Resistant Hypertension: An Update

With the recent publication of the revised American Heart Association (AHA) Scientific Statement on Resistant Hypertension: Detection, Evaluation, and Management as well as other critical documents, major advances have been in our in how resistant hypertension (RHTN) and is defined, diagnosed, and best treated as well as our understanding of the pathophysiology of RHTN.1 The new Scientific Statement is important in defining RHTN much more comprehensively than simply based on the blood pressure (BP) level and number of prescribed medications as it has been expanded to incorporate exclusion of common pseudocauses of treatment resistance, specifically inaccurate BP measurement, a prominent white-coat effect, undertreatment, and poor medication adherence. The new American College of Cardiology (ACC)/AHA hypertension guidelines are important in providing a preliminary estimate of the prevalence of RHTN based on the now lower recommended BP goal of 130/80 mm Hg.2 The landmark PATHWAY-2 study adds importantly to our understanding of the pathophysiology of RHTN and provides compelling evidence for the most effective multiple-drug combination for treating RHTN, including especially, preferential use of spironolactone.3 This editorial serves to highlight these recent advances. The revised AHA Statement defines RHTN as “…the BP of a hypertensive patient that remains elevated above goal despite the concurrent use of 3 antihypertensive agents of different classes, commonly including a long-acting calcium channel blocker (CCB), a blocker of the renin-angiotensin system (angiotensin converting enzyme [ACE] inhibitor or angiotensin receptor blocker [ARB]), and a diuretic. All agents should be administered at maximum or maximally tolerated doses and at the appropriate dosing frequency.”1 This part of the definition is largely the same as the prior AHA definition in stating that RHTN is BP above goal in spite of use of 3 or more antihypertensive agents of different classes, at maximally tolerated doses.4 The revised definition, however, goes further than the prior definition in suggesting that the first 3 agents, if possible, should be comprised specifically of an ACE inhibitor or ARB, a CCB, and a diuretic. Although the rational for the recommendation of this standardized triple regimen is not provided in detail, it is no doubt based on (i) the recognition that the these 3 classes of agents are complimentary in their mechanisms of action, (ii) the antihypertensive efficacy of these classes of agents is well established, (iii) all of the classes of agents are available in long-acting, generic formulations, (iv) individual agents within each of the 3 classes are generally well tolerated and safe, (v) and agents from these classes are available in dual and even triple combinations allowing for simplification of dosing and potentially lower out-of-pocket costs for patients. The document does specifically recommend use of dihydropyridine CCBs, i.e., amlodipine and nifedipine, because they have been much more widely used than non-dihydropyridine CCBs, i.e., diltiazem and verapamil, in studies of RHTN, particularly, in studies establishing the benefit of spironolactone for treatment of RHTN. The statement also indicates that the diuretic used in this standardized triple regimen should, in most patients, be a thiazide or thiazide-like diuretic. It does not specify preferential use of chlorthalidone over hydrochlorothiazide (HCTZ) for initial use but changing from HCTZ to chlorthalidone is recommended as part of the treatment algorithm if the BP remains uncontrolled. The statement further indicates that HCTZ will provide diminishing benefit as the estimated glomerular filtration rate (eGFR) declines below 45 ml/min−1/1.73 min−2, while chlorthalidone can be effective with eGFRs down to 25–30 ml/min−1/1.73 min−2. Below this level eGFR or in hypoalbuminuric states (serum albumin <3.0 g/l), a long-acting loop diuretic such as torsemide is recommended.1 Importantly, the revised definition is different than the prior AHA definition in that it specifically requires exclusion of so-called pseudocauses of treatment resistance, i.e., poor BP measurement technique, white-coat effect, and poor medication adherence before diagnosing RHTN.1 Incorporation of these requirements into the definition of RHTN is based on the growing recognition that pseudocauses of treatment resistance are common and must to accounted for, as much as possible, to confirm true treatment resistance. In summary, the definition of RHTN has been expanded beyond the 2008 definition to specifically require (i) BP above goal despite concurrent use of 3 or more antihypertensive agents at maximum or maximally tolerated doses, including, if possible, a ACE inhibitor or ARB, a CCB, and a diuretic, (ii) measurement of BP according to clinical practice guidelines, (iii) exclusion of a white-coat effect, (iv) exclusion of poor antihypertensive medication adherence.1 Accordingly, the current definition of RHTN is more comprehensive in standardizing