Nonproportional Hazards for Time-to-Event Outcomes in Clinical Trials

Gregson, John; Sharples, Linda D.; Stone, Gregg W.; Burman, Carl‐Fredrik; Öhrn, Fredrik; Pocock, Stuart J.

doi:10.1016/j.jacc.2019.08.1034

Cited by 64 publications

(52 citation statements)

References 25 publications

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“…One of the strengths of this study is the use of the RMST to compare survival times in different subsets of patients who underwent or did not undergo TAVR. The RMST analysis yields results that are not only more intuitive to interpret, but are also more accurate for scenarios in which the hazard of an event changes over time [5,19]. Cox proportional hazards analysis assumes that the hazard of an event is constant over the entire follow-up period, while logistic regression analysis assumes that the follow-up time period is constant and fixed for all patients; neither of which would have been ideal in this patient population.…”

Section: Discussionmentioning

confidence: 99%

“…The RMST indicates the average survival time over a pre-specified time frame, reflecting the differences in areas under Kaplan-Meier curves for patient groups. The RMST is not dependent on the proportional hazards assumption, and it reflects the entire time frame rather than instantaneous time points [5]. In the no TAVR group, 1-year survival was compared between subgroups of pre-defined reasons for not proceeding with TAVR.…”

Section: Statistical Approachmentioning

confidence: 99%

“…Fourthly, the RMST does not represent the true benefits of TAVR relative to BAV over a modest 1-year time period. The RMST is known to be skewed in scenarios with few early events [5]. Finally, this study was not designed to define indications for proceeding with TAVR or other treatment strategies; rather, to clearly understand the reasons and outcomes of patients not proceeding with this procedure.…”

Section: Limitationsmentioning

confidence: 99%

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Restricted mean survival time of older adults with severe aortic stenosis referred for transcatheter aortic valve replacement

Rodighiero

Piazza

Martucci

et al. 2020

BMC Cardiovasc Disord

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Background: Few studies have measured frailty as a potential reason for foregoing transcatheter aortic valve replacement (TAVR) in older adults with severe aortic stenosis (AS). This study sought to determine the impact of frailty and other clinician-cited reasons on restricted mean survival time (RMST). Methods: An analysis of the McGill Frailty Registry was conducted between 2014 and 2018 at the McGill University Health Center Structural Valve Clinic. Consecutive nonsurgical patients referred for TAVR were included. In those that underwent balloon aortic valvuloplasty or medical management, the primary clinician-cited reason for foregoing TAVR was codified. Vital status was ascertained at 1 year and analysed using RMST and Kaplan-Meier analyses. Results: The study consisted of 373 patients with a mean age of 82.4 years, of which 233 underwent TAVR and 140 did not. Patients who did not undergo TAVR were more likely to be nonagenarians, with left ventricular dysfunction, chronic kidney disease, dementia, disability, depression, malnutrition, and frailty. The primary cliniciancited reason was: comorbidity in 34%, frailty in 23%, procedural feasibility and risks in 16%, and mild or unrelated symptoms in 27%. Compared to the TAVR group, 1-year RMST was reduced by 2.0 months in the medical management group (95% CI 1.2, 2.7) and by 1.1 months in the valvuloplasty group (95% CI-0.2, 2.5). Conclusions: Patients with severe AS referred for TAVR may never undergo the procedure on the basis of comorbidity, frailty, procedural issues, and symptoms. The best treatment decision is one that follows from multidisciplinary assessment encompassing frailty.

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Section: Discussionmentioning

confidence: 99%

Section: Statistical Approachmentioning

confidence: 99%

Section: Limitationsmentioning

confidence: 99%

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Restricted mean survival time of older adults with severe aortic stenosis referred for transcatheter aortic valve replacement

Rodighiero

Piazza

Martucci

et al. 2020

BMC Cardiovasc Disord

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“…Restricted mean survival time (RMST) was used to measure the average survival time from randomisation to any follow up time point. 13,14 Restricted mean survival time was chosen to model the data because the survival curves of the ramipril and placebo groups crossed over during follow up and the hazard ratio was time dependent. A superficial interpretation is that after a while, ramipril may start to become hazardous.…”

Section: Statistical Analysesmentioning

confidence: 99%

Long-term survival benefit of ramipril in patients with acute myocardial infarction complicated by heart failure

Hall

Gale

2021

Heart

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AimsACE inhibition reduces mortality and morbidity in patients with heart failure after acute myocardial infarction (AMI). However, there are limited randomised data about the long-term survival benefits of ACE inhibition in this population.MethodsIn 1993, the Acute Infarction Ramipril Efficacy (AIRE) study randomly allocated patients with AMI and clinical heart failure to ramipril or placebo. The duration of masked trial therapy in the UK cohort (603 patients, mean age=64.7 years, 455 male patients) was 12.4 and 13.4 months for ramipril (n=302) and placebo (n=301), respectively. We estimated life expectancy and extensions of life (difference in median survival times) according to duration of follow-up (range 0–29.6 years).ResultsBy 9 April 2019, death from all causes occurred in 266 (88.4%) patients in placebo arm and 275 (91.1%) patients in ramipril arm. The extension of life between ramipril and placebo groups was 14.5 months (95% CI 13.2 to 15.8). Ramipril increased life expectancy more for patients with than without diabetes (life expectancy difference 32.1 vs 5.0 months), previous AMI (20.1 vs 4.9 months), previous heart failure (19.5 vs 4.9 months), hypertension (16.6 vs 8.3 months), angina (16.2 vs 5.0 months) and age >65 years (11.3 vs 5.7 months). Given potential treatment switching, the true absolute treatment effect could be underestimated by 28%.ConclusionFor patients with clinically defined heart failure following AMI, ramipril results in a sustained survival benefit, and is associated with an extension of life of up to 14.5 months for, on average, 13 months treatment duration.

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“…In such cases, when a diminishing effect of the exposure on the endpoint is observed, restricted mean survival time is a more appropriate method to report the association, both from a clinician and a statistician perspective. 7 Third, when analyzing the prognostic value of a clinical variable, one must pay careful attention to the underlying population's characteristics to understand how the findings can be applied to external populations. In the current study, it is important to emphasize that the cohort presumably did not include consecutive patients because it is unlikely that 92.0% of the coronary angiograms performed during the study period were based on an ACS diagnosis in the enrolling centres.…”

mentioning

confidence: 99%

The Prognostic Value of Intraventricular Conduction Disturbances: A Matter of Time?

Marquis‐Gravel

Raymond-Paquin

McIntyre

2020

Canadian Journal of Cardiology

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Nonproportional Hazards for Time-to-Event Outcomes in Clinical Trials

Abstract: We thank Daniel Jackson and Jonathan Wessen for their helpful comments on the article.

Cited by 64 publications

References 25 publications

Restricted mean survival time of older adults with severe aortic stenosis referred for transcatheter aortic valve replacement

Restricted mean survival time of older adults with severe aortic stenosis referred for transcatheter aortic valve replacement

Long-term survival benefit of ramipril in patients with acute myocardial infarction complicated by heart failure

The Prognostic Value of Intraventricular Conduction Disturbances: A Matter of Time?

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