Acute coronary syndromes - clopidogrel

4. Evidence and interpretation

The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).

4.1. Clinical effectiveness

4.1.1. The Assessment Group found one randomised controlled trial of clopidogrel in patients with non-ST-segment-elevation ACS that met the inclusion criteria for its review – the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study. CURE was a randomised, double-blind, placebo-controlled trial in 12,562 people with non-ST-segment-elevation ACS who had presented within 24 hours after the onset of symptoms. At the outset of the study, people with no new ECG changes could be included, provided they were older than 60 years and had a history of coronary artery disease. However, a lower than anticipated event rate in the first 3000 participants prompted a change in the inclusion criteria, in order to recruit a higher-risk population. All new participants, regardless of their age, were required to have either ECG changes indicative of new ischaemia or serum levels of biochemical markers of myocardial damage twice the upper limit of the normal reference range. Participants in the study were randomised to receive either clopidogrel 300 mg immediately followed by 75 mg once daily, or placebo. All participants also received aspirin and other standard therapy, as deemed necessary. Other standard drug treatments included heparin, angiotensin-converting enzyme inhibitors, beta-blockers, nitrates, calcium channel blockers and lipid-lowering agents. Glycoprotein IIb/IIIa inhibitors were not routinely used and only 6.6% of the trial population received them. Follow-up was for 3–12 months (mean 9 months). The protocol specified two ‘primary’ end-points: the first was a composite of death from cardiovascular causes, non-fatal MI, or stroke; the second was a composite of death from cardiovascular causes, non-fatal MI, stroke, or refractory ischaemia.

4.1.2. The CURE study found a statistically significantly lower incidence of death from cardiovascular causes, non-fatal MI or stroke with clopidogrel plus aspirin therapy compared with placebo plus aspirin: 582 (9.3%) and 719 (11.4%), respectively. This equates to a relative risk reduction in the first composite primary end-point of 20% (95% confidence interval [CI], 10 to 28%, p < 0.001) or an absolute risk reduction of 2.1% (95% CI, 1.0 to 3.2%). For the second composite primary end-point, which also included refractory ischaemia, the relative risk reduction with clopidogrel was 14% (95% CI, 6 to 21%, p < 0.001) and the absolute risk reduction was 2.3% (95% CI, 1.0 to 3.2%).

4.1.3. The published report presented nine key subgroup analyses (associated MI versus no associated MI, male versus female, ≤ 65 versus > 65 years of age, ST-segment-deviation versus no ST-segment-deviation, elevated cardiac enzymes at entry versus no elevated enzymes at entry, diabetes versus no diabetes, low versus intermediate versus high risk, history of revascularisation versus no history of revascularisation, and revascularisation after randomisation versus no revascularisation after randomisation). These generally showed consistent relative benefits of clopidogrel across the subgroups, with the exception of a tendency towards greater benefit for clopidogrel in those who had previously undergone revascularisation. However, given the number of subgroup analyses, this result may have occurred by chance.

4.1.4. Analysis of the events in different time periods of the trial suggested that the greatest benefits occurred within the first 3 months of treatment. However, the trial was not adequately powered to detect temporal differences between the groups, so these results should be interpreted cautiously.

4.1.5. The rates of both major and minor bleeding episodes were higher in the clopidogrel group compared with the placebo group. Major bleeding (defined as substantially disabling bleeding, intraocular bleeding leading to loss of vision, or bleeding necessitating the transfusion of at least 2 units of blood) occurred in 231 (3.7%) of the clopidogrel group compared with 169 (2.7%) of the placebo group (relative risk [RR], 1.38; 95% CI, 1.13 to 1.67). The rate of major bleeding episodes was highest within 30 days after randomisation. There was no difference in the number of fatal bleeding episodes, bleeding requiring surgical intervention or haemorrhagic stroke between the treatment groups.

4.1.6. A total of 2658 (21.2%) participants in the CURE study underwent PCI and were included in a pre-designed substudy (PCI-CURE). The objective of this substudy was to determine whether a strategy of pretreatment with clopidogrel followed by long-term use was better than a strategy of no pretreatment and short-term use of a thienopyridine antiplatelet agent only when a stent has been inserted. More than 80% of the participants in PCI-CURE received a stent and were prescribed open-label clopidogrel or ticlopidine for 2–4 weeks, after which they resumed randomly assigned medication. The primary end-point of PCI-CURE was the composite of death from cardiovascular causes, non-fatal MI or urgent revascularisation of the target vessel within 30 days of PCI. The primary end-point occurred in 59 (4.5%) of the clopidogrel group compared with 86 (6.4%) of the placebo group (RR 0.70; 95% CI, 0.50 to 0.97). Cardiovascular death and MI from the time of PCI to the end of the study were also assessed to determine the effects of long-term continuation of clopidogrel. From the time of PCI to the end of follow-up (mean 8 months), there were significantly fewer cardiovascular deaths and non-fatal MIs in the clopidogrel group compared with the placebo group: 79 (6.0%) and 108 (8.0%), respectively (RR 0.75; 95% CI, 0.56 to 1.00; p = 0.047).