the initial 3 drug regimen and in requiring exclusion of common causes of pseudotreatment resistance. The revised definition will better distinguish true treatment resistance from the much larger category of uncontrolled hypertension attributable to undertreatment, including underdosing and/or use of ineffective drug combinations; falsely elevated BP readings because of poor BP measuring technique; a large white-coat effect; and poor medication adherence. However, application of the revised definition will engender challenges for clinicians in requiring lengthier and more systematic assessments of office BP, use of reliable and affordable methods for determining out-of-office BP levels, and access to accurate determinations of medication adherence. Application of the new definition of RHTN in combination with the lower BP goal of 130/80 mm Hg included in the 2017 American College of Cardiology ACC/AHA Hypertension Guidelines will result in a higher prevalence of RHTN. Although unreferenced, in the ACC/AHA document, it was estimated that the prevalence of RHTN will increase by about 4% with use of the lower BP goals.2 Although this intuitively may seem like an underestimate based on the much lower BP threshold, upon consideration, this small change makes sense in that the only group of patients whose categorization changes is those patients whose BP had been previously controlled between 130–139/80–89 mm Hg on 3 medications. Based on the old BP threshold of 140/90 mm Hg, such patients did not have RHTN because they were controlled with 3 medications, but because of the lower BP threshold, they are now uncontrolled on 3 medications and fulfill the current definition of RHTN. Patients controlled to less than 130/80 mm Hg on 3 or more medications still have controlled RHTN by the prior and current definition, while patients with a BP >140/90 still have uncontrolled RHTN by both definitions. Accordingly, while the change in prevalence of RHTN with application of the revised definition has not yet been rigorously determined, a 4% increase is likely correct as the only relevant change will be in the narrow group of patients whose BP is 130–139/80–89 mm Hg on 3 medications, who now have RHTN based on the revised definition. An earlier study of patients referred to a hypertension specialty reported an overall prevalence of RHTN within their clinic of 14.7%.5 Importantly however, during a median follow-up period of 7 months, the period prevalence had increased up to 43.6%. This dramatic increase in the prevalence of RHTN within this specialty clinic was because of continued up-titration of existing medications along with the addition of new ones. With intensification of treatment, many additional patients met criteria for having RHTN. These findings indicate that cross-sectional of community-based cohorts likely underestimate the true prevalence of RHTN as many patients remained undertreated, falsely lowering the prevalence of apparent RHTN. Perhaps the most important finding since publication of the 2008 Scientific Statement has been the clear confirmation of spironolactone as the most appropriate fourth agent for treating RHTN. The original 2008 Scientific Statement on RHTN included a strong recommendation for adding spironolactone after the first 3 medications, but this recommendation was largely based on observational data or open-label assessments of spironolactone.4 Absent at the time was rigorous demonstration of the superiority of spironolactone for treating RHTN compared with other classes of antihypertensive agents. In 2015, this deficiency was overcome with publication of the PATHWAY-2 study.3 In this landmark study, the antihypertensive benefit of placebo, spironolactone 25–50 mg daily, a β-blocker (bisoprolol 10–20 mg), and an α-blocker (doxazosin 4–8 mg) were compared in a double-blind, randomized study design in patients uncontrolled on a standardized regimen of an ACE inhibitor or an ARB, amlodipine, and indapamide. After 3 months of treatment with each agent, spironolactone was clearly superior to placebo and the 2 active agents, with spironolactone reducing home systolic BP by 8.7 mm Hg more than placebo, 4.5 mm Hg more than bisoprolol, and 4.0 mm Hg more than doxazosin. The percentage of patients whose BP was controlled was 58.0% for spironolactone compared with 23.9% for placebo, 43.3% for bisoprolol, and 41.5% for doxazosin. These findings clearly establish spironolactone as the most appropriate fourth agent to be used if a patient’s BP remains above goal on the standard triple regimen of an ACE inhibitor or ARB, amlodipine, and chlorthalidone or indapamide, a regimen consistent with that recommended in the new ACC/AHA guidelines. The PATHWAY-2 study provided 2 additional findings that are clinically relevant for treating RHTN. Firstly, prior studies evaluating the effectiveness of spironolactone for treating RHTN were largely limited to a maximum daily dose of 25 mg. PATHWAY-2, however, demonstrated that spironolactone 50 mg daily provided as much additional benefit as the initial starting dose