This nationwide study of PCI treated MI patients examined the difference in effect and safety of 6- and 12-months clopidogrel treatment. The main result is that clopidogrel treatment beyond 6 months provided no benefit in rates of death, recurrent MI or a combined endpoint. We found a trend of increased number of bleedings among patients treated in the 2004-2005 regimen compared with those treated with the 2002-2003 regimen (p = 0.06).
Several studies have addressed the question of different durations of clopidogrel treatment after acute coronary syndrome and PCI[2
]. Eisenstein et al reported benefit of 12 months treatment compared with 6 months in patients treated with drug-eluting stents and concluded that at least 12 months' treatment was appropriate in this group of patients with lifelong treatment as a possibility. Patients treated with bare-metal stents had no advantage in respect to recurrent MI or death with clopidogrel treatment >6 months[16
]. The main weakness of the study by Eisenstein et al is that the choice of 6 or 12 months' treatment for the patient was based on a decision by the patient or the physician and was thus subject to confounding by indication. In comparison, our study avoided this selection of patients as we compared different treatment regimens based on standardized recommendations. The randomized Clopidogrel for the Reduction of Events During Observation (CREDO) trial found that 12 months' clopidogrel treatment was superior to 2-4 weeks of treatment[3
]. The PCI-CURE trial revealed a superior effect of combined treatment with aspirin and clopidogrel vs. aspirin in non-ST-elevation MI/acute coronary syndrome patients treated with PCI. The main benefit was observed from Day 2 to Day 30. Considering the period from PCI to end of follow-up, the PCI-CURE investigators found less occurrence of MI in the clopidogrel + aspirin group but comparable mortality-rates between the groups. However, the trial did not report the additional reduction of events that happened from Day 30 after PCI to end of follow-up, as no landmark analysis was presented. In the PCI-CURE study all stent-treated PCI patients received 2-4 weeks open-label clopidogrel followed by the randomized study drug[2
]. Eisenstein et al, the CREDO study and the PCI-CURE study did not report differences in event rates between 6- and 12-months' treatment, hence a direct comparison with our study is not possible.
In our sensitivity analysis, where persistence with treatment was ensured, we found no additional effect of 12 months treatment compared with 6 months treatment among patients with PCI Day 0-1. In patients treated with PCI Day 2-29, a reduced mortality was found among patients in clopidogrel treatment more than 6 months (Log rank p = 0.001, HR 0.55 (CI 0.35-0.86), p-value 0.01). Thus, the sensitivity analyses confirm the findings from the main analysis, except in patients treated with PCI day 2-29, where we found an effect on mortality. However, this result should be interpreted with caution, since it could be due to selection bias of low risk patients (with no endpoint the first six month of the study).
Other studies have focused on variations in clinical outcome between different stent-types (bare-metal stents and drug-eluting stents) and found small differences in early and late event rates[9
]. In these studies the information on use of clopidogrel is often inadequate, and some have referred to written guidelines[18
]. In our study we have no information on the stent types used, but another Danish study using a regional register from 2002 to mid-2005 reported the use of drug-eluting stents to be 0% in 2002 increasing to 75% in 2005[19
]. We considered the effect of different durations of clopidogrel treatment on a population level in PCI treated MI patients, with regard to recurrent MI and all-cause mortality. Knowledge of the stent types and coronary lesions would have given a more detailed picture of the patients' risk profiles. The effect of prolonged clopidogrel treatment should be interpreted in the context of a substantial change of stent use in the same period and the lack of knowledge of the stent types used is a limitation of our study. An increased use of drug-eluting stents would possibly give more in-stent thromboses and thus more recurrent MIs[9
]. Our results showed both unchanged rates of mortality and recurrent MIs. A meta-analysis by De Luca et al of ST-elevation MI patients treated with either bare-metal stents or drug-eluting stents compared short duration of clopidogrel treatment (3-9 months) with 12 months' treatment and found, like our study, no differences in respect to recurrent MI, death or a combination of these, between the stent types and different duration of clopidogrel treatment[17
The risk of bleeding is increased with use of antithrombotic medication. However, there are conflicting results from both randomized and observational studies regarding bleeding risk[1
]. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Advoidance (CHARISMA) trial tested long-term treatment in patients at high risk of atherothrombotic events[21
]. Among the symptomatic patients, they found a significant increase of moderate bleedings[21
]. The PCI-CURE and the CHARISMA study reported event rates of major bleedings of 1.6-2.7% [2
] whereas the CREDO study had event rates of 6.7 to 8.8%[3
]. Major bleedings in the CREDO trial were slightly differently defined than in the PCI-CURE and CHARISMA trial, which could explain some of the variation. In our study the average event rate for patients treated on both Day 0-1 and Day 2-29 was 3.8%. Our observed bleeding rates were higher than those reported from most randomized trials, although not as high as reported in the CREDO trial. This could be explained by the real-life setting of our study.
Strengths and Limitations
The main strength of our study is the completeness of data, with a complete and unselected cohort of patients followed in a real-life setting. We had exact information on clopidogrel use, by individual-level linkage to dispensed prescriptions and complete data on events. Treatment duration and persistence with clopidogrel was calculated individually[10
]. The concordance between drug dispensing and drug consumption is likely to be very high, since reimbursement of drug expenses is only partial in Denmark. In Denmark, aspirin can be bought as a prescribed drug as well as over-the-counter. In our study, we assessed aspirin use by dispensed prescriptions since patients in chronic treatment usually receive aspirin on prescription in order to receive financial reimbursement. This occurrence is substantiated by the high baseline use of aspirin seen in the study population (92.6%).
The main limitations of our study are inherent in the observational nature of the study. We have no information on important prognostic factors i.e. lipid levels, smoking status, or left ventricular systolic function, stent types used, coronary lesions and the treatment given during index admission, e.g. loading dose of aspirin and clopidogrel, treatment with glycoprotein IIb/IIIa inhibitors, and heparins. These factors, may have influenced the results and affected the decision by the physician to prescribe clopidogrel for a shorter or a longer period[2
]. During the study period there were slight changes in the baseline characteristics of the population. However, we do not believe this had a major effect on our conclsions. More patients were treated invasively in close connection to the diagnosis of MI during the later period, with 58.5% treated Day 0-1 in 2002-2003 increasing to 63.9% in 2004-2005. This change of practice can be explained by an adaptation to national guidelines, which were altered after publication of the Danish Multicenter Randomized Study on Fibrinolytic Therapy versus Acute Coronary Angioplasty in Acute Myocardial Infarction II trial[24
]. In our analyses we stratified the patients according to the time of PCI, which limited the influence on the results. We were unable to accurately distinguish between the diagnoses of non-ST-elevation myocardial infarction and ST-elevation myocardial infarction and despite we stratified the patients according to the time of PCI treatment, this is a limitation. Throughout the period a change of age and use of concomitant medical treatment were seen. We included both age and various concomitant medications in the Cox proportional hazards models to eliminate confounding by these variables, but effect of residual confounding cannot fully be excluded.