Stefan Anker, MD PhD Charit Medical School Berlin, Germany. CoI: - PowerPoint PPT Presentation

Effect of ivabradine on recurrent hospitalization for worsening heart failure: findings from SHIFT Commentary Stefan Anker, MD PhD Charité Medical School Berlin, Germany. CoI: Servier (speakers fees)

Congratulations to the authors

The Problem In a trial using the composite of CV death or HF hospitalization, a patient has a ‘primary endpoint’, if he or she experiences CV death as the first of these two possible events or HF hospitalization. A patient may experience CV death after HF hospitalization and may also experience repeat HF hospitalization. Neither of these subsequent events count in the ‘time -to- first’ event analysis. Hence, ‘time -to- first’ event analyses do not fully reflect the true burden of HF-REF in a contemporary population.

A vast amount of information is ignored % of all observed events ignored in ‚time -to- first‘ analysis CHARM-Added 51.2 CHARM-Alternative 51.4 EMPHASIS-HF 41.5 SHIFT 43.3 I-PRESERVE 41.1 CHARM-Preserved 46.4

A vast amount of information is ignored SHIFT: 1186 patients had at least one HF hospitalization (which contributed to the ‘time -to- first’ event analysis, along with 544 CV deaths). 472 patients had two or more admissions and there were 2113 hospitalizations for HF and 940 CV deaths in total. This means, 44% of all HF hospitalizations and 42% of CV deaths were ‘ignored’ in the (primary) ‘time -to- first’ event analysis of SHIFT.

What was found is an important effect

What was found is an important effect

What was found is an important effect ‘Time -to-first- event‘ analysis: Ivabradine treatment prevented 47 hospital admissions for HF per 1000 patients treated. ‘Repeat events‘ analysis: Ivabradine treatment prevented 93 hospital admissions for HF per 1000 patients treated. Death prevents hospitalization. These analyses are not adjusted for the impact of death.

Analyses not free of complications Statistical tests: - negative binomial regression - Poisson regression (with adjustment for over-dispersion) - Andersen – Gill method (with robust standard errors) - method of Wei, Lin & Weissfeld (WLW) - WIN-ratio - method of Finklestein & Schoenfeld (F-S) Power calculation approaches not fully solved. Regulatory acceptance to be resolved. One HF-trial has prospective uses this methodology: CHAMPION. Trials that use this methodology: PHARM-CHF, RESHAPE-HF, one current Novartis programme.

Congratulations to the authors In many scenarios, this may indeed be useful