Section I: RAS manipulation C. Update on clinical trials in CAD HOPE: Reduction in fatal/nonfatal MI with ramipril 10 mg Content Points: New reports from the Heart Outcomes Prevention Evaluation (HOPE) study investigators expand on the initial report by providing further details on outcomes.12 As shown, there was a 21% risk reduction in fatal or nonfatal myocardial infarction (MI) associated with ramipril 10 mg (P < 0.0003). Kaplan Meier curves showing the cumulative fatal and nonfatal MI began to diverge after 2 years, and the divergence continued thereafter, throughout the follow-up.

HOPE: Effect of ACEI plus concomitant cardiovascular therapy on MI Content Points: The effect of ramipril was consistent in various subgroups. In particular, consistent results were observed among those on other treatments known to reduce the risk of MI, such as antiplatelet agents (14%), lipid-lowering agents (24%), and ß-blockers (16%).12 The beneficial effect of ramipril on MI was also observed among patients who were not taking these agents, indicating that the effects are independent and additive to these agents.

HOPE: Reduction of risk for LVH in high-risk patient subgroups Content Points: Left ventricular hypertrophy (LVH) as measured by the electrocardiogram (ECG-LVH) predicts a poor cardiovascular prognosis. However, data have been lacking on whether regression of ECG-LVH improves prognosis. In a substudy of HOPE, the impact of ramipril on ECG-LVH was measured.13 ECGs were recorded in 676 patients at the beginning and end of the study. Regression of LVH was defined as disappearance of electrocardiographic (ECG) markers of LVH. As shown, patients assigned to ramipril 10 mg had a lower risk of development or persistence of ECG-LVH in all the subgroups assessed. This finding is consistent with other studies demonstrating the particularly beneficial effects of ACE inhibitors on LVH.14 The effect of ramipril 10 mg on ECG-LVH was independent of blood pressure status or presence/absence of coronary artery disease. The clinical impact of the decline in ECG-LVH is discussed on the next slide.

HOPE: Impact of LVH reversal or prevention on primary outcome and heart failure Content Points: Patients in whom ECG-LVH regressed or was prevented had a lower risk of the primary study outcome including cardiovascular death, MI, and stroke compared to those in whom ECG-LVH developed or persisted (12.3% vs 15.8%, P = 0.006).13 They also had a lower risk of congestive heart failure (CHF) with or without hospitalization (9.3% vs 15.4%, P < 0.0001). Reversal or prevention of LVH also lowered the risk for the primary outcome plus hospitalization for CHF, for hospitalization for unstable angina, for revascularization, diabetes complications, and sudden death. The investigators concluded that ramipril decreases development and causes regression of ECG-LVH in a broad range of high-risk patients regardless of their blood pressure status and presence or absence of coronary artery disease. These changes are associated with a lower risk of death, MI, stroke, and CHF.

HOPE: Estimated vs observed risk reductions Content Points: The reduction from baseline in office systolic blood pressure at study end in the overall HOPE population was 3.3 mm Hg.15 Based on a meta-analysis of all hypertension trials reported in the World Health Organization/International Society of Hypertension (WHO/ISH) guidelines, Sleight et al concluded that this reduction would be expected to result in relative risk reductions of 5% and 13% for MI and stroke, respectively.16 In fact, the observed risk reductions in the ramipril group of the HOPE study were much greater than expected from blood pressure reduction alone, at 20% and 32%, respectively.16 Sleight et al concluded that the benefits observed in the ramipril 10 mg group in HOPE were not due to blood pressure reduction alone. Other mechanisms of benefit were operative. These data along with the results of other ACE inhibitor trials stress the importance of using ACE inhibitors in patients with normal blood pressure if they have evidence of vascular disease.16

HOPE: Clinical benefits compare favorably with major statin trials in CAD patients Content Points: Otterstad and Sleight calculated the number needed to treat to prevent 1 primary outcome event in HOPE and in the major secondary prevention trials of statins, including the Scandinavian Simvastatin Survival Study (4S), Cholesterol And Recurrent Events study (CARE), and the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID).17 As noted by Otterstad and Sleight, these trials had different primary outcomes: cardiovascular death, MI, stroke (HOPE); total mortality (4S); cardiovascular death, MI (CARE); cardiovascular death (LIPID). Nevertheless, the benefits in HOPE are comparable with the other trials with respect to the number needed to treat to prevent a primary outcome: 26 in HOPE and from 30 to 52 in the statin trials. Even after adjusting for the different study durations, the treatment effect seen in HOPE is comparable with that observed in the statin trials.

