Estimating the Lifetime Benefits of Treatments for Heart Failure

Abstract

Objectives: This study compared ways of describing treatment effects. The objective was to better explain to clinicians and patients what they might expect from a given treatment, not only in terms of relative and absolute risk reduction, but also in projections of long-term survival.

Background: The restricted mean survival time (RMST) can be used to estimate of long-term survival, providing a complementary approach to more conventional metrics (e.g., absolute and relative risk), which may suggest greater benefits of therapy in high-risk patients compared with low-risk patients.

Methods: Relative and absolute risk, as well as the RMST, were calculated in heart failure with reduced ejection fraction (HFrEF) trials.

Results: As examples, in the RALES trial (more severe HFrEF), the treatment effect metrics for spironolactone versus placebo on heart failure hospitalization and/or cardiovascular death were a hazard ratio (HR) of 0.67 (95% confidence interval [CI]: 0.5 to 0.77), number needed to treat = 9 (7 to 14), and age extension of event-free survival +1.1 years (-0.1 to + 2.3 years). The corresponding metrics for EMPHASIS-HF (eplerenone vs. placebo in less severe HFrEF) were 0.64 (0.54 to 0.75), 14 (1 to 22), and +2.9 (1.2 to 4.5). In patients in PARADIGM-HF aged younger than 65 years, the metrics for sacubitril/valsartan versus enalapril were 0.77 (95% CI: 0.68 to 0.88), 23 (15 to 44), and +1.7 (0.6 to 2.8) years; for those aged 65 years or older, the metrics were 0.83 (95% CI: 0.73 to 0.94), 29 (17 to 83), and +0.9 (0.2 to 1.6) years, which provided evidence of a greater potential life extension in younger patients. Similar observations were found for lower risk patients.

Conclusions: RMST event-free (and overall) survival estimates provided a complementary means of evaluating the effect of therapy in relation to age and risk. They also provided a clinically useful metric that should be routinely reported and used to explain the potential long-term benefits of a given treatment, especially to younger and less symptomatic patients.

Keywords: restricted mean survival time; survival models; treatment effects; trials.

Graphical abstract

Figure 1

RMST Using Age Instead of Time for the Trials Included The restricted mean survival time (RMST) is expressed in potential years gained without an event from 60 to 80 years of age. The number of patients at risk represents the number of patients who were enrolled in the trial(s) in whom the event of interest had not occurred at a given age. A longer potential life extension (area under the Kaplan-Meier curve) was observed for patients at lower risk. Because they were less likely to have events or dying during follow-up, their potential life extension was improved with treatment. (A) PARADIGM-HF (Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure): potential years gained without event were observed across all the age groups in patients treated with sacubitril/valsartan (vs. enalapril), especially for the composite outcome of cardiovascular death (CVD) or heart failure hospitalization (HFH). (B) RALES (The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure): high-risk population, the potential years gained without event in favor of spironolactone (vs. placebo) were observed especially at younger ages within the trial. (C) EMPHASIS-HF (Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms): a lower risk population than that in the RALES trial with a treatment effect of eplerenone (vs. placebo) on life extension that was observed across all the ages (60 to 80 years) within the trial. (D) DIG (The Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure): digoxin extended the time free of HFH but did not prolong life. ACM = all-cause mortality.

Figure 2

PARADIGM-HF: RMST Using Age Instead of Time in Subgroups Reflecting Patient Risk and Age The number of patients at risk represents the number of patients who were enrolled in the trial(s) in whom the event of interest had not occurred at a given age. A longer potential life extension (area under the Kaplan-Meier curve) was observed for patients with lower N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels, who were in New York Heart Association (NYHA) functional class I and/or II, and were younger than 65 years, which suggested that the long-term benefits of sacubitril/valsartan were particularly important in less symptomatic and younger patients (i.e., patients with lower risk). Abbreviations as in Figure 1.

Central Illustration

Comparison of Age-Based Lifetime Estimates Using the Restricted Mean Survival Time With Conventional Measures of Risk Reduction The restricted mean survival time (RMST) using age instead of time allows the estimation of long-term, event-free survival, which is a clinically meaningful metric for both the clinicians and patients. The projections of long-term survival may be particularly useful for explaining the potential long-term benefits of treatments to less symptomatic/lower risk patients. In contrast, the absolute risk reduction may be less pronounced in lower risk patients, which may discourage them from taking additional therapies that could substantially increase the long-term event-free time. DIG = The Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure; EMPHASIS-HF = Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms; Eple. = eplerenone; HF = heart failure; HR = hazard ratio; PARADIGM-HF = Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure; RALES = The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure Sac./Val. = sacubitril/valsartan; Spiro. = spironolactone.