MD FRCP FESC FACC
Professor of Medical Cardiology &
Honorary Consultant Cardiologist
Department of Cardiology
Though early reperfusion therapy, antiplatelet agents, beta-blockers, statins and angiotensin-converting enzyme (ACE) inhibitors have greatly improved the progress of patients suffering from an acute myocardial infarction (MI), some patients remain at high risk. These have acute MI complicated by heart failure (HF), evidence of substantial left ventricular systolic dysfunction (LVSD) or both. The Valsartan in Acute Myocardial Infarction (VALIANT) registry showed that, though these patients account for only 40% of all MIs, they experience 60% of all inpatient deaths and 80% of all fatal and nonfatal cardiovascular events. Consequently, these high-risk patients remain the focus of efforts to develop new treatments to improve outcome after acute MI.
The Valsartan in Acute Myocardial Infarction trial was an international, multicentre study designed to examine the efficacy and safety of long-term treatment with the angiotensin receptor blocker (ARB) valsartan, the ACE inhibitor captopril and a regimen including both agents.(1) More than 14,700 patients who developed HF and/or LVSD following recent MI were included in the trial, making it the largest long-term study to date of treatment in this setting. (2)
The VALIANT study demonstrates that valsartan is clinically equivalent to the ACE inhibitor captopril, which is of proven efficacy in this population.
Renin–angiotensin–aldosterone system inhibition
Angiotensin II has many potentially damaging effects through its actions on the AT(1) receptor, including:
- Alteration of water and sodium homeostasis.
- Elevation of blood pressure (BP).
- Promotion of atherosclerotic processes, including endothelial dysfunction and inflammation.
- Prothrombotic actions, including elevation of plasminogen activator inhibitor (PAI)-1 and promotion of platelet aggregation.
- Stimulation of smooth muscle cell proliferation.
- Vascular and myocardial remodelling.
The finding that RAAS blockade improves outcomes in patients with cardiovascular disease (CVD) has been confirmed by a number of large clinical trials.
ACE inhibitors are known to play a major cardioprotective role in the post-MI setting. The greatest clinical benefits of this treatment have been achieved in patients with LV dysfunction.(3) ACE inhibitors have been shown to decrease the risk of death and/or further major cardiovascular (CV) events or complications by 20–25%.(4–6) Further follow-up suggests that the survival benefit of ACE inhibition persists over the long term.(7)
Angiotensin receptor blockers
ARBs prevent the effects of angiotensin II at the AT1 receptor, theoretically leading to more complete inhibition of its deleterious effects than occurs with ACE inhibitors. They may also stimulate the AT(2) receptor, which may lead to beneficial effects such as vasodilation, inhibition of vascular smooth muscle cell growth(8) and, potentially, improvement of inflammation-related vascular injury.(9)
Patients with moderate to severe HF who received valsartan in addition to standard therapy had a 13.2% lower rate of combined morbidity and mortality in the Valsartan Heart Failure Trial (Val-HeFT).(7) The effect was most apparent in a small subgroup of patients whose therapy did not include an ACE inhibitor.(10) In the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) programme, the use of candesartan in addition to (CHARM- Added) or instead of (CHARM-Alternative) an ACE inhibitor also significantly reduced morbidity and mortality in patients with HF.(11)
The VALIANT trial evaluated the comparative efficacy of valsartan (target dose 160mg twice daily), the ACE inhibitor captopril (50mg three times daily) and a combination of the two (captopril 50mg three times daily plus valsartan 80mg twice daily) in subjects with MI associated with radiological or clinical evidence of HF and/or LV systolic dysfunction.
