VALIANT

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Pfeffer, MA et al. "Valsartan, Captopril, or Both in Myocardial Infarction Complicated by Heart Failure, Left Ventricular Dysfunction, or Both". The New England Journal of Medicine. 2003. 349(20):1893-1903.
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Clinical Question

Among patients in the post-MI period complicated by HF and/or LV systolic dysfunction, what is the efficacy of ARBs compared with ACE-I in improving survival?

Bottom Line

Valsartan was as effective as captopril in improving survival among patients with HF and/or LV dysfunction in the post-MI period.

Major Points

The SAVE (1992) trial established the survival benefit of ACE-inhibitor therapy in patients after MI with HF and/or LV systolic dysfunction. The two major trials that compared ARBs to ACE-inhibitors among high-risk patients after MI were OPTIMAAL and VALIANT.

The Valsartan in Acute Myocardial Infarction (VALIANT) trial randomized 14,703 patients post-MI complicated by HF and/or LV dysfunction to valsartan, captopril or a combination of valsartan and captopril, and demonstrated that there was no significant difference in mortality among the three arms. Valsartan was as effective as captopril in improving survival after MI, and the combination of valsartan and captopril did not add any addition survival benefit, but did increase frequency of drug-related adverse events requiring reductions in drug doses.

Some concerns were raised with VALIANT in that its results were discordant with those of CHARM-Added and Val-HeFT, which demonstrated the efficacy of ARBs in patients with systolic HF.[1] However, the populations studied were quite different (post-MI in VALIANT, and chronic HF in the others), and differences in baseline medications were also apparent between study populations.

Guidelines

ACCF/AHA STEMI (2013, adapted)[2]

  • ACE-inhibitor administration within 24 hours after STEMI if its location was anterior, if there is a history of HF, or an LVEF ≤40% unless if otherwise contraindicated (class I, level A)
  • ACE inhibitor for all patients with STEMI if no contraindications (class IIa, level A)

ACCF/AHA NSTE-ACS (2014, adapted)[3]

  • Unless contraindicated, indefinite ACE-inhibitor therapy for patients with LVEF <40% and those with HTN, DM, or stable CKD (class I, level A)
  • ARBs in patients with HF or MI with LVEF <40% if intolerant to ACE-inhibitors (class I, level A)
  • ACE-inhibitors may be reasonable in all patients with cardiac or vascular disease (class IIb, level B)
    • ARBs are reasonable in patients with cardiac or vascular disease who are intolerant to ACE-inhibitors (class IIa, level B)

AHA/ACCF Heart Failure (2013, adapted)[4]

  • ACE-inhibitors for all patients with HFrEF with with current or prior symptoms unless contraindicated (class I, level A)

Design

  • Multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=14,703
    • Valsartan (n=4,909)
    • Valsartan and captopril (4,885)
    • Captopril (n=4,909)
  • Setting: 931 centers in 24 countries
  • Enrollment: December 1998 to June 2001
  • Mean follow-up: 24.7 months
  • Analysis: Intention-to-treat and per-protocol
  • Primary outcome: All-cause mortality

Population

Inclusion Criteria

  • Age ≥ 18 years
  • Acute MI within prior 10 days complicated by:
    • HF and/or
    • LVEF ≤35% on echocardiogram or ≤40% on radionuclide ventriculography

Exclusion Criteria

  • SBP < 100 mmHg
  • Serum Cr >2.5 mg/dL
  • Previous intolerance or contraindication to ACE-inhibitor or ARB
  • Received ACE-inhibitor or ARB ≤12 hrs prior to randomization
  • Clinically significant valvular disease
  • Disease known to severely limit life expectancy

Baseline Characteristics

  • Mean age: 65 years
  • Female: 31%
  • White: 94%
  • SBP 123mmHg
  • DBP 72.3mmHg
  • HR: 76.2 bpm
  • BMI 27.24
  • LVEF: 35.3%
  • Killip class: I (28%); II (48%); III (17%); IV (6%)
  • Medical history:
    • HTN: 55%
    • DM: 23%
    • MI: 28%
    • HF: 15%
    • Stroke: 6%
    • Smoking: 31.7%
    • CABG: 7%
    • PCI: 7.3%

