simulations

“In conclusion, this analysis finds short-term clopidogrel therapy to be a highly economically attractive therapy, improving patient outcomes at no increase in costs” (p.14)

Karnon,28

2010 UK

Base Case

Clopidogrel + ASA vs. ASA ICER after 1 month: £2284/QALY (below £2500) ICER after 1 year: £3891/QALY (below £4000) Univariate sensitivity analysis showed no variation

of the included parameters resulted in an ICER greater than £10,000 (COMMIT/CCS-2 data) or £6000 (CLARITY-TIMI 28) Probabilistic sensitivity analyses, presented as

cost-effectiveness acceptability curves, demonstrated the probability that treatment with clopidogrel has higher net benefits than treatment with standard therapy alone for a range of monetary values that a decision-maker may consider the maximum acceptable to gain one QALY. Both cost-effectiveness acceptability curves for 1 month and 1 year showed that the probability of

“In combination with previous economic analyses of clopidogrel in NSTEMI patients, this paper demonstrated that clopidogrel appears to offer a cost-effective treatment option for all ACS patients

Antiplatelets for ACS 39

First Author, Publication Year, Country

Main Findings Authors’ Conclusions

clopidogrel plus standard therapy being cost-effective was around 0.95 at current willingness to pay thresholds.

Thurston,29

2010 UK

Base Case

Clopidogrel + ASA vs. ASA Combined treatment resulted in 0.05 LYG and 0.062 QALYs gained for a cost that was €1929 lower than ASA therapy. Combined treatment was economically dominant. Sensitivity analyses

ICERs were insensitive to variation in all listed factors except the upper margin of the 95% CI of risk reduction of CV mortality Continuation of treatment outside the trial period (2-12 months) was expected to results in ICERs below €20,000 per QALY as long as the real risk reduction (product of risk and risk reduction) of combination treatment is greater than 0.487% per year

“The results indicate that clopidogrel combined with aspirin, according to the regimen seen in CLARITY, and using data from Swedish registries to inform the model, is cost-effective. Sensitivity analyses suggest that the model is robust to a wide range of parameters estimates, including those based on data from Swedish registries. Continued treatment is very likely to be cost effective in light of all the indirect evidence.” (p.641)

Zhang,30

2009 USA

Over life time, 1-year treatment of clopidogrel + ASA produced an ICER of $10,691/LYG Sensitivity analyses showed that ICERs for clopidogrel were well below the common benchmark ceiling ratio of $50,000/LYG

“Additional of clopidogrel to aspirin, given up to 1 year, in the setting of STEMI is a highly cost-effective strategy” (p.353)

Berg,31

2007 France, Sweden and Germany

Base Case

Clopidogrel + ASA vs. ASA Sweden: as for CLARITY and COMMIT population, the ICERs were €2100/LYG and €2772/LYG, respectively Germany: as for CLARITY and COMMIT population, the ICERs were €92/LYG and €4144/LYG, respectively France: as for CLARITY and COMMIT population, the ICERs were dominant and €2786/LYG, respectively Sensitivity analyses

In all three countries, the results were most sensitive to the cost of added LYGs and the exclusion of costs after the first year from the analysis Probabilistic sensitivity analyses

For Sweden at the commonly quoted willingness-to-pay threshold of €50,000/QALY, the clopidogrel strategy was cost-effective in around 90% of the simulations (CLARITY cohort) and 84% when applying COMMIT results

“Treatment of these STEMI patients with clopidogrel appeared to be cost-effective in all 3 European countries studied. Predicted ICERs were below generally accepted threshold values” (p.1184)

Clopidogrel + ASA vs. ASA in ACS patients with NSTEMI

Bruggenjurgen,32

2007 Germany

Direct medical costs per patient in 1 year treatment with clopidogrel + ASA and ASA alone were €8,953 and €8,548, respectively. The model predicted a survival or 9.02 years in clopidogrel + ASA group and 8.89 years in ASA

“Our results are in line with the results from other health care systems. Adding clopidogrel to ASA for patients with acute coronary syndrome without ST-segment elevation generated an

