Orthostatic Hypotension, Hypertension Treatment, and Cardiovascular Disease

Juraschek, Stephen P.; Hu, Jiun-Ruey; Cluett, Jennifer L.; Ishak, Anthony M.; Mita, Carol; Lipsitz, Lewis A.; Appel, Lawrence J.; Beckett, Nigel S.; Coleman, Ruth L.; Cushman, William C.; Davis, Barry R.; Grandits, Greg; Holman, Rury R.; Miller, Edgar R.; Peters, Ruth; Staessen, Jan A.; Taylor, Addison A.; Thijs, Lutgarde; Wright, Jackson T.; Mukamal, Kenneth J.

doi:10.1001/jama.2023.18497

“…In Reply In response to the Letter by Drs Palma and Kaufmann about our recent study, we agree that patients must be treated individually and in the context of their specific conditions. Patients with true autonomic disorders and severe orthostatic hypotension, who are identified by the severity and reproducibility of their orthostatic hypotension, should be referred for specific management.…”

supporting

confidence: 76%

Pharmacologic Treatment for High BP and Risk of CVD—Reply

Juraschek,

Mukamal

2024

JAMA

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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...

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“…To the Editor A recent meta-analysis of randomized trials of pharmacologic treatment for high blood pressure (BP) reported that antihypertensive therapy reduced the risk of cardiovascular disease (CVD) and mortality similarly in patients with and without orthostatic hypotension. The authors therefore advocated for intensive antihypertensive treatment despite the presence of orthostatic hypotension.…”

mentioning

confidence: 99%

“…As noted by the authors, dizziness, syncope, and injurious falls were not considered as end points, so it is unclear whether hypotension-related events were more frequent in the low BP goal/active antihypertensive group. Also, some trials in this meta-analysis excluded patients with standing hypotension at baseline (ie, SPRINT). Patients with symptomatic orthostatic hypotension were also likely not included in this meta-analysis due to exclusion of participants unable to remain in the standing position (eg, HYVET), or those with “other cardiovascular disease, serious illness, or contraindication” (eg, AASK).…”

mentioning

confidence: 99%

Pharmacologic Treatment for High BP and Risk of CVD

Palma,

Kaufmann

2024

JAMA

0

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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...

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“…In the Original Investigation titled “Orthostatic Hypotension, Hypertension Treatment, and Cardiovascular Disease: An Individual Participant Meta-Analysis,” published in the October 17, 2023, issue of JAMA , author Jan Staessen’s affiliations were incorrectly listed. The correct affiliations for Dr Staessen are the Research Association Alliance for the Promotion of Preventive Medicine, Mechelen, Belgium, and the Biomedical Research Group, Faculty of Medicine, University of Leuven, Leuven, Belgium.…”

mentioning

confidence: 99%