VALIANT: Valsartan In Acute Myocardial Infarction

Linda Brookes, MSc

Disclosures

December 30, 2003

Editorial Collaboration

Medscape &

Presenter: Marc A Pfeffer, MD, PhD, Brigham and Women's Hospital (Boston, Massachusetts, USA)

The angiotensin receptor blocker (ARB) valsartan (Diovan; Novartis Pharmaceuticals, East Hanover, New Jersey) and the angiotensin-converting enzyme (ACE) inhibitor captopril are equally effective in reducing rates of death and cardiovascular events in patients at high risk after acute myocardial infarction (AMI), according to the results of the VALsartan In Acute myocardial iNfarcTion trial (VALIANT).[1] However, VALIANT also showed that valsartan and captopril given in combination did not improve survival over the effects of single-agent treatment, but increased the rate of adverse events in these patients. These results are definitive as far as the role of ARBs and ACE inhibitors in patients with AMI and systolic dysfunction is concerned, according to at least 1 commentator (see below), and are likely to change clinical practice guidelines, according to another.

ACE Inhibitors in High-Risk Patients Post MI

Patients who have had an AMI, complicated by heart failure and/or left ventricular (LV) dysfunction, are known to be at heightened risk for subsequent death and major nonfatal cardiovascular events. ACE inhibitors have been shown to be consistently associated with risk reductions of at least 20% post MI. The Survival and Ventricular Enlargement (SAVE) trial,[2] the Acute Infarction Ramipril Efficacy (AIRE) study,[3] and the Trandolapril Cardiac Evaluation (TRACE)[4] were placebo-controlled trials in these higher-risk populations that used ACE inhibitor therapy initiated during the acute phase of MI and maintained long-term (Table 1).

Table 1. Long-term Clinical Trials With ACE Inhibitors Post MI
Trial ACE Inhibitor Entry Criteria
SAVE Captopril Radionuclide ejection fraction ≤ 40%
AIRE Ramipril Clinical and/or radiographic signs of heart failure
TRACE Trandolapril Echocardiographic ejection fraction ≤ 35%

All 3 trials showed an independent survival benefit and a meta-analysis[5] of the trials revealed that ACE inhibition was associated with:

  • 26% risk reduction for death

  • 27% risk reduction for readmission for heart failure

  • 20% risk reduction for reinfarction

  • 25% risk reduction for death/MI or readmission for heart failure

Since the initiation of VALIANT, 2 trials comparing captopril (at the same dose as that evaluated in SAVE) with an ARB -- the Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) trial[6] and the Losartan Heart Failure Survival Study (ELITE II)[7] -- failed to show that the ARB was as effective as, or superior to, an ACE inhibitor.

VALIANT Design

VALIANT was a multicenter, double-blind, randomized, active, controlled, parallel-group study that assessed the efficacy and safety of long-term treatment with valsartan, captopril, and their combination in high-risk patients after MI.[8] The trial was designed to give equal statistical consideration to survival comparisons of captopril vs valsartan and the combination of captopril plus valsartan, compared with a proven effective dose of captopril. If valsartan was not superior to captopril, a noninferiority analysis was prespecified to determine whether valsartan could be considered to be as effective as captopril. Captopril was used as the ACE inhibitor comparator drug because it was the most extensively studied ACE inhibitor, with survival benefits shown in both early initiation and long-term trials post MI.

VALIANT Patients

VALIANT is the largest trial conducted in post MI patients to date, enrolling 14,703 patients from 931 sites in 24 countries worldwide. All patients had AMI complicated with LV dysfunction with documented ejection fraction (EF) ≤ 35%, signs and symptoms of acute heart failure, or both.[9] Patients with hypotension, creatinine > 2.5 mg/dL, or prior intolerance to either an ACE inhibitor or ARB were excluded from the study.