4.1.7. Overall, it appears that adding clopidogrel to standard therapy reduces the risk of adverse vascular events in the first year after an episode of non-ST-segment-elevation ACS, but this was combined with an increase in the incidence of bleeding complications.

4.2. Cost effectiveness

4.2.1. The systematic review of the economic evidence performed by the Assessment Group found only one study published in full that met the inclusion criteria. This was an analysis of five treatment strategies using antiplatelet agents for the treatment of coronary artery disease compared with no treatment over a period of 25 years. However, the analysis was conducted from the perspective of the US healthcare system and the population consisted of patients with recently diagnosed coronary artery disease rather than non-ST-segment-elevation ACS specifically. The Assessment Group therefore concluded that this analysis was of limited value to this appraisal.

4.2.2. The sponsors of clopidogrel (Sanofi-Synthelabo, Bristol-Myers Squibb) submitted an economic analysis from the perspective of the UK NHS. The model was designed to assess the long-term cost effectiveness of treatment with clopidogrel added to standard treatment (including aspirin) compared with standard treatment alone. It was assumed that treatment with clopidogrel was for 12 months (reflecting the follow-up period of the CURE trial rounded up to the nearest full year). After 1 year, it was assumed that all patients received aspirin as their sole antiplatelet agent for the remainder of their lives. The model comprised two components: a short-term decision tree to model the costs and effects over the 12-month treatment period, and a long-term element that extended the analysis over a 40-year time horizon (corresponding to a lifetime of treatment, given that the cohort of patients entered into the model were assumed to be 60 years old). Over the full term of the model, a total of 87 life years and 82 quality-adjusted life years (QALYs) were gained in a hypothetical cohort of 1000 people with ST-segment-elevation ACS. The cost per additional QALY associated with clopidogrel combination therapy for 1 year compared with aspirin alone was £5668.

4.2.3. The Assessment Group developed a model that was similar in structure to that submitted by the sponsors of this product (both were based on a previously published model to evaluate the cost effectiveness of glycoprotein IIb/IIIa inhibitors in non-ST-segment-elevation ACS). The main differences between the Assessment Group’s model and the manufacturer’s model were in the estimation of resource use and the estimates of utility for the different health states. In the Assessment Group's model, the age of the patients in the model is not incorporated as an explicit parameter. The age to which the analysis relates reflects that of the patients in the cohorts used to populate the model. Two separate observational data sets were used: the Prospective Registry of Acute Ischaemic Syndromes in the UK (PRAIS-UK) and the Nottingham Heart Attack Registry (NHAR). In PRAIS-UK, the mean age of patients was 66 years; in the NHAR, the mean age of the two cohorts was 68 years. The Assessment Group’s base-case analysis calculated an incremental cost-effectiveness ratio (ICER) of £6078 per QALY for standard therapy plus clopidogrel compared with standard therapy alone. A range of sensitivity analyses was conducted to assess the robustness of the base-case analysis to alternative assumptions. Reducing the time horizon of the model from 40 years to 5 years had the largest effect: the ICER increased to £14,844 per QALY.

4.2.4. The Assessment Group also explored the cost effectiveness of using clopidogrel for periods shorter than 1 year. This was an analysis of five strategies: lifetime treatment with standard therapy (including aspirin) alone, or clopidogrel as an adjunct to standard therapy (including aspirin) for 1 month, 3 months, 6 months or 12 months. The ICER for 1 month of treatment with clopidogrel compared with standard care alone was calculated to be £824 per QALY. The strategies of using clopidogrel for 3 or 6 months were ruled out by extended dominance, and the ICER for 12 months of treatment with clopidogrel compared with 1 month was £5159 per QALY. An alternative method of extrapolation to estimate the transition probabilities between 6 and 12 months gave results more consistent with a continued decline in the absolute risk of events over this period. Using these estimates, none of the five strategies were ruled out on the grounds of dominance/extended dominance. The ICER became less favourable as the duration of treatment with clopidogrel increased:

• 1 month of treatment with clopidogrel compared with standard therapy alone, ICER = £895 per QALY
• 3 months compared with 1 month of treatment, ICER = £5625 per QALY
• 6 months compared with 3 months of treatment, ICER = £6591 per QALY
• 12 months compared with 6 months of treatment, ICER = £13,988 per QALY.