Cost-effectiveness of proven CV and non-CV interventions for risk reduction Content Points: This study by Malik and colleagues examined cost-effectiveness of ramipril in patients with low, medium, and high pretreatment cardiovascular risk based on the data from the HOPE trial.18 The findings show that ramipril 10 mg is a cost-effective treatment for patients with proven vascular disease or diabetes plus an additional risk factor. The slide compares the cost-effectiveness of proven cardiovascular and non-cardiovascular interventions per year of life saved at 5 years. As seen, use of ramipril to reduce cardiovascular risk is as cost-effective as other medical treatments and it compares favorably with statin treatment. The cost per year of life saved would be substantially lower at 20 years (lifetime treatment) in high, medium, and low-risk patients. Of note, the cost-effectiveness of ramipril is substantially below the cost of hemodialysis per year of life gained and clearly more cost-effective than a driver’s side air bag, which is mandated by law.

AHA/ACC secondary CHD prevention guidelines: Lifestyle modifications Content Points: Emerging data from major clinical trials prompted a recent update of the guidelines for preventing heart attack and death in patients with atherosclerotic cardiovascular disease jointly issued by the American Heart Association (AHA) and the American College of Cardiology (ACC).19 The aging of the population continues to expand the number of patients living with a diagnosis of cardiovascular disease. The next few slides will highlight major aspects of the updated guidelines. Lifestyle modification goals are summarized on this slide: Complete cessation of smoking A minimum of 30 minutes of physical activity 3 to 4 times weekly Weight control to maintain a body mass index (BMI) between 18.5 and 24.9 kg/m2 and waist size below 40 inches in men and 35 inches in women Moderate intake of alcohol (<1 drink daily for women, <2 drinks daily for men) and moderate sodium restriction promote blood pressure control and lipid management. The diet should emphasize fruits and vegetables. Dairy products should be low fat. For lipid reduction, the diet should contain <7 g saturated fat and <200 g cholesterol.

AHA/ACC secondary CHD prevention guidelines: Drug treatment Content Points: Recommendations for anticoagulation, ACE inhibition, and b-blockade in the AHA/ACC secondary prevention guidelines are as follows:19 Aspirin in daily doses of 75 to 325 mg should be started unless contraindicated and continued indefinitely. Clopidogrel 75 mg daily or warfarin should be considered when aspirin is contraindicated. In post-MI patients, warfarin (international normalized ratio of 2.0 to 3.0) should be given when it is clinically indicated, or when the patient is not able to take aspirin or clopidogrel. ACE inhibitors should be used in all post-MI patients and continued indefinitely. They should also be considered for all other patients with coronary or peripheral vascular disease, based on the results of the HOPE study. ß-Blockers should be started in all post-MI patients or patients with acute ischemic syndrome and continued indefinitely. They can be used as needed to manage angina, rhythm, or blood pressure in all other patients.

AHA/ACC secondary CHD prevention guidelines: Goals for BP, lipids, glucose Content points: The updated guidelines for BP management advise that lifestyle modifications should be initiated in all patients with blood pressure >130 mm Hg.19 The blood pressure goal is lower for patients with diabetes or heart failure than for all other secondary prevention patients. Blood pressure medication should be tailored to the patient. Following recent NCEP guidelines, the LDL-C goal is <100 mg/dL for all patients with CHD and for patients with diabetes.20 HDL-C levels should be >40 mg/dL. (The new NCEP guidelines recommend an HDL-C >50 mg/dL in women.) Triglycerides should be <200 mg/dL (or non-HDL-C should be <130 mg/dL). Patients with diabetes should receive hypoglycemic therapy to achieve near-normal fasting plasma, as indicated by HbA1c level, with <7% HbA1c as a target.