Antiplatelets for ACS 40

First Author, Publication Year, Country

Main Findings Authors’ Conclusions

group ICER was €3,113 per LYG In sensitivity analyses, variations of key parameters did not alter the overall results of the base-case scenario. ICERs ranged from €1,338 to €9,322

additional life-year saved at a comparably low value of €3.113. One-year treatment with clopidogrel is a cost-effective treatment option in patients with acute coronary syndrome from the perspective of a third-party payer in Germany” (p.51)

Kolm,33

2007 Canada

Clopidogrel was shown to be cost-effective, with ICERs less than $10,000 per event prevented and less than $4,000 per LYG. The probability of clopidogrel resulting in cost/LYG of less than $20,000 was 0.975 for CURE patients and 0.904 for PCI-CURE patients

“The economic analysis demonstrated that clopidogrel combination therapy is not only cost-effective as antiplatelet therapy compared with ASA alone, but it is also cost-effective compared with other commonly used and openly reimbursed cardiovascular therapies in the Canadian health care system.” (p.1037)

Clopidogrel + ASA vs. ASA in ACS patients undergoing PCI

Berg,34

2008 Sweden, Germany and France

Base Case

Clopidogrel + ASA vs. ASA Sweden: With all costs included, the ICER was €4,225/QALY German: From a payer perspective, the ICER was €7,871/QALY France: With direct medical costs, the ICER was €5,226/QALY One-way sensitivity analyses

Costs of added years of life had highest impact on the overall results Clopidogrel is cost saving across all countries when assessing pre-treatment only The results were relatively stable when key parameters were varied. Probabilistic sensitivity analyses

Using the commonly quoted willingness-to-pay threshold of €50,000 per QALY, at least 99% of simulations can be considered cost-effective in three countries. At a lower threshold of €10,000 per QALY, 91% of simulation would be cost-effective in Sweden, 87% in France and 59% in Germany (mainly due to higher unit cost of clopidogrel)

“The results of this modeling analysis suggest that pre-treatment and long-term treatment of PCI patients with clopidogrel for up to 1 year are cost-effective in a range of patients and settings, with predicted cost-effectiveness ratios well below generally accepted thresholds (in countries where such threshold exist)” (p.2100)

Heeg,35

2007 The Netherlands

PCI-CURE Base Case

Long-term vs. short term: dominant (more effective, less costly) One-way sensitivity analyses

The results were robust over the entire range of the univariate sensitivity analyses Probabilistic sensitivity analyses

Long-tern clopidogrel had 0.98 probability of being cost-saving and a 0.65 probability of being more

“This analysis suggests that in the Netherlands a loading dose of clopidogrel before PCI followed by long-term therapy (9-12 months) is dominant (cost saving and more effective) for the prevention of subsequent ischaemic events in patients undergoing either elective procedure (CREDO) or in patients with ACS (PCI-CURE) compared with short-term treatment with clopidogrel without a bolus dose.”

Antiplatelets for ACS 41

First Author, Publication Year, Country

Main Findings Authors’ Conclusions

effective, with additional life-years saved and QALYs gained. At €20,000/LYG threshold, the probability that long-term clopidogrel was cost-effective was 87%. CREDO Base Case

Long-term vs. short term: dominant (more effective, less costly) One-way sensitivity analyses

The results were robust over the entire range of the univariate sensitivity analyses Probabilistic sensitivity analyses

Long-term clopidogrel therapy was more effective in 99% and cost saving in 99% of the 1000 simulations. At €20,000/LYG threshold, the probability that long-term clopidogrel was cost-effective was 99%.

(p.780-781)

CV=cardiovascular; ICER=incremental cost effectiveness ratio; MI=myocardial infarction; LYG=life year gained; QALY=quality adjusted life year

Antiplatelets for ACS 42

APPENDIX 7: Grading of Recommendations and Levels of Evidence Guideline Society or Institute

Recommendation Level of Evidence

Atlantic Cardiovascular Society

40

The higher the quality of evidence, the greater the probability that a strong recommendation is indicated.

The greater the difference between desirable and undesirable effects, the greater the probability that a strong recommendation is indicated.

The greater the variation or uncertainty in values and preferences, the higher the probability that a conditional recommendation is indicated.

The higher the cost, the lower the likelihood that a strong recommendation is indicated.

