Estimating the Lifetime Benefits of Treatments for Heart Failure

João Pedro Ferreira, MD, PHD; Kieran F. Docherty, MBCHB; Susan Stienen, MD, PHD; Pardeep S. Jhund, MBBCH, PHD; Brian L. Claggett, PHD; Scott D. Solomon, MD; Mark C. Petrie, MBCHB; John Gregson, PHD; Stuart J. Pocock, PHD; Faiez Zannad, MD, PHD; John J.V. McMurray, MD

Disclosures

JACC Heart Fail. 2020;8(12):984-995. 

In This Article

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 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 analysis 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 treatment at aged 65 years or older. We previously illustrated 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 treatments 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 assumptions 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 proposed 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.

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