Pharmacologic Treatment for High BP and Risk of CVD—Reply

Abstract

In Reply We thank Dr Turner and colleagues for their interest in our meta-analysis 1 and for the opportunity to clarify aspects of the study. We agree that we should not dismiss the use of gefapixant in clinical practice based on our analysis. Few treatment options exist for patients with refractory or unexplained chronic cough. For those who have tried all other therapies without success, we believe that gefapixant provides an option, one that is likely safer than alternatives (ie, opioids, pregabalin, gabapentin).In their first comment related to dosing in our metaanalysis, Turner and colleagues state that the equivalent 45-mg dose in the phase 3 trials is the 50-mg dose in phase 2, and that the equivalent 15-mg dose in phase 3 is the 17-mg dose in phase 2. We have confirmed, however, with the company and study authors that the formulations in phase 2 and phase 3 demonstrated bioequivalence. 2 In particular, under fed conditions in which participants could eat 30 minutes prior to drug administration, single 50-mg doses of the phase 3 and phase 2 formulations led to similar plasma concentrations, with the 90% CIs of the geometric mean ratios within the bioequivalence bounds of 0.80 and 1.25. Doses of 45 mg and 15 mg in phase 3 are thus equivalent to the 45-mg and 15-mg doses in phase 2 and did not require adjustment in our meta-analysis.Their second comment concerns how we defined minimum important differences for the adverse event outcomes. To understand how patients may experience the trade-off between the benefits and harms of gefapixant, we surveyed 5 patient partners on the smallest increase in an adverse event outcome that would warrant them to reconsider taking the drug. While we acknowledge the small sample size, the main objective of our study was not to rigorously ascertain minimum important differences for adverse event outcomes. Should our results inform future guidelines, we would survey a larger group of patients.In their final comment, Turner and colleagues assert that patients in clinical practice will not compare their improvement with that of those who are placebo treated, and thus that we should emphasize the within-group change from baseline among those receiving gefapixant. We advise against this interpretation because patients in the placebo group also had large improvements, demonstrating that most improvement was unrelated to gefapixant but rather to placebo effects and other factors (ie, patient expectation, Hawthorne effect [the alteration of behavior due to awareness of being observed], regression to the mean, natural course of disease). One cannot assume that placebo effects and other factors will occur in the same magnitude in clinical practice.With that said, we wish to express agreement with Turner and colleagues that the benefits of gefapixant should not be dismissed. In the Discussion section of our article, we note that current therapies for refractory or unexplained chronic cough pose substantial harms and have only low-quality evidence to support their benefits. Given the pa...