VALIANT Dosing

Patients were randomized to 1 of the following 3 regimens, uptitrated over 3 months:

  1. Valsartan 20 mg twice daily, titrated to 160 mg twice daily (n = 4090);

  2. Captopril 6.25 mg 3 times daily, titrated to captopril 50 mg 3 times daily (n = 4090);

  3. Valsartan 20 mg twice daily + captopril 6.25 mg 3 times daily titrated to valsartan 80 mg twice daily + 50 mg captopril 50 mg 3 times daily (n = 4885).

Use of other ACE inhibitors and ARBs was stopped at the time of randomization; however, 70.4% of patients continued beta-blocker use, 91.3% continued on aspirin, and 24.8% continued with other antiplatelet agents. Median duration of treatment was 24.7 months.

Mortality and Morbidity Endpoints

All-cause mortality, the primary endpoint of VALIANT, was 19.9% in the captopril group, 19.5% in the captopril group, and 19.3% in the combination group (Table 2).

Table 2. Primary Endpoint (All-cause Mortality)
Valsartan Captopril Valsartan + Captopril
All-cause mortality (n%) 979 (19.9) 958 (19.5) 941 (19.3)
Hazard ratio (97.5% CI):
Valsartan vs captopril
Valsartan + captopril vs valsartan

1.00 (0.90-1.11); P = .98
0.98 (0.89-1.09); P = .73

Since valsartan could not be considered to be superior or inferior to captopril alone, the prespecified analysis of noninferiority was carried out and showed valsartan to be noninferior to captopril in both intention-to-treat and per-protocol analyses (Table 3).

Table 3. Noninferiority Test for Mortality: Valsartan vs Captopril
Analysis P Value for Noninferiority
Intention to treat
Per protocol
.004
.002

Valsartan was estimated to have 99.6% of the effect of captopril.

Secondary endpoints of cardiovascular death, MI, heart failure, or the combined endpoint of cardiovascular death, MI, or heart failure hospitalization, were also similar in the 3 treatment groups (Table 4).

Table 4. Cardiovascular Mortality and Morbidity: Valsartan vs Captopril
Endpoint No. of endpoints (%) Valsartan vs Captopril
Valsartan Captopril Hazard ratio
(97.5% CI)
P Value for
Noninferiority
CV death 870 (16.8) 830 (16.9) 0.98 (0.87-1.09) .001
CV death or MI 1102 (22.4) 1132 (23.1) 0.95 (0.87-1.05) .00001
CV death or HF 1326 (27.0) 1335 (27.2) 0.97 (0.90-1.95) .0001
CV death, MI, or HF 1529 (31.1) 1567 (31.9) 0.95 (0.88-1.03) .000001
CV, cardiovascular; HF, heart failure; MI, myocardial infarction

This relative efficacy was seen in all subgroups, including patients taking or not taking beta-blockers.

Safety and Tolerability

Approximately 55% of patients in each of the monotherapy groups reached target medication dose with titration, but patients in the combined treatment group were less likely to reach target doses.

Discontinuation due to adverse events was lowest in the valsartan group. More patients on combination treatment discontinued treatment for any reason, and more of these patients discontinued treatment due to drug-related adverse events (Table 5).

Table 5. Adverse Events (%) Leading to Discontinuation of Study Drug
Valsartan Captopril Valsartan + Captopril
Hypotension 1.4* 0.8 1.9*
Renal causes 1.1 0.8 1.3*
Hyperkalemia 0.1 0.1 0.2
Cough 0.6* 2.5 2.1
Rash 0.3* 0.8 0.7
Taste disturbance 0.2* 0.4 0.3
Angioedema 0.2 0.3 0.2
Any of the above events 4.0* 5.7 6.8
Any adverse event 5.8* 7.7 9.0
Any reason 20.5 21.6 23.4*
*Significant difference vs captopril, P < .05.

