Prospective Comparison of ARNi with ACE-I to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF): paragon of a study or further investigation paramount?

(PARADIGM-HF) study clearly represents a landmark in the history of heart failure (HF) trials. Not since the era of β-blocker HF studies have we had a new class of agent for this condition that not only met its primary efficacy end point but also resulted in a stand-alone mortality benefit compared with conventional therapy, and did so with an acceptable safety profile. What was missing from the PARADIGM-HF main results article, 1 however, was the clinical impact of the novel intervention, an angiotensin receptor neprilysin (or neutral endopeptidase) inhibitor (ARNi), over the period of follow-up postrandomization. That gap in our knowledge regarding clinical outcomes of this new agent has now been addressed by the article by Packer et al 2 in this issue of Circulation. These new findings are focused entirely on surviving patients, drilling down into their clinical course, resource use, and in particular hospitalization requirements. From the data presented , a clear picture emerges of fewer hospitalizations and less need to intensify therapy (via increased use of pharmacological agents, implantation of devices, or cardiac transplantation) with the ARNi, LCZ-696, in comparison with the angiotensin converting enzyme (ACE) inhibitor, enalapril. In addition to clear data supporting attenuated worsening of clinical status, there was also strong evidence that patients had improved quality of life (as assessed by Kansas City Quality of Life Questionnaire) and overall clinical status (as assessed by New York Heart Association functional class) with LCZ-696 versus enalapril. These clinical findings were also supported by favorable biomarker data. These data are all the more impressive given that more patients died in the enalapril group than the LCZ-696 group over the course of the PARADIGM-HF study. 1 Thus, the pool of surviving patients was larger within the LCZ-696 group and a greater number potentially able to be hospitalized. As well, more of the sicker patients had been " removed " from the enalapril group via premature death. The above issue of " competing risks " is highly relevant to the interpretation of these clinical data in surviving patients. Not only were first hospitalizations reduced but also recurrent hospitalizations. This latter end point is of course highly relevant to not only the patient and treating physician, but also to healthcare payers. For this reason, recurrent HF hospitalisation is increasingly being used in clinical trials for regulatory purposes as a formal end point, rather than just a post hoc analysis. The …