Incremental Reduction in Risk of Death Associated With Use of Guideline-Recommended Therapies in Patients With Heart Failure: A Nested Case-Control Analysis of IMPROVE HF

Abstract

Background: Several therapies are guideline-recommended to reduce mortality in patients with heart failure (HF) and reduced left ventricular ejection fraction, but the incremental clinical effectiveness of these therapies has not been well studied. We aimed to evaluate the individual and incremental benefits of guideline-recommended HF therapies associated with 24-month survival.

Methods and results: We performed a nested case-control study of HF patients enrolled in IMPROVE HF. Cases were patients who died within 24 months and controls were patients who survived to 24 months, propensity-matched 1:2 for multiple prognostic variables. Logistic regression was performed, and the attributable mortality risk from incomplete application of each evidence-based therapy among eligible patients was calculated. A total of 1376 cases and 2752 matched controls were identified. β-Blocker and cardiac resynchronization therapy were associated with the greatest 24-month survival benefit (adjusted odds ratio for death 0.42, 95% confidence interval (CI), 0.34-0.52; and 0.44, 95% CI, 0.29-0.67, respectively). Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, implantable cardioverter-defibrillators, anticoagulation for atrial fibrillation, and HF education were also associated with benefit, whereas aldosterone antagonist use was not. Incremental benefits were observed with each successive therapy, plateauing once any 4 to 5 therapies were provided (adjusted odds ratio 0.31, 95% CI, 0.23-0.42 for 5 or more versus 0/1, P<0.0001).

Conclusions: Individual, with a single exception, and incremental use of guideline-recommended therapies was associated with survival benefit, with a potential plateau at 4 to 5 therapies. These data provide further rationale to implement guideline-recommended HF therapies in the absence of contraindications to patients with HF and reduced left ventricular ejection fraction. (J Am Heart Assoc. 2012;1:16-26.).

Keywords: guideline-recommended therapies; heart failure; nested case-control studies; survival benefit.

Figure 1.

Use of guideline-recommended therapies at baseline in cases and controls. Baseline use of each of the guideline-recommended therapies for cases (dead at 24 mo) compared with controls (alive at 24 mo). ACEI indicates angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; CRT, cardiac resynchronization therapy (with defibrillator or pacemaker); HF, heart failure; ICD, implantable cardioverter-defibrillator (including CRT with defibrillator).

Figure 2.

ORs for 24-month mortality associated with the number of guideline-recommended therapies received at baseline. Analysis includes all patients from the case-control population (N=4128). The number (%) of patients receiving each number of therapies at baseline was as follows: 0 or 1, 238 (5.8%); 2, 712 (17.3%); 3, 1327 (32.2%); 4, 1123 (27.2%); and 5, 6, or 7, 728 (17.6%). OR indicates odds ratio.

Figure 3.

Cumulative percent reduction in odds of death at 24 months with each sequentially applied guideline-recommended HF therapy. Therapies were sequenced on the basis of their β-coefficients and the order in which they are commonly applied clinically. Variables retained in the model were race, HF etiology, and diastolic blood pressure. Incremental P values for the sequentially applied therapies (left to right) were as follows: <0.0001, <0.0001, <0.0001, 0.0038, 0.1388, and 0.1208, respectively. ACEI indicates angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; CRT, cardiac resynchronization therapy (with defibrillator or pacemaker); HF, heart failure; ICD, implantable cardioverter-defibrillator (including CRT with defibrillator).

Figure 4.

Cumulative percent reduction in odds of death at 24 months associated with sequential treatments compared with no treatment. Analysis includes only patients eligible for all 4 therapies (N=368). ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator.