# Estimating the Lifetime Benefits of Treatments for Heart Failure

João Pedro Ferreira, Kieran F Docherty, Susan Stienen, Pardeep S Jhund, Brian L Claggett, Scott D Solomon, Mark C Petrie, John Gregson, Stuart J Pocock, Faiez Zannad, et al.

<figure><img src="image_1.png" /></figure>

## To cite this version:

João Pedro Ferreira, Kieran F Docherty, Susan Stienen, Pardeep S Jhund, Brian L Claggett, et al. "Estimating the Lifetime Benefits of Treatments for Heart Failure." JACC: Heart Failure, 2020, 8 (12), pp.984-995. 10.1016/j.jchf.2020.08.004. hal-03009640

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https://hal.univ-lorraine.fr/hal-03009640

Submitted on 17 Nov 2020

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# Estimating the Lifetime Benefits of Treatments for Heart Failure

João Pedro Ferreira, MD, PhD,<sup>a,b</sup> Kieran F. Docherty, MBCHB,<sup>a</sup> Susan Stienen, MD, PhD,<sup>c</sup>
Pardeep S. Jhund, MBCHB, PhD,<sup>a</sup> Brian L. Claggett, PhD,<sup>d</sup> Scott D. Solomon, MD,<sup>d</sup> Mark C. Petrie, MBCHB,<sup>a</sup>
John Gregson, PhD,<sup>e</sup> Stuart J. Pocock, PhD,<sup>e</sup> Faiez Zannad, MD, PhD,<sup>b</sup> John J.V. McMurray, MD<sup>a</sup>

## 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. (J Am Coll Cardiol HF 2020; ■:■-■) © 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

From the <sup>a</sup>BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom; <sup>b</sup>National Institute of Health and Medical Research (INSERM), Center for Clinical Multidisciplinary Research 1433, INSERM U1116, University of Lorraine, Regional University Hospital of Nancy, French Clinical Research Infrastructure Network (F-CRIN) Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists (INI-CRCT), Nancy, France; <sup>c</sup>Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences. Amsterdam University Medical Center, University of Amsterdam, Amsterdam the Netherlands; <sup>d</sup>Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts; and the <sup>e</sup>Department of Biostatistics, London School of Hygiene and Tropical Medicine, London, United Kingdom. Drs. Ferreira and Zannad are supported by ANR-15-RHU-0004 and ANR-15-IDEX-04-LUE. Drs. Jhund, Petrie, McMurray are supported by the British Heart Foundation (grant RE/18/6/34217). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Heart Failure author instructions page.

Manuscript received April 14, 2020; revised manuscript received August 4, 2020, accepted August 4, 2020.
ABBREVIATIONS
AND ACRONYMS

CI = confidence interval

HF = heart failure

HFrEF = heart failure with
reduced ejection fraction

HR = hazard ratio

NNT = number needed to treat

NT-proBNP = N-terminal pro-
B-type natriuretic peptide

NYHA = New York Heart
Association

RMST = restricted mean
survival time

In randomized controlled trials, the effect of treatment is usually estimated using a time-to-first-event survival model that compares the hazard rate of the experimental treatment group (or groups) and the control group, which produces a hazard ratio (HR) and corresponding 95% confidence interval (CI) (1). By convention, if the upper 95% CI does not cross unity, the effect of treatment is considered statistically significant. Although this is the standard way of reporting the effect of treatment at medical presentations and in publications, it may exaggerate the effect of therapy (e.g., if the absolute risk reduction is small) and may not be readily interpretable by patients in terms of understanding their survival free of adverse clinical events, including death (2). Reporting the absolute treatment effect, as a percent reduction, reduction in event rate, or number needed to treat (NNT), overcomes the first of these criticisms (although NNT should be standardized for duration of follow-up). However, metrics of absolute benefit will generally look better in a high-risk than in a low-risk population, assuming the proportional risk reduction with the treatment is similar, at least in the relatively short follow-up that typifies most trials. Conversely, treatments started earlier in the course of a disease when patients are at lower risk (or even in younger patients) may have the potential to lead to greater prolongation of life. Another assessment of treatment effect that complements HR and absolute risk reduction or NNT, is the restricted mean survival time (RMST) (3,4). The RMST can be interpreted as the mean event-free survival time up to a pre-specified time point and is equivalent to the area under the Kaplan-Meier curve from the start of the study up to that point. Using age at randomization instead of time, the RMST approach allows for estimation of long-term, event-free survival that can be obtained with a specific intervention compared with a control group, across different age groups (5). The RMST provides an estimate of the effect of treatment in terms of time “free of an event,” years of life gained, or both. Such measures may be more readily interpretable and quantifiable for patients and clinicians. To better understand the use of RMST and how it compares with other conventional measures of treatment effect, we analyzed HR, NNT, and RMST in several large cardiovascular outcome trials. We also analyzed these metrics in low-risk versus high-risk subgroups to illustrate how the RMST could provide relevant information that is less dependent on the risk of

patients, providing a clinically relevant long-term
outlook.

METHODS

**TRIALS AND ENDPOINTS.** The incidence rate and the effect of treatment illustrated as a relative risk reduction, absolute event difference, NNT, and RMST were calculated (see Statistical Analysis section) in 4 heart failure (HF) trials: 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), EMPHASIS-HF Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms-Heart Failure), and DIG (The Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure). A brief description of each of these trials and their outcomes is provided in the *Supplemental Appendix*. In this study, we examined 2 outcomes: 1) the composite of time to first occurrence of either HF hospitalization or cardiovascular death (used to estimate event-free survival); and 2) all-cause mortality (used to estimate overall survival). To homogenize the estimates, all follow-up times were capped at 3 years. The RMST, using age instead of time, was performed from 60 to 80 years in all trials, except for the age subgroups in PARADIGM-HF, in which in patients younger than 65 years, the age range was 50 to 64 years and in patients aged 65 or older, the age range was 65 to 80 years.