High: Future research unlikely to change confidence in estimate of effect (e.g., multiple well-designed, well-conducted clinical trials)

Moderate: Further research likely to have an important impact on confidence in estimate of effect and may change the estimate (e.g., limited clinical trials, inconsistency of results or study limitations)

Low: Further research very likely to have significant impact on the estimate and is likely to change the estimate (e.g., small number of clinical studies or cohort observations)

Very low: The estimate of effect is very uncertain (e.g., case studies, consensus opinion)

European Society of Cardiology (ECS)

38

I: Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective. II: Conflict evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure. IIa: Weight on evidence/opinion is in favour of usefulness/efficacy. IIb: Usefulness/efficacy is less well established by evidence/opinion III: Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful

A: Data derived from multiple randomized clinical trials or meta-analyses B: Data derived from a single randomized clinical trial or large non-randomized studies C: Consensus of opinion of the experts and/or small studies, retrospective studies, registries.

Institute for Clinical System Improvement (ICSI)

37

A: RCT B: Cohort study C: non-randomized trial with concurrent or historical controls D: Cross sectional study M: Meta-analysis R: Consensus document X: Medical opinion

National Institute for Health and Clinical Excellence (NICE), UK, 2011

39,40

NICE single technology appraisal process52

Antiplatelets for ACS 43

APPENDIX 8: Guidelines and Recommendations on Antiplatelets for ACS Guideline Society, Country, Author, Year, Indication

Recommendations

Atlantic Cardiovascular Society, Canada Love et al.,

36 2012

STEMI

Thrombolytic therapy,

Primary PCI,

Planned medical management

NSTE-ACS

Urgent invasive assessment

Planned invasive assessment

Planned medical management

Other ACS-related guidance

ACS patients undergoing early CABG

ACS subgroup considerations

Generic clopidogrel

Aspirin

1. “Aspirin should be administered to all patients with definite or suspected ACS who do not have contraindications to therapy and who have not been taken aspirin previously (160-325 – mg non-enteric coated oral loading dose followed by 81 mg od) [Strong recommendation, high-quality evidence]

STEMI receiving thrombolytic therapy:

1. “In the absence of any clinical evidence supporting the use of prasugrel or ticagrelor in patients with STEMI receiving thrombolytic therapy, clopidogrel should continue to be the preferred P2Y12 inhibitor in this setting (300-mg oral loading dose followed by 75 mg od; loading dose should be omitted in patients aged >75 years) [Strong recommendation, high-quality evidence]” (p.9)

STEMI undergoing primary PCI:

1. “If a patient with STEMI undergoing primary PCI is administered a P2Y12 inhibitor prior to cardiac catheterization laboratory arrival, clopidogrel should continue to be the preferred agent; the dose of clopidogrel administered should be according to exiting local protocols (typically 300-600-mg oral loading dose followed by 75 mg od) [Strong recommendation, high quality evidence]” (p.9)

2. “Pre-hospital or emergency Department administration of prasugrel or ticagrelor in this setting is not recommended at the present time [Conditional recommendation, very low-quality evidence]” (p.9)

3. “If a patient with STEMI undergoing primary PCI is first administered a P2Y12 inhibitor in the cardiac catheterization laboratory and there are no contraindication, prasugrel (60-mg oral loading dose followed by 10 mg od) or ticagrelor (180-mg oral loading dose followed by 90 mg bid) should be considered instead of clopidogrel [Strong recommendation, moderate-quality evidence]” (p.10)

“If there are no contraindications to either prasugrel or ticagrelor, ticagrelor should generally be the preferred agent [Conditional recommendation, moderate-quality evidence]” (p.10)

4. “If a patient with STEMI undergoing PCI was administered clopidogrel prior to cardiac catheterization laboratory arrival and there are no contraindication, switching to prasugrel [Conditional recommendation, very low-quality evidence] or ticagrelor [Strong recommendation, moderate-quality evidence] during or after cardiac

catheterization can be considered if a higher degree of platelet inhibition is desired” (p.10)

“If there are no contraindications to either prasugrel or ticagrelor, ticagrelor should generally be the preferred agent [Conditional recommendation, moderate-quality evidence]” (p.10)

STEMI with planned medical management

1. “In the absence of clinical trial evidence supporting the use of prasugrel or ticagrelor in the setting of STEMI with planned medical management, clopidogrel should be the preferred P2Y12 inhibitor if the clinical circumstances are left to warrant dual anti-platelet therapy (300-mg oral loading dose followed by 75 mg od; loading dose should be omitted in patients aged >75 years) [Strong recommendation, high-quality evidence]” (p.11)

NSTE-ACS requiring urgent invasive assessment

1. “Clopidogrel should be the preferred agent, with dosing according to existing local protocols (typically 300-600-mg oral loading dose followed by 75 mg od) [Strong recommendation, high-quality evidence]” (p.11)

“Ticagrelor should generally not be administered prior to cardiac catheterization in this setting due to increased risk of major bleeding should urgent cardiac surgery required [Conditional recommendation, very low-quality evidence]” (p.11)

Antiplatelets for ACS 44

Guideline Society, Country, Author, Year, Indication

Recommendations

“Prasugrel should not be administered prior to cardiac catheterization in this setting due to a lack of evidence supporting this approach [Conditional recommendation, very low-quality evidence]” (p.11-12)

2. “In patients with very high-risk of NSTEACS who receive clopidogrel prior to cardiac catheterization laboratory arrival, switching to prasugrel [Conditional recommendation, very low-quality evidence] or ticagrelor [Strong recommendation, moderate-quality evidence] can be considered in the absence

of contraindications” (p.12)

“Switching to prasugrel should only be considered if PCI is going to be performed [Conditional recommendation, very low-quality evidence]” (p.12)

“If there are no contraindications to prasugrel or ticagrelor, ticagrelor should generally be the preferred agent [Conditional recommendation, moderate-quality evidence]” (p.12)

NSTE-ACS with planned invasive management

1. “For the majority of patients with definite NSTEACS likely to undergo cardiac catheterization and possible revascularization prior to discharge, the preferred P2Y12 inhibitor for acute administration should be clopidogrel (300-mg oral loading dose followed by 75 mg od) [Strong recommendation, high-quality evidence]” (p.12-13)

“For patients with high clinical risk (e.g., GRACE risk score >140 or TIMI risk score 5-7), acute administration of ticagrelor (180-mg oral loading dose followed by 90 mg bid) instead of clopidogrel can be considered in the absence of contraindications [Conditional recommendation, moderate-quality evidence]”

(p.13) 2. “For higher risk patients initially treated with clopidogrel, irrespective of whether they

undergo PCI, a transition to ticagrelor should be considered once more is known about the patient’s clinical characteristics, coronary anatomy and anticipated ability to tolerate/comply with therapy [Strong recommendation, moderate-quality evidence]” (p.13)

“Transition from clopidogrel to prasugrel is generally not recommended in this setting because TRITON-TIMI 38 did not establish the safety and efficacy of this approach [Conditional recommendation, very low-quality evidence]” (p.13)

NSTE-ACS with planned medical management

1. “For the majority of patients with definite NSTEACS likely to be medically managed, the preferred P2Y12 inhibitor for acute administration should be clopidogrel (300-mg oral loading dose followed by 75 mg od) [Strong recommendation, high-quality evidence]” (p.13)

“For patients with high clinical risk (e.g., GRACE risk score >140 or TIMI risk score 5-7), acute administration of ticagrelor (180-mg oral loading dose followed by 90 mg bid) instead of clopidogrel can be considered in the absence of contraindications [Conditional recommendation, moderate-quality evidence]”

(p.13-14) 2. “For patients with NSTEACS likely to be medically managed who were initially treated

with clopidogrel, subsequent transitioning to ticagrelor should be considered in higher risk patients once more is known about their clinical characteristics, coronary anatomy (if cardiac catheterization performed) and anticipated ability to tolerate/comply with therapy [Strong recommendation, moderate-quality evidence]” (p. 14)

3. “Due to lack of evidence, prasugrel is currently not recommended for patients with NSTEACS likely to be medically managed [Conditional recommendation, very low-quality evidence]” (p.14)

Patients with ACS undergoing early CABG

1. “In patients with very high-risk ACS who have clinical features that predict an increased likelihood of the need for urgent cardiac surgery, it is recommended that a P2Y12 inhibitor should generally not be administered prior to cardiac catheterization