The study’s primary endpoint was all-cause mortality. The most important secondary endpoint was the composite of CV death, MI or hospitalisation for new or worsening HF. Additional efficacy parameters included the rates of recurrent acute coronary syndromes, revascularisation procedures and other CV morbidity.(12) A total of 14,703 patients were enrolled in the study (60% males, mean age 65 years).(13) The results demonstrate that, in patients with an MI complicated by HF, LV systolic dysfunction or both, valsartan is as effective as a proven dose of captopril in reducing the risk of death, CV death or hospitalisation for HF or MI. After a median follow-up of 24.7 months, all-cause mortality was similar in patients treated with valsartan or captopril, or the combination, in addition to standard background therapy. Kaplan–Meier estimates of death at one year were 12.5% for valsartan-treated patients, 12.3% for those receiving combination therapy and 13.3% for those receiving captopril monotherapy. Mortality from CV causes, recurrent MI or hospitalisation for HF was also similar in all three treatment groups.(1)
Valsartan treatment was deemed to preserve 99.6% of the benefits of captopril in the post-MI population. This finding translates into a 25% reduction (versus placebo) in premature death by valsartan in patients at high risk following a heart attack. The combination of valsartan with captopril in this post-MI population was associated with a higher rate of adverse events without any further improvement in survival. Discontinuations due to adverse events were least frequent in the valsartan-treated patients and most common among patients taking both agents. The overall rate of treatment discontinuation was, however, similar in the captopril and valsartan groups. As expected, captopril monotherapy was more likely than valsartan therapy to be associated with cough, rash and taste disturbances. Rates of hypotension and renal dysfunction were slightly higher in the valsartan group than in the captopril group.
Implications for management
Valsartan should now be considered as an alternative to ACE inhibitors in the treatment of post-MI patients.
Looking to the future
Other trials now in progress will provide additional information on the role of valsartan in reducing morbidity and mortality in early CVD. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study is assessing time to mortality or a first nonfatal cardiac event in more than 15,000 high-risk patients with hypertension treated with valsartan or amlodipine.(14) The Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study (n=9,150) will evaluate the ability of valsartan, nateglinide or both agents to prevent the onset of type 2 diabetes and reduce CV morbidity and mortality. (15)
- Pfeffer MA, McMurray J, Leizorovicz A, et al. Valsartan in acute myocardial infarction trial (VALIANT): rationale and design. Am Heart J 2000;140:727-34.
- Velazquez EJ, Pfeffer MA, McMurray JV, et al. VALsartan In Acute myocardial iNfarcTion (VALIANT) trial: baseline characteristics in context. Eur J Heart Fail 2003;5:537-44.
- Pfeffer MA. ACE inhibitors in acute myocardial infarction: patient selection and timing (editorial). Circulation 1998;97:2192-4.
- Pfeffer MA, Braunwald E, Moyé LA, et al, on behalf of the SAVE investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival and Ventricular Enlargement Trial. N Engl J Med 1992;327:669-77.
- Acute Infarction Ramipril Efficacy (AIRE) study investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821-8.
- Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin converting enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995;333:1670-6.
- Hall AS, Murray GD, Ball SG. Follow-up study of patients randomly allocated ramipril or placebo for heart failure after acute myocardial infarction: AIRE Extension (AIREX) study. Acute Infarction Ramipril Efficacy. Lancet 1997;3449:1493-7.
- Nickenig G, Harrison DG. The AT1-type angiotensin receptor in oxidative stress and atherogenesis. Circulation 2002;105:393-6.
- Wu L, Iwai M, Nakagami H, et al. Roles of angiotensin II type 2 receptor stimulation associated with selective angiotensin II type 1 receptor blockade with valsartan in the improvement of inflammation-induced vascular injury. Circulation 2001;104:2716-21.
- Maggioni AP, Anand I, Gottlieb SO, et al. Effects of valsartan on morbidity and mortality in patients with HF not receiving angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 2002;40:1414-21.
- Pfeffer MA, Swedberg G, Granger C, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003;362:759-66.
- Velazquez EJ, Weaver D, Armstrong P, et al. Heart failure and/or left ventricular systolic dysfunction complicating myocardial infarction is common and accounts for the majority of in-hospital myocardial infarction mortality: results of the VALIANT registry [Poster]. American College of Cardiology, Chicago, March 30–April 2, 2003.
- Cohn JN, Tognoni G. A randomized trial of the angiotensin receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-75.
- Mann J, Julius S. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial of cardiovascular events in hypertension: rationale and design. Blood Press 1998;7:176-83.
- Haffner S, Hotman R, Califf R, et al. Targeting post-prandial hyperglycemia to prevent type 2 diabetes: rationale and design of the Navigator trial. European Association for the Study of Diabetes 38th Annual Meeting, September 1–5, 2002, Budapest, Hungary. Abstract 319.