These trials were selected because they allowed
comparison of the different means of quantifying the
effect of treatment, as listed previously, and how
patient characteristics could influence these. Because
of its large sample size, we believed that the
PARADIGM-HF trial would give reasonably robust
estimates of the effect of treatment in subgroups (at
least for the composite hospitalization and/or death
outcome). This allowed us to test the hypothesis that
patient risk and patient age would influence potential
gains in event-free survival and overall survival, and
specifically, that these gains would be smaller in
higher risk and older patients compared with that of
lower risk and younger patients. We tested this hy-
pothesis by examining patients in PARADIGM-HF
with a baseline N-terminal pro-B-type natriuretic
peptide (NT-proBNP) level of <1,000 pg/ml (and also
below the median of 1,615 pg/ml) versus ≥1,000 pg/ml
(and equal or above the median), who were in New
York Heart Association (NYHA) functional class I
and/or II versus class III and/or IV and age younger 65
years versus age 65 years or older. In the subgroups,
we focused on event-free survival, because there was
<table><caption>TABLE 1 Cox, Event Rates, Number Needed to Treat, Proportional Hazards, and RSMT</caption><thead><tr><th>CV Death or HFH*</th><th>Enalapril (n = 4,212)</th><th>Sacubitril/Valsartan (n = 4,187)</th><th>Treatment Effect HR (95% CI)</th><th>p Value</th></tr></thead><tbody><tr><td>PARADIGM-HF (N = 8,399)</td><td></td><td></td><td></td><td></td></tr><tr><td>Events</td><td>1,088 (25.8)</td><td>893 (20.0)</td><td>0.80 (0.73 to 0.88)</td><td>&lt;0.001</td></tr><tr><td>Event-free survival (%)</td><td>69.1 (67.4 to 70.7)</td><td>73.7 (72.1 to 75.3)</td><td>+4.6</td><td>&lt;0.001</td></tr><tr><td>NNT to benefit</td><td></td><td></td><td>25 (18 to 43)</td><td>&lt;0.001</td></tr><tr><td>Event rates and difference (per 100 patient-yrs)</td><td>13.2 (12.5 to 14.1)</td><td>10.6 (9.9 to 11.3)</td><td>to 2.6 (-3.7 to -1.6)</td><td>&lt;0.001</td></tr><tr><td>RMST (using follow-up time in days)</td><td>895 (884 to 906)</td><td>932 (922 to 942)</td><td>+37 (23 to 52)</td><td>&lt;0.001</td></tr><tr><td>RMST (using age instead of follow-up time)†</td><td>7.3 (6.8 to 7.9)</td><td>8.9 (8.2 to 9.5)</td><td>+1.5 (0.7 to 2.4)</td><td>&lt;0.001</td></tr><tr><td>All-cause death*</td><td></td><td></td><td></td><td></td></tr><tr><td>Events</td><td>796 (24.3)</td><td>683 (21.0)</td><td>0.85 (0.77 to 0.94)</td><td>0.002</td></tr><tr><td>Event-free survival (%)</td><td>76.2 (74.6 to 77.7)</td><td>79.4 (77.8 to 80.8)</td><td>+3.2</td><td>0.002</td></tr><tr><td>NNT to benefit</td><td></td><td></td><td>43 (26 to 116)</td><td>0.002</td></tr><tr><td>Event rates and difference (per 100 patient-yrs)</td><td>7.6 (7.1 to 8.2)</td><td>8.9 (8.3 to 9.6)</td><td>-1.3 (-2.2 to -0.1)</td><td>0.002</td></tr><tr><td>RMST (using follow-up time in days)</td><td>961 (952 to 970)</td><td>980 (971 to 988)</td><td>+19 (7 to 31)</td><td>0.002</td></tr><tr><td>RMST (using age instead of follow-up time)†</td><td>10.1 (9.5 to 10.8)</td><td>10.9 (10.2 to 11.6)</td><td>0.8 (-0.2 to 1.7)</td><td>0.12</td></tr><tr><td>RALES (N = 1,663)</td><td></td><td></td><td></td><td></td></tr><tr><td>Events</td><td>512 (60.9)</td><td>381 (46.4)</td><td>0.67 (0.59 to 0.77)</td><td>&lt;0.001</td></tr><tr><td>Event-free survival (%)</td><td>31.9 (27.9 to 36.0)</td><td>48.0 (43.2 to 52.6)</td><td>+16.1</td><td>&lt;0.001</td></tr><tr><td>NNT to benefit</td><td></td><td></td><td>9 (7 to 14)</td><td>&lt;0.001</td></tr><tr><td>Event rates and difference (per 100 patient-yrs)</td><td>45.4 (41.6 to 49.5)</td><td>29.3 (26.5 to 32.5)</td><td>-16.0 (-21.0 to -11.1)</td><td>&lt;0.001</td></tr><tr><td>RMST (using follow-up time in days)</td><td>574 (545 to 602)</td><td>693 (664 to 722)</td><td>+119 (78 to 160)</td><td>&lt;0.001</td></tr><tr><td>RMST (using age instead of follow-up time)†</td><td>2.3 (1.7 to 3.0)</td><td>3.4 (2.5 to 4.4)</td><td>1.1 (-0.1 to 2.3)</td><td>0.062</td></tr><tr><td>All-cause death*</td><td></td><td></td><td></td><td></td></tr><tr><td>Events</td><td>384 (45.7)</td><td>284 (34.5)</td><td>0.71 (0.61 to 0.83)</td><td>&lt;0.001</td></tr><tr><td>Event-free survival (%)</td><td>46.1 (41.5 to 50.5)</td><td>60.9 (56.5 to 65.0)</td><td>+14.8</td><td>&lt;0.001</td></tr><tr><td>NNT to benefit</td><td></td><td></td><td>12 (8 to 21)</td><td>&lt;0.001</td></tr><tr><td>Event rates and difference (per 100 patient-yrs)</td><td>26.6 (24.1 to 29.4)</td><td>18.8 (16.7 to 21.1)</td><td>-7.8 (-11.2 to -4.4)</td><td>&lt;0.001</td></tr><tr><td>RMST (using follow-up time in days)</td><td>736 (709 to 762)</td><td>812 (786 to 837)</td><td>+76 (39 to 113)</td><td>&lt;0.001</td></tr><tr><td>RMST (using age instead of follow-up time)†</td><td>4.2 (3.3 to 5.2)</td><td>5.8 (4.6 to 7.0)</td><td>+1.5 (0.01 to 3.1)</td><td>0.049</td></tr></tbody></table>

Continued on the next page

more statistical power for this outcome than for all-cause mortality.