Patients in the captopril group experienced more cough, rash, and taste disturbance more often, while those in the valsartan group had more hypotension and renal dysfunction, although no serious renal adverse events occurred in this group. A slightly greater blood pressure-lowering effect was seen with valsartan 160 mg twice daily compared with captopril 50 mg 3 times daily. The adverse-event profile of the valsartan plus captopril regimen proved to be the simple combination of the adverse events of each drug administered as monotherapy.

Explaining the Results

According to VALIANT coprincipal investigators, Dr. Pfeffer and John JV McMurray, MD (Western Infirmary, Glasgow, UK), there are 4 potential explanations for why the VALIANT findings differ from those of previous trials such as the Candesartan in Heart Failure -- Assessment of Mortality and Morbidity Trial in Patients Taking ACE Inhibitors (CHARM-Added)[10] and the Valsartan Heart Failure Trial (Val-HeFT).[11]

CHARM-Added and Val-HeFT were trials in chronic heart failure, a different patient population entirely. These patients had a chronic long-term condition with low EF, breathlessness, ankle swelling, and fatigue, with a different natural history and a different pathophysiology. In these patients, the combination of an ARB and an ACE inhibitor appears to be more effective than just an ACE inhibitor alone.

Second, in VALIANT, the ARB and ACE inhibitor in the combination group were begun simultaneously, whereas in the chronic heart failure studies the patients had already been taking an ACE inhibitor for some time before the ARB was added. It is known that during long-term ACE inhibitor treatment, renin-angiotensin-aldosterone escape occurs, and angiotensin II levels in the blood start to increase again. At that time, adding an ARB would have some benefit. Drs. Pfeffer and McMurray believe that this occurs in chronic heart failure, but may not occur in AMI when starting both drugs together at the same time.

The other 2 possibilities are the doses used as combination therapy in VALIANT. In the previous ARB add-on trials that were successful in reducing cardiovascular events, patients were on an ACE inhibitor at a stable dose that the physician deemed appropriate. In VALIANT, however, captopril was used to the full dose (50 mg 3 times daily). However, some heart failure trials used higher doses of other ACE inhibitors, and comparisons are difficult, the investigators agreed. It was also suggested that the dose of valsartan in the combination treatment was 80 mg twice a day, not 160 mg twice a day as in the monotherapy group, so it is possible that a higher dose in combination might have contributed to a reduction in events. However, Drs. Pfeffer and McMurray believe that this would not have happened, since physicians participating in VALIANT were unable to get patients on the combination to the target dose, so raising the dose required at target would probably have resulted in even more patients stopping therapy.

According to Dr. Pfeffer, the results of VALIANT cannot necessarily be extrapolated to other ARBs because different ARBs are given at different doses, and the correct dose is only known for ARBs that have been investigated in the post-MI setting.

Enthusiasm for VALIANT Results

Program discussant for VALIANT, Bertram Pitt, MD (University of Michigan Medical Center, Ann Arbor), hailed VALIANT as a landmark trial. "VALIANT has given us just about all we need to know about the role of ARBs and ACE inhibitors in patients with acute MI and systolic dysfunction," he declared. He would now feel very confident using an ARB as an equivalent to an ACE inhibitor in patients with AMI and LV dysfunction, he said.

Like the VALIANT investigators, he would be very cautious about other ACE inhibitors, ARBs, and other doses, however, although he believes that losartan might have been as effective as captopril in the OPTIMAAL trial, at a higher dose, possibly 200 mg instead of 50 mg.

Dr. Pitt is also cautious about extrapolating the VALIANT data to patients with heart failure, because although overlapping, the pathophysiologies are very different. Until further data are available, the ACE inhibitors should remain the therapy of choice in patients with chronic heart failure. There is "no reason whatsoever to add an ARB to an ACE inhibitor or vice versa" in these patients, since there is no benefit and even an increased risk of side effects.

The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) showed that rather than adding an ARB as triple therapy, an aldosterone blocking agent should be added, where there is clear benefit in overall mortality.[12] Here Dr. Pitt admitted a conflict of interest, as Chair of the EPHESUS steering committee.

