October 2019 post
10/4/2019 10:30:23 AM
At the European Society of Cardiology Congress in Paris, the results of the GALACTIC trial were reported by Prof. Müller (Basel). Early intensive vasodilation using personalized high doses of nitrates, oral hydralazine and rapid up-titration of ACE inhibitors or angiotensin II receptor blockers did not improve 180-day mortality in a cohort of 781 acute heart failure patients. This trial is notable, among other things, for the fact that short-term use of conventional “tried and tested” (and extremely cheap) vasodilators, administered in an intensive regime and at high dose was just as ineffectual at influencing longer-term mortality as novel agents such as ularitide and serelaxin.
The inability to demonstrate survival benefit even from drugs that are established as part of the therapeutic armamentarium for AHF highlights some fundamental issues contributing to the paucity of new drug therapies in recent decades: for example, are we targeting the wrong pathological processes in our drug development programmes or are we privileging inappropriate endpoints in clinical trials and thus hampering the regulatory approval of useful new agents?
The general lack of evidence for an ongoing survival benefit from acute-phase treatments for AHF requires some reflection. While perhaps not fully subscribing to its philosophical outlook we find much to agree with in the views of McCullough [McCullough, P.A. How Trialists and Pharmaceutical Sponsors Have Failed Us by Thinking That Acute Heart Failure Is a 48-Hour Illness. Am J Cardiol 2017, 120, 505–508.], who has argued that AHF (and by extension AdHF) is a situation often long in the making and that to expect any therapy administered for <48 h to make a robust difference to survival or rehospitalization many months after the index admission is to misunderstand the pathophysiology of these conditions.
Hospitalization for heart failure, whether as a presentation of AHF or a decompensation in the context of AdHF, results in a down-shift in the trajectory of the syndrome that is associated with worsening outcomes and patient quality of life and increased costs of care. Medical progress to address these challenges has substantially stalled in the past 20 years but advances in data technology and analytics, along with developments in clinical trials design now offer opportunities to re-envision heart failure as a complex pathophysiological continuum in ways that may help to bring a new generation of therapies into clinical use. Meanwhile it would be advisable for the clinicians to evaluate if the nearly total absence of evidence of benefit with some of the traditional i.v. drugs used in AHF and AdHF (such as the catecholamines) warrants their elimination from routine use in favor of treatments where such evidence has been accrued.