The RALES and EMPHASIS-HF trials provided an indirect comparison of how the effects of a mineralocorticoid receptor antagonist might be modified by patient risk. RALES was a trial that enrolled a high-risk advanced HF population (all patients were in NYHA functional class III and/or IV) who received suboptimal treatment by today's standards (e.g., 10% beta-blocker use). The EMPHASIS-HF trial randomized a lower risk, relatively well-treated patient cohort (all NYHA functional class II; 87% treated with a beta-blocker).

Because digoxin did not reduce all-cause mortality, the DIG trial was used to illustrate the effects of therapy on event-free survival versus overall survival.

All of these trials had similar patient age ranges and follow-up times.

Ethics approval was obtained for each individual trial.

**STATISTICAL ANALYSIS.** Cox proportional hazards models were used to estimate HRs and relative risk

reductions. Event rates and the differences, with the respective 95% CIs were calculated using the quadratic approximation to the Poisson log-likelihood for the log-rate parameter. Event-free survival was computed using the Kaplan-Meier survivor function over the full data and compared using the log-rank test. The NNT to benefit was computed from the cause-specific cumulative incidence functions. The RSMT is a measure of average event-free survival from time 0 to a pre-specified time point (6). We computed the RMST using the within-trial follow-up time and also used age instead of time (the age-specific event rates were then estimated). These estimations were obtained by multiplying the annual conditional survival probabilities of patients included in the studies, starting from a specific age, from projections of the expected duration of event-free survival (up to a pre-specified time horizon [tau]), and were non-parametrically estimated by calculation of the area under the Kaplan-Meier survival curve (5,7). Subsequently, differences in the estimated duration of event-free survival for patients
<table><caption>TABLE 1 Continued</caption><thead><tr><th colspan="2">CV Death or HFH*</th><th>Treatment Effect HR (95% CI)</th><th>p Value</th></tr></thead><tbody><tr><td colspan="2">EMPHASIS-HF (N = 2,737)</td><td></td><td></td></tr><tr><td></td><td>Placebo (n = 1,371)</td><td>Eplerenone (n = 1,362)</td><td></td></tr><tr><td>Events</td><td>349 (25.4)</td><td>235 (17.3)</td><td>0.64 (0.54 to 0.75)</td><td>&lt;0.001</td></tr><tr><td>Event-free survival (%)</td><td>64.1 (60.5 to 67.4)</td><td>73.9 (70.5 to 77.0)</td><td>+9.8</td><td>&lt;0.001</td></tr><tr><td>NNT to benefit</td><td></td><td></td><td>14 (10 to 22)</td><td>&lt;0.001</td></tr><tr><td>Event rates and difference (per 100 patient-yrs)</td><td>16.7 (15.0 to 18.5)</td><td>10.5 (9.3 to 12.0)</td><td>to 6.2 (-8.3 to -4.0)</td><td>&lt;0.001</td></tr><tr><td>RMST (using follow-up time in days)</td><td>827 (806 to 848)</td><td>905 (887 to 923)</td><td>+78 (51 to 106)</td><td>&lt;0.001</td></tr><tr><td>RMST (using age instead of follow-up time)†</td><td>6.3 (5.3 to 7.4)</td><td>9.2 (7.9 to 10.4)</td><td>+2.9 (1.2 to 4.5)</td><td>0.001</td></tr><tr><td colspan="2">All-cause death*</td><td></td><td></td></tr><tr><td>Events</td><td>201 (14.7)</td><td>157 (11.5)</td><td>0.76 (0.62 to 0.94)</td><td>0.010</td></tr><tr><td>Event-free survival (%)</td><td>77.1 (73.7 to 80.0)</td><td>81.8 (78.7 to 84.5)</td><td>+4.7</td><td>0.010</td></tr><tr><td>NNT to benefit</td><td></td><td></td><td>33 (19 to 142)</td><td>0.028</td></tr><tr><td>Event rates and difference (per 100 patient-yrs)</td><td>8.7 (7.6 to 10.0)</td><td>6.6 (5.7 to 7.7)</td><td>-2.1 (-3.7 to -0.5)</td><td>0.010</td></tr><tr><td>RMST (using follow-up time in days)</td><td>949 (932 to 966)</td><td>978 (963 to 994)</td><td>+29 (7 to 52)</td><td>0.010</td></tr><tr><td>RMST (using age instead of follow-up time)†</td><td>8.4 (6.9 to 9.9)</td><td>10.2 (8.9 to 11.6)</td><td>1.8 (-0.2 to 3.8)</td><td>0.075</td></tr><tr><td colspan="2">DIG (N = 6,800)</td><td></td><td></td></tr><tr><td></td><td>Placebo (n = 3,403)</td><td>Digoxin (n = 3,397)</td><td></td></tr><tr><td>Events</td><td>1,515 (44.5)</td><td>1,335 (39.3)</td><td>0.82 (0.76 to 0.88)</td><td>&lt;0.001</td></tr><tr><td>Event free survival (%)</td><td>54.2 (52.5 to 55.9)</td><td>59.4 (57.7 to 61.0)</td><td>+5.2</td><td>&lt;0.001</td></tr><tr><td>NNT to benefit</td><td></td><td></td><td>20 (15 to 32)</td><td>&lt;0.001</td></tr><tr><td>Event rates and difference (per 100 patient-yrs)</td><td>22.0 (20.9 to 23.2)</td><td>18.0 (17.1 to 19.0)</td><td>-4.0 (-5.5 to -2.6)</td><td>&lt;0.001</td></tr><tr><td>RMST (using follow-up time in days)</td><td>767 (753 to 781)</td><td>830 (817 to 843)</td><td>+63 (44 to 82)</td><td>&lt;0.001</td></tr><tr><td>RMST (using age instead of follow-up time)†</td><td>4.9 (4.5 to 5.4)</td><td>5.8 (5.3 to 6.2)</td><td>+0.8 (0.2 to 1.5)</td><td>0.010</td></tr><tr><td colspan="2">All-cause death*</td><td></td><td></td></tr><tr><td>Events</td><td>1,004 (29.5)</td><td>1,007 (29.6)</td><td>1.00 (0.92 to 1.09)</td><td>0.99</td></tr><tr><td>Event-free survival (%)</td><td>69.8 (68.2 to 71.4)</td><td>69.6 (68.0 to 71.1)</td><td>0.2</td><td>0.99</td></tr><tr><td>NNT to benefit</td><td></td><td></td><td>NA</td><td>—</td></tr><tr><td>Event rates and difference (per 100 patient-yrs)</td><td>12.0 (11.3 to 12.8)</td><td>12.1 (11.3 to 12.8)</td><td>0.0 (-1.0 to 1.0)</td><td>0.99</td></tr><tr><td>RMST (using follow-up time in days)</td><td>916 (905 to 927)</td><td>922 (912 to 933)</td><td>6 (-9 to 21)</td><td>0.46</td></tr><tr><td>RMST (using age instead of follow-up time)†</td><td>7.9 (7.3 to 8.4)</td><td>8.0 (7.5 to 8.5)</td><td>0.1 (-0.6 to 0.9)</td><td>0.71</td></tr></tbody></table>

