Does clopidogrel improve the long-term outcome after coronary artery bypass surgery?

The long-term outcome of patients undergoing coronary artery bypass surgery is threatened by the occurrence of bypass graft stenosis and occlusion as well as the progression of coronary and peripheral artery disease. During the 1980s and early 1990s a number of studies addressed the value of antiplatelet therapy to decrease the risk of coronary bypass occlusion and the occurrence of recurrent ischemic events, and a positive effect of aspirin with or without dipyridamole on vein graft patency has been demonstrated 1–3. A more recent study demonstrated that antiplatelet therapy effectively prevents fatal and non-fatal vascular events 4. As a result, antiplatelet therapy is, nowadays, considered a cornerstone in the treatment of atherosclerosis and long-term administration of aspirin at various dosages is currently adopted in all patients with coronary and peripheral vascular disease. Aspirin can prevent about one quarter of serious vascular events in a wide range of high-risk patients, but still the risk of ischemic events remains high 4. Thus, other more effective antiplatelet drugs are needed and, so far, only clopidogrel has been shown to be somewhat more effective than aspirin.

In the CAPRIE trial 5, clopidogrel was superior to aspirin in patients with recent myocardial infarction, recent ischemic stroke or symptomatic peripheral arterial disease. In the latter study, clopidogrel was associated with a relative risk reduction of 8.7% (p=0.043) for the composite endpoint ischemic stroke, myocardial infarction or vascular death 5. Furthermore, the use of clopidogrel was associated with a favourable safety-tolerability profile.

More recently, a subanalysis of the CAPRIE database showed that in patients with history of ischemic stroke and/or myocardial infarction, clopidogrel was associated with a relative risk reduction of 14.9% (p=0.045) for the composite endpoint ischemic stroke, myocardial infarction or vascular death 6. Seventy-one patients would need to be treated for 1 year and 29 patients for 3 years with clopidogrel instead of aspirin to prevent one ischemic event 6.

The CURE trial 7 confirmed the benefit of a long-term treatment (3–12 months) with clopidogrel combined with aspirin over aspirin alone. However, a certain increased risk of major bleeding complications exists by combining clopidogrel and aspirin, but not in terms of life-threatening bleeding.

Two studies (CREDO, PCI-CURE) 8,9 demonstrated that pre-procedural and long-term administration of clopidogrel significantly reduces the risk of late vascular events after percutaneous coronary intervention.

A study by the CREDO Investigators 10 showed that up-front and long-term treatment with clopidogrel is associated with a much larger relative risk reduction (42.4% vs 21.7%) in ischemic events at 1 year follow-up in patients undergone repeat percutaneous coronary intervention compared with those undergone primary percutaneous coronary intervention. Indeed, a large relative risk reduction has been previously demonstrated for several long-term endpoints in a study by the CAPRIE Investigators in patients with a history of previous cardiac surgery 11. The rate per year of vascular death, myocardial infarction, ischemic stroke or rehospitalization for ischemia was reduced from 21.6% to 15.2% (relative risk reduction, 29.3%; 95% CI, 13.3–42.3; p=0.0008). Multivariate analysis showed that in patients with history of cardiac surgery clopidogrel vs aspirin was associated with a relative risk reduction of 31.2% for the composite endpoint vascular death, myocardial infarction, stroke or rehospitalization for ischemia or bleeding 11. A major pitfall of this study is the lack of information about the type of cardiac surgery previously performed in these patients. Thus, it is possible that patients previously undergone cardiac surgery for diseases other than coronary artery disease have been included in the analysis.

A recent study by the CURE Investigators 12 showed that among patients who required coronary artery bypass surgery, clopidogrel provided some benefits before surgery, 71 patients (6.7%) experienced a primary endpoint in the placebo group compared with 57 (5.6%) of the clopidogrel group (RR, 0.82; 95% CI, 0.58–1.16). A similar number of events occurred after coronary artery bypass surgery in the placebo and clopidogrel groups (112 vs 103; RR, 0.97; 95% CI, 0.74–1.26), but clopidogrel therapy was stopped for a median of 10 d after surgery and was restarted in 75.3% of patients who stopped the drug before surgery. Even though clopidogrel had better survival freedom rates from cardiovascular death, myocardial infarction and stroke, such a difference was not significant (CI, 0.71–1.11) 12. These findings are far from being conclusive as no data about the severity of coronary artery disease, the amount and type of bypass grafts as well as important preoperative risk factors potentially associated with late adverse events have either been reported or analysed in this study. It is not known whether the length of clopidogrel therapy might have had an impact on the late outcome. It is also unclear whether patients of the clopidogrel study who stopped the medication before surgery and did not take the drug after surgery (24.7%) were still included in the clopidogrel group and, thus, in the long-term outcome analysis. Furthermore, the effect of clopidogrel was not adjusted with other risk factors.

Thus, the superiority of treatment with clopidogrel over aspirin after coronary artery bypass surgery has yet to be demonstrated. A prospective, randomized study in this patient population is needed to evaluate whether clopidogrel may prevent late adverse events after coronary artery bypass surgery and/or whether some subgroups of patients may benefit from clopidogrel therapy more than others. This is especially relevant as the use of clopidogrel has been shown to be associated with an excessive incremental cost 13. Marshall calculated an incremental cost per event prevented in patients at a pre-treatment risk of a coronary event over 5 years of 5% from £7900 for treatment with aspirin to £1 054 000 with clopidogrel 13. In patients with a pre-treatment coronary event risk over 5 years of 30% the incremental cost was from £1100 to £175 700 13. As a consequence, long-term treatment with clopidogrel instead of aspirin alone after coronary artery bypass surgery cannot yet be recommended.