Antiplatelets for ACS 45

Guideline Society, Country, Author, Year, Indication

Recommendations

[Conditional recommendation, low-quality evidence]” (p.14)

2. “In patients with ACS who have received a P2Y12 inhibitor and require urgent CABG,…, P2Y12 inhibitor therapy should be discontinued 5 days before surgery in patients who have received clopidogrel or ticagrelor and 7 days before surgery in patients who have received prasugrel [Strong recommendation, moderate-quality evidence]” (p. 15)

3. “…, it is recommended that P2Y12 inhibitor therapy be restarted after surgery in patients with ACS who undergo CABG; patients should generally be restarted on the same P2Y12 inhibitor that was administered pre-operatively [Conditional recommendation, low-quality evidence]” (p.15)

ACS sub-group considerations

1. “In principle, it is recommended that the subgroup findings of major ACS anti-platelet trials be interpreted with caution and that the greatest emphasis be placed upon the overall trial results. Contemporary risk stratification and prediction of bleeding typically requires consideration of multiple clinical and patients factors. Consequently, the choice of P2Y12 inhibitor should be generally not based on the presence or absence of isolated clinical features [Conditional recommendation, moderate-quality evidence]” (p. 15)

Generic clopidogrel

1. “…, either generic clopidogrel or banded Plavix can be prescribed in both the emergent and non-emergent ACS settings. Repeated switching between different clopidogrel preparations in either acute or chronic phase of ACS care should be avoided if possible [Conditional recommendation, low-quality evidence]” (p. 16)

European Society of Cardiology (ESC), Europe Hamm et al.,

38 2011

Management of NSTE-ACS

Recommendations for oral antiplatelet agents

1. “A P2Y12 inhibitor should be added to aspirin as soon as possible and maintained over 12 months, unless there are contraindications such as excessive risk of bleeding [Class I, Level A]” (p.3018)

2. “Prolonged or permanent withdrawal of P2Y12 inhibitors within 12 months after the index events is discouraged unless clinically indicated [Class I, Level C]” (p.3018)

3. “Ticagrelor (180-mg loading dose, 90 mg twice daily) is recommended for all patients at moderate-to-high risk of ischeamic events (e.g. elevated troponins), regardless of initial treatment strategy and including those pre-treated with clopidogrel (which should be discontinued when ticagrelor is commenced) [Class I, Level B]” (p.3108)

4. “Prasugrel (60-mg loading dose, 10-mg daily dose) is recommended for P2Y12-inhibitor-naïve patients (especially diabetics) in whom coronary anatomy is known and who are proceeding to PCI unless there is a high risk of life-threatening bleeding or other contraindications [Class I, Level B]” (p.3018)

5. “Clopidogrel (300-mg loading dose, 75-mg daily dose) is recommended for patients who cannot receive ticagrelor or prasugrel [Class I, Level A]” (p.3018)

6. “A 600-mg loading dose of clopidogrel (or a supplementary 300-mg dose at PCI following an initial 300-mg loading dose) is recommended for patients scheduled for an invasive strategy when ticagrelor or prasugrel is not an option [Class I, Level B]”

(p.3018) 7. “A higher maintenance dose of clopidogrel 150 mg daily should be considered for the

first 7 days in patients managed with PCI and without increased risk of bleeding [Class IIa, Level B]” (p.3018)

8. “Increasing the maintenance dose of clopidogrel based on platelet function testing is not advised as routine, but may be considered in selected cases [Class IIb, Level B]” (p.3018)

9. “Genotyping and/or platelet function testing may be considered in selected cases when clopidogrel is used [Class IIb, Level B]” (p.3018)

10. “In patients pre-treated with P2Y12 inhibitors who need to undergo non-emergent major surgery (including CABG), postponing surgery at least 5 days after cessation of ticagrelor, and 7days for prasugrel, if clinically feasible and unless the patient is at high risk of ischaemic events should be considered [Class IIa, Level C]” (p.3018)

11. “Ticagrelor or clopidogrel should be considered to be (re-) started after CABG