Values are n, n (%), or median (interquartile range). The event-free survival was computed using the Kaplan-Meier survivor function over the full data and compared using the log-rank test. The number needed to treat (NNT) to benefit was computed from the cause-specific cumulative incidence functions. Median (25th to 75th percentile) follow-up time (days) and age at randomization (yrs); PARADIGM-HF: 810 days (564 to 1,069) days and 64 yrs (57 to 72 yrs); EMPHASIS-HF: 639 days (292 to 992 days) and 68 yrs (63 to 74 yrs); RALES: 714 days (381 to 909 days) and 67 yrs (59 to 73 yrs); DIG: 1,152 days (843 to 1,423 days) and 65 yrs (57 to 71 yrs). *For consistency, the analysis the follow-up time was capped at 3 yrs †For consistency, the RMST used age instead of time and used the same age range from 60 to 80 yrs in all the studied trials.

CV = cardiovascular; 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; HR = hazard ratio; PARADIGM-HF = Angiotensin-Nephrilysin Inhibition versus Enalapril in Heart Failure; RALES = The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure; RMST = restricted mean survival time.

treated with active drug and treatment versus those in a placebo and/or control group were interpreted as mean years of life gained (or lost). In other words, for any given age, a survival curve was estimated that represented the survival probabilities over time for patients alive at that age and who receiving an active drug and/or treatment. A corresponding survival curve was then estimated using data from patients who were in the placebo and/or control group. From each survival curve, the average time spent before the event of interest was estimated by the area under the survival curve. Because patient age and treatment assignment were independent of one another due to randomization, the difference in the areas under the survival curve could be interpreted as the effect of

treatment on time spent event free. The key statistical assumption required to obtain valid long-term survival projections based on short-term follow-up data was that a patient's risk for a given event depended on age and treatment but not on the duration of exposure to the treatment (5,8). This meant that a 79-year-old patient who took sacubitril-valtsartan since the age of 60 years (i.e., 19 years of treatment exposure) had the same assumed risk of dying by age 80 years as a 79-year-old patient who started taking sacubitril-valtsartan at age 78 years (i.e., 1 year of treatment exposure). For consistency, we assessed the survival data over a maximum follow-up of 3 years and an age range from 60 to 80 years (tau =20) in all trials. In the PARADIGM-HF
<figure><img src="image_3.png" /><figcaption>FIGURE 1 RMST Using Age Instead of Time for the Trials Included</figcaption></figure>
trial, age projection estimates were also performed for the previously described subgroups described. The p values < 0.05 were considered statistically significant. All analyses were conducted using Stata version 16 (StataCorp, College Station, Texas).

## RESULTS

**TRIALS ANALYZED.** The overall results for each of the 4 trials analyzed are shown in **Table 1 and Figure 1**. **PARAGIGM-HF.** Overall, in the PARADIGM-HF trial, 25.8% (13.2 per 100 patient-years) of the patients in the enalapril group versus 20.0% (10.6 per 100 patient-years) of the patients in the sacubitril and/or valsartan group experienced the primary composite outcome (HF hospitalization or cardiovascular death) at 3 years of follow-up, which gave an HR of 0.80 (95% CI: 0.73 to 0.88), and a NNT of 25 (18 to 43). The RMST days gained over this follow-up was +37 (23 to 52) days, and the potential extension of life without an event was estimated at +1.5 (0.7 to 2.4) years. The findings for all-cause death and an increase in overall survival are shown in **Table 1 and Figure 1**.