4.2.5. The Assessment Group also explored the cost effectiveness of treatment in people at either ‘higher’ or ‘lower’ risk, as defined within the observational data set, as part of their sensitivity analyses. For the purposes of this analysis, people were considered at higher risk if they had diabetes mellitus, or were over 70 years old, or if they had ST-segment-depression or bundle branch block on ECG, and were considered at lower risk if they had none of these characteristics. This differed from the definitions of high and low risk used in subgroup analyses of the CURE study. In this sensitivity analysis, the ICER for 12 months’ treatment with clopidogrel compared with standard treatment alone was £4939 per QALY in people who were considered at higher risk on the basis of these criteria, and £8734 in people considered at lower risk.

4.3. Consideration of the evidence

4.3.1. The Committee reviewed the evidence available on the clinical and cost effectiveness of clopidogrel in non-ST-segment-elevation ACS, having considered evidence on the nature of the condition and the value placed by users on the benefits of clopidogrel from people with coronary artery disease, those who represent them, and clinical experts. It was also mindful of the need to ensure that its advice took account of the efficient use of NHS resources.

4.3.2. The Committee considered that the evidence reviewed in the Assessment Report supported the case that clopidogrel, used as an adjunct to standard therapy with low-dose aspirin, was clinically and cost effective in the management of non-ST-segment-elevation ACS. The Committee noted that this conclusion was based on evidence from a single clinical trial, which mainly recruited patients with ACS and a moderate to high risk of suffering a subsequent occlusive vascular event. The Committee heard from the experts that most patients presenting with non-ST-segment-elevation ACS would fulfil the amended and more stringent criteria for entry to the CURE study, but that there is a significant minority of patients who present with no significant ECG changes and no change in biochemical markers of cardiac damage, for whom the value of additional antiplatelet therapy with clopidogrel was unclear. After discussion with the experts, and in light of the decision made by the CURE investigators to change the inclusion criteria of the study, the Committee concluded that the use of clopidogrel should be directed at those patients for whom there is good evidence of benefit and who have an elevated risk of progressing to MI or death (that is, patients who would have fulfilled the more stringent set of criteria for entering the CURE study).

4.3.3. In the CURE trial, clopidogrel treatment was given for 3–12 months (mean duration of treatment: 9 months). Although the greatest difference in event rates, and hence the greatest benefit of clopidogrel, occurred in the first 3 months of treatment (see Section 4.1.4), the Committee felt that appreciable benefit still occurred between 3 and 12 months. In the light of the Assessment Group’s cost-effectiveness analysis, the Committee concluded that treatment with clopidogrel for up to 12 months was likely to be cost effective.

4.3.4. Neither the sponsors’ nor the Assessment Group’s cost-effectiveness analysis attempted to model the costs and effects of treatment with clopidogrel beyond the 12-month duration of the clinical trial. In the absence of direct evidence for the clinical and cost effectiveness of clopidogrel for longer periods, and in view of the smaller absolute benefits seen in the later stages of the CURE study, the Committee’s view was that treatment with clopidogrel should continue for no longer than 12 months after the most recent episode of non-ST-segment-elevation ACS. They were not persuaded to recommend treatment for longer than 12 months after the most recent episode of non-ST-segment-elevation ACS. They concluded that, on the basis of current evidence, after 12 months, antiplatelet therapy should revert to standard use of low-dose aspirin.

4.3.5. In light of the sensitivity analyses performed by the Assessment Group (see Section 4.2.5), the Committee saw no reason to base the decision about whether or not to use clopidogrel in an individual on their age (over 70 years or not), whether or not they had diabetes mellitus, or whether or not they had ST-segment-depression or bundle branch block on ECG

4.3.6. The Committee noted that clopidogrel was associated with an excess risk of bleeding compared with standard therapy in the CURE study. Standard therapy included aspirin and heparin, but most people in CURE did not receive any other drugs that interfere with clotting, for example, only 6.6% of the study population received glycoprotein IIb/IIIa inhibitors. The additional risks and benefits associated with the combined use of clopidogrel and other antithrombotic agents, such as glycoprotein IIb/IIIa inhibitors, in the medical management of ACS are unknown. Therefore, the Committee was unable to make a recommendation on the use of these combinations.