of 25 mg, i.e., the antihypertensive benefit was almost equally divided between the 25 and 50 mg doses.3 This clear demonstration of continued benefit provides important demonstration of an effective dose range for spironolactone up to at least 50 mg daily for treating RHTN. As the dose benefit had clearly not plateaued, additional studies to determine whether further benefit is accrued with titration of spironolactone above 50 mg seem warranted. The other important finding from PATHWAY-2 was demonstration of the enhanced benefit of spironolactone in patients with suppressed renin levels.3 While spironolactone was more effective than the other 2 agents across the entire range of renin levels, patients with suppressed renin manifested especially large benefit, with mean home systolic BP reductions exceeding 20 mm Hg. This is an extraordinary degree of benefit from a single antihypertensive agent and is seemingly unique in being predicted by a routine biochemical assessment. The ability of suppressed renin levels (or plasma renin activity) to predict the BP response to spironolactone certainly supports assessing renin levels or renin activity in all patients with RHTN but raises the question if suppressed renin levels might also more predict the BP response to spironolactone in hypertensive patients in general. If so, it suggests the potentially far-reaching possibility of targeting initial drug selection based on a simple and inexpensive biochemical test. PATHWAY-2 included 3 substudies that likewise yielded important clinical findings regarding treatment of RHTN. In the first substudy, the BP response to spironolactone was related to baseline renin levels, plasma aldosterone levels, and the ratio of plasma aldosterone and renin concentration.6 A high aldosterone and renin concentration and a low renin level both strongly predicted a large BP response to spironolactone, with the former being overall slightly better. In contrast, plasma aldosterone was positive but weakly related to spironolactone-induced changes in BP. In the second substudy, the effect of the 3 different agents on thoracic fluid content, an index of volume status, was determined.6 Bisoprolol, the β-blocker, had no effect on thoracic fluid content, while doxazosin, the α-antagonist, increased it, indicating increased fluid retention. In contrast, spironolactone reduced thoracic fluid content by about 7%, consistent with a significant reduction in intravascular fluid retention. Combined, these 2 PATWAY-2 substudy results strongly implicate inappropriate fluid retention attributable to varying degrees of hyperaldosteronism as a broad mediator of antihypertensive treatment resistance. The results of the earlier main PATHWAY-2 are consistent with this underlying pathophysiology in demonstrating that this fluid retention is best overcome by the natuiretic and diuretic effects of spironolactone. Lastly, the third PATWAY-2 substudy assessed the benefit of amiloride for treating RHTN.6 After completion of the blinded protocol, participants willing to continue were crossed over to amiloride 10–20 mg daily for 6–12 weeks. After 6 weeks, amiloride 10 mg had reduced the home systolic BP by 20.4 mm Hg, which was slightly better than the 18.3 mm Hg observed with spironolactone 25 mg. In patients uncontrolled on amiloride 10 mg after 6 weeks and so titrated up to 20 mg, a similar dose-response as with spironolactone 25–50 mg was observed. While not as rigorous as the evaluation of spironolactone because of its open-label assessment, the findings do provide compelling rationale for considering amiloride as an effective alternative to spironolactone, especially if the latter is not tolerated. In summary, since publication of the 2008 AHA Scientific Statement on RHTN, important advances in how we diagnose and treatment RHN have occurred. Firstly, with the recent revision of the AHA Scientific Statement, the importance of accounting for common pseudocauses of RHTN is emphasized by incorporating into the definition use of proper BP technique to ensure accurate BP measurement, confirmation of uncontrolled out-of-office BP with use of home or ambulatory BP assessments, and ensuring adequate medication adherence. Secondly, the 2017 ACC/AHA Hypertension Guidelines provide a preliminary, but important, estimate that the lower goal BP of 130/80 mm Hg will only increase the prevalence of RHTN by the relatively modest amount of about 4%. Lastly, with publication of the PATHWAY-2 study and accompanying substudies, RHTN was shown be broadly attributable to excess fluid retention secondary varying degrees of hyperaldosteronism that is most effectively overcome by use of spironolactone, or alternatively, amiloride. Dr Calhoun received grant support from ReCor Medical (NCT02649426), and Dr Flack received grant support from ReCor Medical (NCT02649426) and Vascular Dynamics (NCT03179800). Dr Calhoun is a consultant for Selenity Therapeutics, and Idorsia Pharmaceuticals. Flack is a consultant for Back Beat Hypertension.

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