**RALES.** In the RALES study, 60.9% (45.5 per 100 patient-years) of the patients in the placebo group versus 46.4% (29.3 per 100 patient-years) of the patients in the spironolactone group experienced the primary outcome over 3 years of follow-up, with a corresponding HR of 0.67 (95% CI: 0.59 to 0.77) and NNT of 9 (7 to 14). The RMST days gained during follow-up were +119 (78 to 160) days and an extension of event-free survival of +1.1 (−0.1 to +2.3) years. The findings for all-cause death and increase in overall survival are shown in **Table 1 and Figure 1**.

**EMPHASIS-HF.** In the EMPHASIS-HF trial, 25.4% (16.7 per 100 patient-years) of the patients in the placebo group versus 17.3% (10.5 per 100 patient-years) of the patients in the eplerenone group experienced the primary outcome at 3 years of

follow-up, which gave an HR of 0.64 (95% CI: 0.54 to 0.75) and a NNT of 14 (10 to 22). The RMST days gained were +78 (51 to 106) days and an extension of event-free survival of +2.9 (1.2 to 4.5) years. The findings for all-cause death and increase in overall survival are shown in **Table 1 and Figure 1**.

**DIG.** In the DIG trial, 44.5% (22.0 per 100 patient-years) of the patients in the placebo group versus 39.3% (18.0 per 100 patient-years) of the patients in the digoxin group experienced the primary outcome over 3 years of follow-up; the HR was 0.82 (95% CI: 0.76 to 0.88) in favor of digoxin, and the NNT was 20 (15 to 32). Patients who took digoxin gained +63 (44 to 82) days of follow-up and +0.8 (0.2 to 1.5) years of event-free survival. Digoxin did not reduce all-cause death because there was no increase in event-free survival (**Table 1**).

**SUBGROUPS IN PARADIGM-HF.** The results for each of the 3 subgroups analyzed are shown in **Table 2**, **Figure 2**, and **Supplemental Table 1**.

**Lower baseline NT-proBNP level versus higher baseline NT-proBNP level.** Low NT-proBNP was defined as <1,000 pg/ml and high NT-proBNP as ≥1,000 pg/ml (**Table 2**). The analysis was also performed using the trial median NT-pro BNP of 1, 615 pg/ml (Supplemental Table 1).

Among patients with a NT-pro BNP <1,000 pg/ml, the levels were 680 pg/ml (quartile 1 to quartile 3 [Q1 to Q3]: 527 to 827 pg/ml), and the mean ± SD age was 61.8 ± 11.2 years. The primary outcome was experienced in 16.8% (7.6 per 100 patient-years) of those in the enalapril group and 12.6% (5.6 per 100 patient-years) in the sacubitril/valsartan group over 3 years of follow-up, which gave a HR of 0.73 (95% CI: 0.59 to 0.91), a NNT of 27 (16 to 83), and +26 (6 to 47) days of RSMT gained during follow-up. The estimated extension of event-free survival was +2.3 (0.6 to 4.0) years.