According to Scientific Sessions Program Chairman 2003 Raymond J Gibbons, MD (Mayo Clinic and Foundation, Rochester, Minnesota), the results of VALIANT will change clinical practice and have an impact on existing guidelines.

Results Published

The results of VALIANT have been published in the November 13 issue of The New England Journal of Medicine,[13] with an accompanying editorial by Douglas L Mann, MD, and Anita Deswal, MD, MPH (Houston Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas).[14] Drs. Mann and Deswal suggest several reasons why valsartan did not show superiority over captopril in VALIANT. They stress the importance of giving a high enough dose of an ARB, pointing out that in OPTIMAAL, losartan might have been more effective in reducing rates of cardiovascular events if it had been given at a dose of 100 mg instead of 50 mg. They also doubt that the ARBs have a class effect, citing in evidence the different clinical outcomes of OPTIMAAL and VALIANT. They note that since the cost of using valsartan in VALIANT was 4-6 times as expensive as the cost of generic captopril at doses used in the same study, ACE inhibitors "remain the logical first-line therapy for high risk patients after acute [MI]." However, they welcome the "good news" provided by VALIANT that there is a "safe and equally effective alternative strategy" for reducing the risks of death and cardiovascular events in these patients.

More Data Expected From ONTARGET

Another long-term trial comparing an ACE inhibitor with an ARB and their combination is the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET).[15] ONTARGET is comparing ramipril 10 mg, telmisartan 80 mg, and ramipril 10 mg + telmisartan 80 mg in high-risk patients on the basis of the criteria of the Heart Outcomes Prevention Evaluation (HOPE) study.[16] These patients will be aged ≥ 55 years with a history of coronary artery disease, stroke, transient ischemic attack, or peripheral vascular disease, or high-risk diabetics with evidence of end-organ damage, such as microalbuminuria. ONTARGET has completed enrollment of 28,317 patients worldwide, and the study is expected to be completed in 2007.

References
  1. Pfeffer AM. Valsartan in Acute Myocardial Infarction Trial (VALIANT). American Heart Association Scientific Sessions 2003; November 9-12, 2003; Orlando, Florida. Plenary Session III: Late Breaking Clinical Trials.

  2. Pfeffer AM, Braunwald E, Moye LA, et al. 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;327:669-677.

  3. The Acute Infarction Ramipril Efficacy (AIRE) study investigators. Effect of ramipril on mortality and morbidity of survivors of myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342:821-828.

  4. Kober L, Topr-Pedersen C, Carlsen JR, 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;333:1670-1676.

  5. Flather MD, Yusuf S, Kober L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. Lancet. 2000;355:1575-1581.

  6. Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomized trial. Lancet. 2002;360:752-760.

  7. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial--the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355:1582-1587.

  8. Pfeffer AM, McMurray J, Leizorovicz A, et al. Valsartan in acute myocardial infarction trial (VALIANT): rationale and design. Am Heart J. 2000;140:727-750.

  9. Velazquez EJ, Pfeffer MA, McMurray JV, for the VALIANT Investigators. VALsartan In Acute myocardial iNfarcTion (VALIANT) trial: baseline characteristics in context. Eur J Heart Fail. 2003;5:537-544.

  10. McMurray JJV, Ostergren J, Swedberg K, et al, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:759-756.

  11. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor inhibitor valsartan in chronic heart failure. N Engl J Med. 2001;345:1667-1675.

  12. Pitt B, Remme W, Zannad F, et al, for the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-1321.

  13. Pfeffer MA, McMurray JJV, Velazquez EJ, et al, for the Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893-1906.

  14. Mann DL, Deswal A. Angiotensin-receptor blockade in acute myocardial infarction – A matter of dose. N Engl J Med. 2003;349:1963-1965.

  15. Unger T. The Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial program. Am J Cardiol. 2003;91(10A):28G-34G.

  16. The HOPE study investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. N Engl J Med. 2000;32:145-153.

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