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PARADIGM‐HF : does dose matter?
Author(s) -
Cleland John G.F.,
Pellicori Pierpaolo
Publication year - 2016
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1002/ejhf.634
Subject(s) - medicine , heart failure , cardiology , intensive care medicine
The PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial showed unequivocal superiority of sacubitril–valsartan (target dose 200 mg twice daily) over enalapril (target dose 10 mg twice daily) in clinically stable patients with heart failure, a reduced ejection fraction (HFrEF) and mostly mild symptoms who were initially able to tolerate the protocol-specified target doses of each agent.1 The trial was designed to satisfy regulators’ requirements and was not meant to be a practical blueprint for a clinical care plan. Like most clinical trials, it should be regarded as an aid to clinical judgement rather than a precise set of instructions. Clinicians must extrapolate evidence from clinical trials to individual patients and judge what is in their patients’ best interests rather than merely decide whether the patient fulfils the trial entry criteria. A very conservative stance on dose, as in recent European Society of Cardiology (ESC) guidelines on sacubitril/valsartan,2 may apply to rather few patients; a more liberal stance, as suggested by the European Medicines Agency or National Institute for Health & Care Excellence may apply to many.3 Who is right? Does dose matter? PARADIGM-HF required all patients to tolerate pre-specified doses of both medications. It did not set out to prove that the target dose of either agent was optimal. Indeed, the concept of a single universal target dose appropriate for all patients is implausible. Plasma concentrations of medicines will depend on absorption, body size and composition, and the rate of clearance by the kidney, liver, and other mechanisms, and not just the dose ingested. For many patients, higher doses will be tolerated and might be more effective; for others they will not be tolerated and might be deleterious. Lower doses will usually be better tolerated in the short term but might offer less long-term protection from disease progression.4 Identifying the optimal dose for an individual patient is difficult. Clearly a zero-dose must be ineffective, although not necessarily suboptimal for some individuals, and