**FIGURE 1** Continued

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-Nephrilysin 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.
<table><caption>TABLE 2 Treatment Effect Estimates in PARADIGM-HF Subgroups (N = 8,399)</caption><thead><tr><th>CV death or HFH*</th><th>Enalapril (n = 4,212)</th><th>Sacubitril/Valsartan (n = 4,187)</th><th>Treatment Effect HR (95% CI)</th><th>p Value</th></tr></thead><tbody><tr><td>NT-proBNP &lt;1,000 pg/ml (N = 2,481)</td><td>1,262</td><td>1,219</td><td></td><td></td></tr><tr><td>Events</td><td>212 (16.8)</td><td>153 (12.6)</td><td>0.73 (0.59 to 0.91)</td><td>0.004</td></tr><tr><td>Event-free survival (%)</td><td>79.2 (76.2 to 81.8)</td><td>84.5 (82.2 to 87.2)</td><td>+5.3</td><td>0.004</td></tr><tr><td>NNT to benefit</td><td></td><td></td><td>27 (16 to 83)</td><td>0.004</td></tr><tr><td>Event rates and difference (per 100 patient-yrs)</td><td>7.6 (6.6 to 8.7)</td><td>5.6 (4.7 to 6.5)</td><td>to 2.0 (-3.4 to -0.7)</td><td>0.004</td></tr><tr><td>RMST (using follow-up time in days)</td><td>979 (964 to 994)</td><td>1,005 (991 to 1,019)</td><td>+26 (6 to 47)</td><td>0.013</td></tr><tr><td>RMST (using age instead of follow-up time)†</td><td>9.9 (8.7 to 11.0)</td><td>12.2 (10.9 to 13.5)</td><td>+2.3 (0.6 to 4.0)</td><td>0.009</td></tr><tr><td>NT-proBNP ≥1,000 pg/ml) (N = 5,904)</td><td>2,941</td><td>2,963</td><td></td><td></td></tr><tr><td>Events</td><td>902 (30.7)</td><td>760 (25.7)</td><td>0.81 (0.73 to 0.89)</td><td>&lt;0.001</td></tr><tr><td>Event-free survival (%)</td><td>64.8 (62.7 to 66.8)</td><td>69.0 (66.8 to 71.0)</td><td>+4.2</td><td>&lt;0.001</td></tr><tr><td>NNT to benefit</td><td></td><td></td><td>24 (16 to 44)</td><td>&lt;0.001</td></tr><tr><td>Event rates and difference (per 100 patient-yrs)</td><td>16.0 (15.0 to 17.1)</td><td>12.9 (12.0 to 13.9)</td><td>-3.1 (-4.5 to -1.7)</td><td>&lt;0.001</td></tr><tr><td>RMST (using follow-up time in days)</td><td>849 (835 to 862)</td><td>891 (879 to 903)</td><td>+42 (24 to 61)</td><td>&lt;0.001</td></tr><tr><td>RMST (using age instead of follow-up time)†</td><td>6.4 (5.7 to 7.0)</td><td>7.8 (7.0 to 8.5)</td><td>+1.4 (0.4 to 2.4)</td><td>0.006</td></tr><tr><td>NYHA functional class I/II (N = 5,057)</td><td>2,511</td><td>2,546</td><td></td><td></td></tr><tr><td>Events</td><td>759 (30.2)</td><td>597 (23.4)</td><td>0.75 (0.68 to 0.84)</td><td>&lt;0.001</td></tr><tr><td>Event-free survival (%)</td><td>70.8 (68.8 to 72.6)</td><td>76.6 (74.7 to 78.3)</td><td>+5.8</td><td>&lt;0.001</td></tr><tr><td>NNT to benefit</td><td></td><td></td><td>21 (15 to 34)</td><td>&lt;0.001</td></tr><tr><td>Event rates and difference (per 100 patient-yrs)</td><td>12.2 (11.4 to 13.1)</td><td>9.2 (8.5 to 9.9)</td><td>-3.0 (-4.1 to -1.8)</td><td>&lt;0.001</td></tr><tr><td>RMST (using follow-up time in days)</td><td>910 (898 to 922)</td><td>952 (942 to 963)</td><td>+42 (26 to 58)</td><td>&lt;0.001</td></tr><tr><td>RMST (using age instead of follow-up time)†</td><td>7.8 (7.1 to 8.5)</td><td>9.6 (8.9 to 10.4)</td><td>+1.9 (0.8 to 2.9)</td><td>&lt;0.001</td></tr><tr><td>NYHA functional class III/IV (N = 1,695)</td><td>892</td><td>803</td><td></td><td></td></tr><tr><td>Events</td><td>329 (36.9)</td><td>295 (36.7)</td><td>0.93 (0.80 to 1.09)</td><td>0.40</td></tr><tr><td>Event-free survival (%)</td><td>63.9 (60.3 to 67.2)</td><td>64.7 (61.1 to 68.2)</td><td>0.8</td><td>0.40</td></tr><tr><td>NNT to benefit</td><td></td><td></td><td>NA</td><td>-</td></tr><tr><td>Event rates and difference (per 100 patient-yrs)</td><td>16.2 (14.9 to 18.5)</td><td>15.5 (13.7 to 17.3)</td><td>-1.1 (-3.6 to 1.4)</td><td>0.36</td></tr><tr><td>RMST (using follow-up time in days)</td><td>828 (806 to 850)</td><td>847 (825 to 869)</td><td>19 (-12 to 49)</td><td>0.24</td></tr><tr><td>RMST (using age instead of follow-up time)†</td><td>6.2 (5.2 to 7.3)</td><td>6.8 (5.6 to 8.0)</td><td>0.6 (-1.0 to 2.2)</td><td>0.48</td></tr><tr><td>Age &lt;65 y (N = 4,279)</td><td>2,168</td><td>2,111</td><td></td><td></td></tr><tr><td>Events</td><td>545 (25.1)</td><td>422 (20.0)</td><td>0.77 (0.68 to 0.88)</td><td>&lt;0.001</td></tr><tr><td>Event-free survival (%)</td><td>70.0 (67.6 to 72.2)</td><td>75.6 (73.3 to 77.8)</td><td>+5.6</td><td>&lt;0.001</td></tr><tr><td>NNT to benefit</td><td></td><td></td><td>23 (15 to 44)</td><td>&lt;0.001</td></tr><tr><td>Event rates and difference (per 100 patient-yrs)</td><td>13.0 (11.9 to 14.1)</td><td>10.0 (9.1 to 11.0)</td><td>-3.0 (-4.4 to -1.5)</td><td>&lt;0.001</td></tr><tr><td>RMST (using follow-up time in days)</td><td>889 (874 to 904)</td><td>930 (916 to 943)</td><td>+40 (21 to 61)</td><td>&lt;0.001</td></tr><tr><td>RMST (using age instead of follow-up time)†</td><td>6.0 (5.2 to 6.7)</td><td>7.7 (6.9 to 8.4)</td><td>+1.7 (0.6 to 2.8)</td><td>0.003</td></tr><tr><td>Age ≥ 65 y (N = 4,120)</td><td>2,044</td><td>2,076</td><td></td><td></td></tr><tr><td>Events</td><td>543 (26.6)</td><td>471 (22.7)</td><td>0.83 (0.73 to 0.94)</td><td>0.003</td></tr><tr><td>Event-free survival (%)</td><td>68.2 (65.7 to 70.5)</td><td>72.0 (69.5 to 74.2)</td><td>+3.8</td><td>0.001</td></tr><tr><td>NNT to benefit</td><td></td><td></td><td>29 (17 to 83)</td><td>0.003</td></tr><tr><td>Event rates and difference (per 100 patient-yrs)</td><td>13.5 (12.4 to 14.7)</td><td>11.2 (10.2 to 12.2)</td><td>-2.3 (-3.9 to -0.1)</td><td>0.001</td></tr><tr><td>RMST (using follow-up time in days)</td><td>892 (877 to 907)</td><td>925 (912 to 940)</td><td>+33 (13 to 54)</td><td>0.002</td></tr><tr><td>RMST (using age instead of follow-up time)†</td><td>6.9 (6.4 to 7.3)</td><td>7.8 (7.3 to 8.3)</td><td>+0.9 (0.2 to 1.6)</td><td>0.010</td></tr></tbody></table>

Values are n, n (%), or median (interquartile range). The event-free survival was computed using the Kaplan-Meier survivor function over the full data and compared using the log-rank test. The number needed to treat (NNT) to benefit was computed from the cause-specific cumulative incidence functions. *For consistency, the analysis using follow-up time was capped at 3 yrs. †For consistency, the restricted mean survival time (RMST) using age instead of time used the same age range from 60 to 80 yrs in the studied subgroups of the PARADIGM-HF (Angiotensin-Nephrilysin Inhibition versus Enalapril in Heart Failure) trial, except for the age subgroups in which in patients younger than 65 yrs, the age range was 50 to 64 yrs and in patients aged 65 or older, the age range was 65 to 80 yrs (i.e., tau = 15). This metric is expressed in yrs.