Antiplatelets for ACS 46

Guideline Society, Country, Author, Year, Indication

Recommendations

surgery as soon as considered safe [Class IIa, Level B]” (p.3018)

Institute for Clinical System Improvement (ICSI), USA, 201137 ACS

Early therapy for high-risk patients 1. “For patients where an initial invasive strategy is planned, it is recommended to give a

loading dose of a P2Y12 inhibitor as soon as possible prior to PCI…Treatment with a P2Y12 inhibitor should be continued for at least 12 months” (p.22)

2. “If an initial non-invasive (conservative) strategy is planned, a loading dose of P2Y12 inhibitor (clopidogrel or ticagrelor) should be given in addition to aspirin as soon as possible. The P2Y12 inhibitor should be continued for at least one month and ideally up to 12 months” (p.22)

3. “When an initial conservative management is planned, GP IIbIIIa inhibitors may be considered in high-risk UA/NSTEMI patients in addition to aspirin and a P2Y12 inhibitor prior to PCI if the risk of bleeding is low” (p.22)

4. “For STEMI and primary PCI, a loading dose of a P2Y12 inhibitor should be given as soon as possible or before the PCI” (p.26)

“Prasugrel is not recommended to be used in patients with a prior history of stroke or transient ischemic attack (TIA), or who are >75 years of age due to increased risk of bleeding except in high-risk situations (diabetes mellitus or prior MI history)” (p.26)

5. “For STEMI patients undergoing non-primary PCI, the following regimens are recommended:

If the patient has received fibrinolytic therapy and has been given clopidogrel, clopidogrel should be continued as the P2Y12 inhibitor of choice

If the patient received fibrinolytic therapy without P2Y12 inhibitor, a loading dose of clopidogrel should be given as the P2Y12 inhibitor of choice

If the patient did not receive fibrinolytic therapy, either loading dose of clopidogrel or ticagrelor should be given, or once the coronary anatomy is known and PCI is planned, a loading dose of prasugrel should be given promptly and no later than one hour after PCI” (p.26)

6. “If the patient requires revascularization and a CABG is planned, it is recommended to withhold clopidogrel and ticagrelor for at least five days and prasugrel for at least seven days if possible to decrease the isk of excess bleeding” (p.6)

National Institute for Health and Clinical Excellence (NICE), UK, 201139 ACS

Ticagrelor for the treatment of acute coronary syndromes 1. “Ticagrelor in combination with low-dose aspirin is recommended for up to 12 months as a

treatment option in adults with acute coronary syndromes (ACS) that is, people:

with ST-segment-elevation myocardial infarction (STEMI) – defined as ST elevation or new left bundle branch block on electrocardiogram – that cardiologists intend to treat with primary percutaneous coronary intervention (PCI) or

with non-ST-segment-elevation myocardial infarction (NSTEMI) or

admitted to hospital with unstable angina” (p.3) 2. “characteristics to be used in defining treatment with ticagrelor for unstable angina are:

age 60 years or older; previous myocardial infarction or previous coronary artery bypass grafting (CABG); coronary artery disease with stenosis of 50% or more in at least two vessels; previous ischaemic stroke; previous transient ischaemic attack, carotid stenosis of at least 50%, or cerebral revascularization; diabetes mellitus; peripheral arterial disease; or chronic renal dysfunction” (p.3)

National Institute for Health and Clinical Excellence (NICE), UK, 201140 ACS and PCI

Prasugrel for the treatment of ACS with PCI 1. “Prasugrel in combination with aspirin is recommended as an option for preventing

atherothrombotic events in people with acute coronary syndromes having percutaneous coronary intervention, only when:

immediate primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction is necessary or

stent thrombosis has occurred during clopidogrel treatment or

the patient has diabetes mellitus” (p.4) 2. “People currently receiving prasugrel for treatment of acute coronary syndromes whose

circumstances do not meet the criteria in 1. should have the option to continue therapy until they and their clinicians consider it appropriate to stop” (p.4)

ACS=acute coronary syndrome; bid=twice daily; CABG=coronary artery bypass grafting; GRACE=Global Registry of Acute Coronary Events; NSTE=Non-ST elevation; od=once daily; PCI=percutaneous coronary intervention; STEMI=ST-elevation myocardial infarction; UA=unstable angina