Baseline Medications

  • Ace-inhibitors: 39.6%
  • ARBs: 1.2%
  • ß-blockers: 70.3%
  • Aspirin: 91.3%
  • Other antiplatelet agents: 24.8%
  • K-sparing diuretics: 9.1%
  • Other diuretics: 50.3%
  • Statins: 34.1%

Interventions

  • Randomized to:
    • Valsartan 20mg PO BID with goal of reaching 160 mg PO BID
    • Valsartan 20mg PO BID plus captopril 6.25mg PO TID with goal of reaching 80mg PO BID and 25mg PO TID, respectively
    • Captopril 6.25mg PO TID with goal of reaching 50mg PO TID
  • Study visits every 2 months during first year and every 4 months thereafter

Outcomes

Comparisons are valsartan vs. captopril on 1st line, and valsartan plus captopril vs. captopril on 2nd line.

Primary Outcomes

All-cause mortality
19.9% vs. 19.5% (HR 1.00; 97.5% CI 0.90-1.11; P=0.98)
19.3% vs. 19.5% (HR 0.98; 97.5% CI 0.89-1.09; P=0.73)

Secondary Outcomes

Death from CV causes
16.8% vs. 16.9% (HR 0.98; 97.5% CI 0.87-1.09; P=0.62; P for non-inferiority=0.001)
16.9% vs. 16.9% (HR 1.00; 97.5% CI 0.89-1.11; P=0.95)
Death from CV causes or MI
22.4% vs. 23.1% (HR 0.95; 97.5% CI 0.87-1.05; P=0.25; P for non-inferiority<0.001)
22.4% vs. 23.1% (HR 0.96; 97.5% CI 0.88-1.06; P=0.40)
Death from CV causes or HF
27.0% vs. 27.2% (HR 0.97; 97.5% CI 0.90-1.05; P=0.51; P for non-inferiority<0.001)
27.2% vs. 27.2% (HR 1.00; 97.5% CI 0.92-1.09; P=0.94)
Death from CV causes, MI or HF
31.1% vs. 31.9% (HR 0.95; 97.5% CI 0.88-1.03; P=0.20; P for non-inferiority<0.001)
31.1% vs. 31.9% (HR 0.97; 97.5% CI 0.89-1.05; P=0.37)
Death from CV causes, MI, HF, resuscitation after cardiac arrest, or stroke
32.8% vs. 33.4% (HR 0.96; 97.5% CI 0.89-1.04; P=0.25; P for non-inferiority<0.001)
32.3% vs. 33.4% (HR 0.96; 97.5% CI 0.89-1.04; P=0.26)

Subgroup Analysis

  • No significant difference in all-cause mortality or combined CV outcomes
  • Subgroups analyzed included: age <65 vs. ≥65, gender, previous MI, DM, SBP, Killip classes, HF, LV dysfunction, ß-blocker use, ACE-inhibitor use, K-sparing diuretic use

Adverse Events

  • Permanent discontinuation of study drug due to adverse events was most frequent in the valsartan and captopril combination therapy arm and lowest in valsartan monotherapy arm
  • Hypotension was most frequent in the valsartan monotherapy and combination arms and lowest in the captopril monotherapy arm.
  • Adverse events due to renal causes were more frequent in the valsartan monotherapy and combination therapy arm.
  • Cough, taste disturbance, and rash were most common in both arms that received captopril.

Criticisms

  • Not a criticism per se, but concerns were raised about the outcomes of VALIANT in comparison to the CHARM-Added and Val-HeFT studies. The main differences were in the study populations between each trial, as well as the baseline medications used by each study population.

Funding

Supported by grant from Novartis Pharmaceuticals.

Further Reading

  1. Hughes S. "VALIANT: No benefit of valsartan on top of captopril post MI." Medscape. 2003 Nov 10. Accessed 2015-07-05.
  2. O'Gara PT, et al. "2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines." Circulation. 2013;127(4):e362-e425.
  3. Amsterdam EA, et al. "2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes." Journal of the American College of Cardiology. 2014;epublished 2014-09-23. Accessed 2014-09-24.
  4. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.