CI = confidence interval; CVD = cardiovascular death; HFH = hospitalization for heart failure; HR = hazard ratio; NA = not applicable because the absolute risk reduction is not statistically significant; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association.

Among patients with a NT-proBNP ≥1,000 pg/ml, the levels were 2,330 pg/ml (Q1 to Q3: 1,512 to 4,361 pg/ml), and mean ± SD age was 64.6 ± 11.4 years. Among these patients, the event rates were higher (30.7%; 16.0 per 100 patient-years in the enalapril group vs. 25.7%; 12.9 per 100 patient-years in the sacubitril/valsartan group), and the relative risk

reduction was smaller (HR: 0.81; 95% CI: 0.73 to 0.89), but there was a lower NNT of 24 (16 to 44). RMST days gained during the follow-up were similar +42 (24 to 61) days, and the estimated extension of event-free survival was smaller, at +1.4 (0.4 to 2.4) years.

Among patients with NT-proBNP below the median, the levels were 888 pg/ml (Q1 to Q3: 642 to 1201
<figure><img src="image_4.png" /><figcaption>FIGURE 2 PARADIGM-HF: RMST Using Age Instead of Time in Subgroups Reflecting Patient Risk and Age</figcaption></figure>

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). Other abbreviations as in Figure 1.
pg/ml), and the mean ± SD age was 62.8 ± 11.1 years. These patients experienced the primary outcome in 18.2% (8.8 per 100 patient-years) of those in the enalapril group and in 13.9% (6.5 per 100 patient-years) in the sacubitril/valsartan group over 3 years of follow-up, which gave an HR of 0.74 (95% CI: 0.63 to 0.86), a NNT of 24 (16 to 48), and +34 (17 to 51) days of RSMT gained during follow-up. The estimated extension of event-free survival was +2.4 (1.1 to 3.8) years.

Among patients with a NT-pro BNP above the median, the levels (Q1, Q3) were 3,231 (2,186, 5,593) pg/ml; and mean (SD) age was 64.8 (11.6) years. Among these individuals, the event rates were higher (33.4%, 18.4 per 100 patient-years in the enalapril group vs. 28.7%, 15.2 per 100 patient-years in the sacubitril/valsartan group). The relative risk reduction was smaller (HR: 0.83; 95% CI: 0.75 to 0.93), but there was a similar NNT of 25 (16 to 61). RMST days gained during the follow-up were similar at +41 (18 to 63) days, and the estimated extension of event-free survival was smaller 0.9 (−0.1 to 2.0) years.

**Patients in NYHA functional class I/II versus NYHA functional class III/IV.** Among individuals in NYHA functional class I and/or II (mean ± SD age: 63.1 ± 11.5 years), 30.2% (12.2 per 100 patient-years) of those in the enalapril group and 23.4% (9.2 per 100 patient-years) of patients in the sacubitril/valsartan group experienced the primary outcome over 3 years of follow-up, which gave an HR of 0.75 (95% CI: 0.68 to 0.84), a NNT of 21 (15 to 34), and +42 (26 to 58) days of RSMT gained during follow-up. The estimated extension of event-free survival was +1.9 (0.8 to 2.9) years.

In patients in NYHA functional class III and/or IV (mean ± SD age: 66.0 ± 10.6 years), the event rates were higher (36.9%, 16.2 per 100 patient-years in the enalapril group vs 36.7%, 15.5 per 100 patient-years in the sacubitril/valsartan group), and the relative risk reduction was smaller (HR: 0.93; 95% CI: 0.80 to 1.09). The RMST days gained during the follow-up were 19 (−12 to 49) days, and the estimated extension of event-free survival was 0.6 (−1.0 to 2.2) years, both of which were nonsignificant and of smaller magnitude than in the NYHA functional class I and/or II group.

**YOUNGER PATIENTS VERSUS OLDER PATIENTS.** Among individuals aged younger than 65 years (mean ± SD age: 54.9 ± 8.0 years), 25.1% (13.0 per 100 patient-years) of those in the enalapril group and 20.0% (10.0 per 100 patient-years) of patients in the sacubitril/valsartan group experienced the primary outcome over 3 years of follow-up, which gave an HR

of 0.77 (95% CI: 0.68 to 0.88), a NNT of 23 (15 to 44) and +40 (21 to 61 days) of RSMT gained during follow-up. The estimated extension of event-free survival was +1.7 (0.6 to 2.8) years.

In patients aged 65 years or older (mean ± SD age: 73.0 ± 5.7 years), the event rates were higher (26.6%; 13.5 per 100 patient-years in the enalapril group vs. 22.7%; 11.2 per 100 patient-years in the sacubitril/valsartan group), the relative risk reduction was smaller (HR: 0.83; 95% CI: 0.73 to 0.94), and the NNT was larger at 29 (17 to 83). RMST days gained during the follow-up was similar +33 (13 to 54) days, and the estimated extension of event-free survival was smaller +0.9 (0.2 to 1.6) years.

The summary of the main characteristics of the RMST compared with absolute and relative risk metrics is provided in the **Central Illustration**.

