From the hope to the ontarget and the transcend studies: challenges in improving prognosis

doi:10.1016/S0002-9149(01)02323-2

The American Journal of Cardiology

Volume 89, Issue 2, Supplement 1, 24 January 2002, Pages 18-25

https://doi.org/10.1016/S0002-9149(01)02323-2 Get rights and content

Abstract

The Heart Outcomes Prevention Evaluation (HOPE) study conclusively demonstrated that ramipril, an angiotensin-converting enzyme (ACE) inhibitor, reduces the risk of cardiovascular death, myocardial infarction (MI), and death in patients at risk for cardiovascular events but without heart failure. The Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE) substudy demonstrated that ramipril also reduced atherosclerosis. These results suggest that the renin-angiotensin system (RAS) has a more important role in the development and progression of atherosclerosis than previously believed, and they indicate the need for further clinical studies to define the range of benefits available from modifying the RAS. Achieving maximum benefit may require treatment with both an ACE inhibitor and an angiotensin II type-1 receptor blocker (ARB). The Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) study indicated that combining an ACE inhibitor with an ARB decreased blood pressure and improved the ejection fraction more than treatment with either drug alone in patients with congestive heart failure. The Valsartan in Heart Failure Trial (Val-HeFT) showed that the combination of an ACE inhibitor and an ARB reduced hospitalization for heart failure in patients with congestive heart failure by 27.5%, although no decrease in all-cause mortality was observed. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) is a large, long-term study (23,400 patients, 5.5 years). It will compare the benefits of ACE inhibitor treatment, ARB treatment, and treatment with an ACE inhibitor and ARB together, in a study population with established coronary artery disease, stroke, peripheral vascular disease, or diabetes with end-organ damage. Patients with congestive heart failure will be excluded. In a parallel study, patients unable to tolerate an ACE inhibitor will be randomized to receive telmisartan or placebo (the Telmisartan Randomized Assessment Study in ACE-I Intolerant Patients with Cardiovascular Disease [TRANSCEND]). The primary endpoint for both trials is a composite of cardiovascular death, MI, stroke, and hospitalization for heart failure. Secondary endpoints will investigate reductions in the development of diabetes mellitus, nephropathy, dementia, and atrial fibrillation. These 2 trials are expected to provide new insights into the optimal treatment of patients at high risk of complications from atherosclerosis.

Section snippets

A possible role for angiotensin II in the development and progression of cardiovascular disease

Historically, the RAS has been viewed as a regulatory system limited to blood pressure and fluid electrolyte regulation. Disorders of this system contribute to the pathophysiology of hypertension, renal disease, and congestive heart failure. These conditions can be improved by ACE inhibition and/or blockade of angiotensin II type-1 receptors.2 However, recent work suggests that angiotensin II also has a direct role in atherothrombosis.3

Victor Dzau3 has proposed that angiotensin II, which is

The heart outcomes prevention evaluation study

The HOPE study1 randomized 9,297 high-risk patients >55 years of age, who had clinical evidence of vascular disease (coronary artery disease, cerebrovascular disease, or peripheral arterial disease), or diabetes and 1 other cardiovascular risk factor (hypertension, elevated levels of total cholesterol, low levels of high-density lipoprotein cholesterol, cigarette smoking, or microalbuminuria). None had heart failure or were known to have a low ejection fraction. The population did not include

The study to evaluate carotid ultrasound changes in patients treated with ramipril and Vitamin E

A substudy of the HOPE trial—the Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE)—was directed at measuring the impact of ramipril treatment on progression of atherosclerosis.5 A total of 732 patients matching the previously described selection criteria underwent duplicate B-mode carotid ultrasound examinations at baseline, at about 2.5 years, and at the end of the study. The results are shown in Figure 4. According to these data,

The randomized evaluation of strategies for left ventricular dysfunction study

ACE inhibition does not reduce all sources of angiotensin II. Although ACE is the major mechanism for angiotensin II production, angiotensin II can also be produced through other pathways, such as those involving chymase.8 Thus, angiotensin II continues to be present, despite ACE inhibition. Additional treatment with an ARB may be a potential strategy to amplify the benefits of ACE inhibition, thus preventing angiotensin II type-1 receptor activation by residual angiotensin II (this mechanism

Other preliminary studies on angiotensin II type-1 receptor blocker/angiotensin-converting enzyme inhibitor combination therapy

Another trial studying the benefits resulting from the ARB/ACE inhibitor combination, the Valsartan in Heart Failure Trial (Val-HeFT), was completed in 2000.11 This study involved 5,010 patients with NYHA functional class II–IV, an ejection fraction <0.40, and a left ventricular end-diastolic dimension >2.9 cm/m² who were studied for a mean of 1.9 years. The ARB valsartan (titrated from the starting dose of 40 mg to 160 mg, 3 times per day) or placebo was given with enalapril (approximately 18

The ongoing telmisartan alone and in combination with ramipril global endpoint trial and the telmisartan randomized assessment study in angiotensin-converting enzyme inhibitor-intolerant patients with cardiovascular disease

ONTARGET is a double-blind, parallel-group study with 3 treatment arms: (1) telmisartan (80 mg), (2) ramipril (10 mg), and (3) telmisartan (80 mg) plus ramipril (10 mg). The trial will involve approximately 23,400 patients in 40 countries over a 5.5-year period. Participating patients will be similar to the patients studied in HOPE: >55 years of age and with a history of (1) coronary artery disease, (2) stroke, (3) peripheral vascular disease, or (4) diabetes mellitus with end-organ damage

Conclusion

Significant advances in the prevention and treatment of cardiovascular disease are becoming possible as new drug therapies are developed. Large clinical trials, such as the HOPE study, provide important information for evidence-based treatment protocols, and they suggest approaches for further improvement. The HOPE study identified a central role for angiotensin II in the progression of atherosclerosis. ONTARGET and TRANSCEND build on the successful HOPE study by adopting 3 strategies for

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There are more references available in the full text version of this article.

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From the hope to the ontarget and the transcend studies: challenges in improving prognosis

Abstract

Section snippets

A possible role for angiotensin II in the development and progression of cardiovascular disease

The heart outcomes prevention evaluation study

The study to evaluate carotid ultrasound changes in patients treated with ramipril and Vitamin E

The randomized evaluation of strategies for left ventricular dysfunction study

Other preliminary studies on angiotensin II type-1 receptor blocker/angiotensin-converting enzyme inhibitor combination therapy

The ongoing telmisartan alone and in combination with ramipril global endpoint trial and the telmisartan randomized assessment study in angiotensin-converting enzyme inhibitor-intolerant patients with cardiovascular disease

Conclusion

Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators

N Engl J Med

Angiotensin II receptor antagonists in the treatment of hypertension

Am Fam Physician

Tissue angiotensin and pathobiology of vascular diseasea unifying hypothesis

Hypertension

Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease

Circulation

Effects of ramipril and vitamin E on atherosclerosisthe study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE)

Circulation

Effects of ramipril on left ventricular mass and function in normotensive, high-risk patients with normal ejection fraction. A substudy of HOPE

J Am Coll Cardiol