PATHWAY-2: spironolactone for resistant hypertension – Authors' reply
Authors: Bryan Williams, Tom M MacDonald, Steven V Morant, Morris J Brown
Journal: The Lancet (2016)

We thank Boutari and colleagues, Gkaliagkousi and colleagues, and Dale and colleagues for their interest in our findings in the PATHWAY-2 study.1Williams B MacDonald TM Morant S et al.Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.Lancet. 2015; 386: 2059-2068Summary Full Text Full Text PDF PubMed Scopus (676) Google Scholar As noted at the end of our Research in context, we also believe that there might be substantial overlap between primary aldosteronism and resistant hypertension. Plasma aldosterone, measured in our substudy was not predictive on its own of blood pressure response (unpublished). However, PATHWAY-2 shows that in patients receiving treatment with three drugs (angiotensin-converting-enzyme inhibitor or an angiotensin II receptor blocker, plus a calcium channel blocker, plus a thiazide-like diuretic—ie, A + C + D) at baseline, plasma renin values in the lower third of the normal range are inappropriately low and might be the sole clue to underlying primary aldosteronism. Patients with classical features of Conn's syndrome were excluded from the study. But in one specialist centre, some patients enrolled in PATHWAY-2 have been subsequently cured of hypertension after discovery of a unilateral adrenal microadenoma.2British Hypertension Society, Pickering Lecture.https://www.youtube.com/watch?v=wqLZD8cvT4oDate: Sept 23, 2014Google Scholar The broader question, which guidelines and prospective trials need to resolve, is whether to wait for the onset of resistant hypertension to suspect and treat hyperaldosteronism, or to promote earlier use of potassium-sparing diuretics in the treatment algorithm, aiming to prevent the consequences of aldosterone excess. With regard to diastolic pressure reduction, the greater reduction in pulse pressure by spironolactone might reflect greater reduction of arterial stiffening by spironolactone than by the comparators and we will soon report data on haemodynamics and arterial stiffness.3Farquharson CA Struthers AD Aldosterone induces acute endothelial dysfunction in vivo in humans: evidence for an aldosterone-induced vasculopathy.Clin Sci (Lond). 2002; 103: 425-431Crossref PubMed Scopus (200) Google Scholar With regard to the choice of home blood pressure monitoring to measure the primary outcome, this idea was from extensive experience of conducting crossover trials and from the high dropout rate of patients asked to perform serial ambulatory blood pressure monitoring measurements. The high precision of our findings, with all primary outcomes significant at p<0·0001, seems a nice affirmation of the decision by National Institute for Health and Care Excellence to recommend an average of at least 3 days of home monitoring as a valid alternative to ambulatory blood pressure monitoring. In response to Dale and colleagues, it should be noted that the PATHWAY programme was devised by eight academic investigators with no vested interests other than a wish to answer previously intractable questions arising from centuries of cumulative experience of hypertension practice and trials. Our 13 authors and 44 collaborators dedicated almost a decade to bringing to fruition the first prospective comparison of drug treatments for resistant hypertension. Commentators should read and write with care. If Dale and colleagues' inference is that spironolactone's overwhelming superiority over licensed antihypertensive drugs is due to selection of multiple results positive at p<0·0001, what are the many negative results that we overlooked? The prespecified analysis of PATHWAY-2 precisely followed a detailed statistical analysis plan (SAP) that was published in BMJ Open before data lock and unblinding of data,4Williams B MacDonald TM Caulfield M et al.Prevention And Treatment of Hypertension With Algorithm-based therapy (PATHWAY) number 2: protocol for a randomised crossover trial to determine optimal treatment for drug-resistant hypertension.BMJ Open. 2015; 5: e008951Google Scholar and was provided in full to The Lancet, dated and signed before any unblinding or analysis. All primary and secondary endpoints reported in The Lancet were listed at ClinicalTrials.gov before data lock and unblinding. The protocol, supplied to the Lancet reviewers, and approved by multiple regulators before a single patient being recruited, documented that the SAP would be written at a later stage, before unblinding. This protocol, also posted on the public domain, EudraCT, before patient recruitment, correctly identified the primary objective as "to test our primary hypothesis that the commonest cause of resistant hypertension is excessive sodium retention, and that further diuretic therapy, i.e. spironolactone, will be superior to other potential add-on drugs". The primary outcome measure was correctly stated on EudraCT to be "the difference in home systolic blood pressure between each active drug (spironolactone, doxazosin, bisoprolol) and placebo". The function and obligation of the SAP was to specify how the primary hypothesis would be addressed, using the prespecified primary outcome measures, capturing the maximum amount of information that has been discovered by the trial. Hierarchical co-primary endpoints permit each endpoint in the hierarchy to be tested only if all previous tests are significant, so rendering it progressively harder for each hypothesis after the first to yield a positive outcome. Moreover, because the SAP prespecified use of all data without selection, averaging blood pressure responses for both the low-dose and high-dose periods, our primary analyses under-represent the true superiority of spironolactone at the end of each drug cycle. This finding is apparent in the figure, showing that the 50 mg dose of spironolactone reduced blood pressure almost twice as much as 25 mg, whereas there was little advantage from increasing the dose of bisoprolol or doxazosin. The obstacles to performing all clinical trials these days are immense, with the power to control what is done for patients inversely related to evaluating patients' real benefits and risks. BW has received honoraria for lectures on hypertension from Novartis, Boehringer Ingelheim, Servier, Daiichi Sankyo, and Pfizer. TMM is chief investigator on two large investigator initiated, industry funded but university sponsored cardiovascular outcome studies (funded by Pfizer and Menarini/IPSEN/Teijin pharmaceuticals). His research unit also does industry funded studies by Novartis and Amgen, but none of these studies focus on blood pressure. TMM has also consulted or received honoraria from Novartis, Takeda, Daiichi Sankyo, Shire, and Astellus. TMM is the current president of the British Hypertension Society. MJB has received honoraria from Novartis. SVM declares no competing interests. PATHWAY-2: spironolactone for resistant hypertensionWe read with great interest the study by Bryan Williams and colleagues (Nov 21, p 2059),1 which confirmed for the first time the superiority of spironolactone over α blockers and β blockers in resistant hypertension—a very important clinical finding. We would like to draw attention to some aspects. Full-Text PDF PATHWAY-2: spironolactone for resistant hypertensionWe read with interest the PATHWAY-2 study.1 Although this study adds valuable information to the field, some issues need to be highlighted. Full-Text PDF PATHWAY-2: spironolactone for resistant hypertensionWe have identified discrepancies in the Article by Williams and colleagues1 between prespecified and reported outcomes. Full-Text PDF