Cardiovascular trials part 2 An evidence-based look at coronary disease and heart failure BY Peter Leong-Sit, MD

1 2 3

Which medications save lives in CAD?
Fifty-seven percent of all cardiovascular (CV) deaths in Canada are attributed to coronary artery disease (CAD), while over 350,000 Canadians suffer from the burden of heart failure (HF).1,2 A large number of therapeutic agents have been shown to lower mortality and morbidity among individuals with CAD, with several groups advocating an "ABC" format to help summarize these key agents (Table 1).3

Can you recap the antithrombotic evidence?
ASA has traditionally played a role in secondary prevention of CAD. The Antithrombotic Trialists' Collaboration published a systematic meta-analysis of 287 randomized studies of different antiplatelet regimens in patients with a previous CV event.4 Of the 65 placebo-controlled trials, which included close to 60,000 patients, ASA was found to decrease major adverse CV events (MACE; vascular death, myocardial infarction [MI] or stroke) by 23% (SD +/-2%, p < 0.0001) while CV deaths dropped by 15% (SD +/- 2%, p < 0.0001).

Clopidogrel, a thienopyridine, adds to the cyclooxygenase inhibitive effects of ASA by blocking the platelet's adenosine diphosphate receptor. Several major trials have shown the benefit of clopidogrel in many settings (Table 2). The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE)5 study first compared clopidogrel against ASA in patients with known cardiovascular disease (CVD). The trial demonstrated that clopidogrel was slightly favourable by decreasing MACE after 1.9 years of follow-up. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE)6 trial was the first to show the advantages of combining ASA with clopidogrel in non-ST elevation acute coronary syndrome (ACS). After treatment for 3-12 months, combined MACE was reduced, though a slight increase in major bleeding (3.7% vs 2.7%, relative risk 1.38, p = 0.001) occurred. The Clopidogrel for the reduction of Events During Observation (CREDO)7 trial extended the benefit of the ASA/clopidogrel combination to a longer period of one year in a more stable patient population undergoing planned percutaneous coronary angioplasty. Recently, the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)8 study and the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT)9 have shown a small, but statistically significant advantage of clopidogrel as an add-on in acute ST-elevation MI.

The efficacy of anticoagulation with warfarin
in known CAD should also be mentioned. The Warfarin-Aspirin Reinfarction Study (WARIS II)10 compared warfarin, ASA or both in 3,630 patients hospitalized with an acute MI. When pitted against ASA alone, the study revealed a decrease in MACE with the warfarin/ASA combo (ARR 5.0%, RRR 29%, p = 0.001) and with warfarin alone (ARR 3.3%, RRR 19%, p = 0.03). Anecdotally, however, adding warfarin to patients with CAD remains uncommon when no other indication for systemic anticoagulation exists. This is possibly due to the higher risk of bleeding (0.62% vs 0.17% per year, p < 0.001) and the inconvenience and cost of warfarin therapy and follow-up.

Where's the evidence for ACE inhibitors after MI?
The role of angiotensin-converting enzyme (ACE) inhibitors in heart disease has expanded in the last 20 years. In the 1980s, the focus began on patients with overt clinical HF and left ventricular (LV) systolic dysfunction (these trials will be discussed in the HF section of this review). In the 1990s, the focus shifted to the post-infarct patient with and without overt LV dysfunction. Researchers are now looking at stable high-risk patients (see summary of the HOPE, EUROPA and PEACE studies found in Part 1, Parkhurst Exchange, February 2006, p. 136).11,12,13

Table 3 summarizes some key trials involving ACE inhibitors and post-infarct patients. The Survival and Ventricular Enlargement (SAVE)14 study, Acute Infarction Ramipril Efficacy (AIRE)15 trial and the Trandalopril Cardiac Evaluation (TRACE)16 study randomized approximately 6,000 patients to captopril, ramipril and trandalopril, respectively, vs placebo in the setting of an acute MI and evidence of HF or LV dysfunction. Results from these three studies were similar, showing a drop in all-cause mortality of 18-27%. Shortly thereafter, the third Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico (GISSI-3)17 study and the fourth International Study of Infarct Survival (ISIS-4)18 enrolled a combined 77,000 individuals with an acute MI, but no requirement for LV dysfunction or clinical HF. Lisinopril and captopril, respectively, were used within one day of presentation vs placebo. A less pronounced, but still significant mortality benefit was found in both trials (ARR 0.5-0.8%, RRR 7.0-11%).