## DISCUSSION

In this study, we showed how analysis of RMST can complement conventional ways of describing the benefit of treatment in clinical trials, which expanded on our previous descriptions of using this metric (5,9). We chose several exemplar trials to illustrate the strengths and limitations of the different ways of describing the effect of treatment. The absolute treatment benefit, whether expressed as a percent reduction, rate reduction, or NNT, was greatly influenced by the absolute risk of the patients studied, assuming the proportional risk reduction with treatment was similar across all populations. The absolute risk also reflected use of effective background therapy. We illustrated this in 2 ways. First, by comparison of patients in the PARADIGM-HF trial with higher NT-proBNP versus lower NT-proBNP (or NYHA functional class I and II vs NYHA functional class III and IV), in which patients with less severe or advanced HF had 2 to 3 times longer event-free survival than patients with more severe or advanced HF. Comparison of overall survival in the RALES and EMPHASIS-HF trials supported these findings, with the sicker, less well-treated patients in the RALES study having a NNT at 3 years to prevent 1 death of only 12 patients, compared with 33 patients in the EMPHASIS-HF trial, despite similar relative risk reductions of 0.71 (0.61 to 0.83) in the RALES study and 0.76 (0.62 to 0.94) in the EMPHASIS-HF trial. Yet, the potential years of life gained in the RALES study was 1.5 years (0.01 to 3.1 years) compared with 1.8 years (0.2 to 3.8 years) in the EMPHASIS-HF trial, with an even bigger difference in event-free survival: 1.1 years (−0.1 to 2.3 years) versus 2.9 years (1.2 to 4.5 years). This was probably because the ability to extend the duration of life in very sick
**CENTRAL ILLUSTRATION** Comparison of Age-Based Lifetime Estimates Using the Restricted Mean Survival Time With Conventional Measures of Risk Reduction

RMST Difference Using Age at Risk

<figure><img src="image_5.png" /></figure>

Lower risk/less symptomatic and younger patients

<figure><img src="image_6.png" /></figure>

Lower event-rate but potentially larger long-term gains in event-free survival

Projections of long-term survival, useful for explaining the potential benefits of treatments to less symptomatic/lower risk patients

Absolute risk-reduction is usually less pronounced in lower risk patients which may discourage them from taking additional therapies that could substantially increase event-free time

Measures of Absolute Benefit

<figure><img src="image_7.png" /></figure>

Higher risk/more symptomatic and older patients

<figure><img src="image_8.png" /></figure>

Higher event-rate but potentially larger short-term absolute risk reduction

<figure><img src="image_9.png" /></figure>

<figure><img src="image_10.png" /></figure>

Ferreira, J.P. et al. J Am Coll Cardiol HF. 2020;■(■):■-■.

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.
patients, with any treatment, was limited. This was
also the case in older patients compared with younger
patients. The latter point was illustrated by our anal-
ysis of the PARADIGM-HF trial, which examined
extension of life over a 15-year follow-up period. In
patients who started treatment before the age of 65
years, the gain in event-free survival was 1.7 years,
compared with 0.9 years in those who started treat-
ment at aged 65 years or older. We previously illus-
trated this for other ages in the PARADIGM-HF and
EMPHASIS-HF studies (5,9).

Consequently, age and risk (which, in part, is
related to age) are both important considerations
when evaluating treatment benefit. In an extreme
case, a treatment might postpone or prevent many
premature events in the short term (i.e., the duration
of a typical trial) but lead to relatively little life-
extension in a very sick, older adult population.
Conversely, the same treatment could result in a much
more modest, short-term absolute risk reduction in
less sick, younger patients, yet lead to a substantial
extension in length of life. In both trials, the relative
risk reduction might be the same. These examples
illustrated how RMST might be useful in discussions
with payers about the use of treatments in younger or
lower risk patients in whom conventional metrics of
treatment benefit (absolute risk reduction, NNT)
might not look favorable. They might also be useful in
patients who might be reluctant to consider embarking
on treatment at a young age (and potentially facing
many years of treatment) or adding another treatment
to several that they might already be taking.

This is not to diminish the importance of delaying
or preventing nonfatal events and prolonging event-
free survival, which is possible even with treat-
ments that do not alter all-cause mortality. This was
illustrated by our analysis of the DIG trial, in which
the gain in event-free survival was due to a reduction
in hospitalizations for HF but not mortality.

STUDY LIMITATIONS. These were post hoc analyses. Our findings were derived from trial data, and their generalizability to a real-world population might be limited. Subgroup analyses might not always provide robust estimates of the true effect of a treatment. Although we used NT-proBNP and NYHA functional class as proxies for risk, risk was a multivariable construct. The use of the RMST with age instead of follow-up time required a wide range of age in the population analyzed and a sufficiently large number of events across the age spectrum to provide relatively stable age-specific risk estimates. The

proposed method made some major statistical as-
sumptions and was therefore only suitable for the
exploratory analyses in this study. The key
assumption was that although a patient's risk of an
event was related to their age and treatment group,
it was not related to the length of time they spent in
the study. Therefore, this methodology would not be
suitable in studies in which the event rate was
substantially elevated in the period shortly after
randomization (e.g., in surgical trials or trials with a
large variation in underlying patient risk). The pro-
posed method would also be unsuitable in the
presence of a competing risk (e.g., non-
cardiovascular death) that was either frequent or
imbalanced between treatment groups.

CONCLUSIONS

RMST event-free (and overall) survival estimates provide a complementary means of evaluating the effect of therapy in relation to age and risk. It provides 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 who might be more reluctant to adhere to a treatment for life.

ADDRESS FOR CORRESPONDENCE: Dr. John J.V. McMurray, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, United Kingdom. E-mail: john.mcmurray@glasgow.ac.uk.

PERSPECTIVES

**COMPETENCY IN MEDICAL KNOWLEDGE:** This work pro-
vided relevant information on the use of RMST, using follow-up
time and age instead of time as a complement to the treatment
effect estimates in HF trials. RMST provided a additional means
of evaluating the effect of therapy in relation to age and risk, and
provided a clinically useful metric that should be routinely re-
ported and used to explain the potential long-term benefits of a
given treatment, especially to younger and less symptomatic
patients who might be more reluctant to adhere to a treatment
for life.

**TRANSLATIONAL OUTLOOK:** This work might help change the landscape of how trial results are presented and help in the discussions with payers, clinicians, and patients.
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**KEY WORDS** restricted mean survival time, survival models, treatment effects, trials

**APPENDIX** For an expanded Methods section and supplemental table, please see the online version of this paper.