American Society of Hypertension Scientific Statements Addressing Resistant Hypertension

Resistant hypertension (RH) can be defined as blood pressure (BP) that remains above its target level despite the use of three or more antihypertensive medications at maximally tolerated doses (ideally, one being a diuretic) or BP requiring four or more drugs to achieve control.1 It is an important clinical problem in many global regions, including the United States.2 The American Society of Hypertension (ASH) therefore published two Scientific Statements addressing severe hypertension and RH. The first, published in October 2014,3 discussed the identification of patients with pseudo-RH vs true RH and the appropriate steps in determining the most suitable pharmacologic regimen for them. It then recommended pharmacologic treatment strategies for patients with true RH: in the hands of skilled hypertension specialists,4 pharmacologically appropriate, complex antihypertensive drug regimens are effective for the majority of patients with RH.3 However, it was recognized that certain individuals are refractory to even this sophisticated level of pharmacotherapy or experience adverse effects (including tolerability issues) that decrease adherence to prescribed regimens. The second Scientific Statement, published in May 2015,5 focused on pathways for moving forward the development of renal sympathetic denervation (RDN) in the United States as a potential complementary therapeutic option for the patients with true RH whose BP is not managed successfully via sophisticated pharmacologic therapy. This Scientific Statement provides a summary of presentations and discussions at a multidisciplinary forum sponsored by ASH held in October 2013.3 It discusses best practices for diagnostic assessment of patients with RH and reviews pharmacologic regimens that have been successful in the treatment of RH by hypertension specialists. Patients with apparent RH can often be categorized into two subgroups: those with pseudo-RH and those with true RH. Pseudo-RH comprises approximately half of all patients and includes those with suboptimal adherence to medication regimens and/or those with artefactual clinical BP measurements.6 When using the definition of an optimal drug treatment regimen of three or more medications with a diuretic and two or more of the medications each prescribed at 50% or more of the maximum recommended dose,7 suboptimal regimens account for approximately 50% of pseudo-RH. Patients with true RH, who comprise an estimated 30% to 50% of apparent RH patients, are at the highest risk for cardiovascular disease.8 Typically, multiple drugs of varying pharmacologic classes are required to achieve goal BP in patients with RH.9-11 One example of a previous set of prescribing guidelines is the 2008 American Heart Association Scientific Statement.12 Three key points were emphasized: maximize diuretic therapy, including the possible addition of a mineralocorticoid receptor agonist; combine agents with different mechanisms of action; and use more potent diuretics in patients with reduced glomerular filtration rates (GFRs; eg, <40 mL/min/1.73 m2) and/or in patients receiving potent vasodilators that might lead to volume retention. Unfortunately, less-than-optimal pharmacologic regimens are common among referred patients with RH.13 These observations suggest a significant opportunity for prevention of the consequences of hypertension, either via improved education for family physicians or greater referrals of such patients to hypertension specialists. Percutaneous RDN is a procedure in which radiofrequency energy is applied with an endovascular catheter inserted via the femoral artery to both renal arteries sequentially, with resultant ablation of the sympathetic nerve fibers.22 The rationale for targeting these nerve fibers is derived from seminal observations that in hypertensive states there is a “persistent and adverse activation of sympathetic outflows to the heart and kidneys.”23 Indeed, the apparent early success of RDN in the SYMPLICITY HTN-124-26 and SYMPLICITY HTN-227-29 trials led to growing support of the persistent sympathetic outflow hypothesis and advocacy for RDN among clinicians. However, that initial optimism was short-lived given the recent failure of the SYMPLICITY HTN-3 trial30, 31 to meet both primary and secondary efficacy endpoints. That SYMPLICITY HTN-3 was the first RDN study to employ a sham-procedure control group suggested that study design limitations may have been responsible for the apparently positive results of SYMPLICITY HTN-1 and HTN-2.22 As the scientific community continues to digest the results of SYMPLICITY HTN-3, subsequent post hoc analyses have identified multiple potential confounding factors emergent from this study's design as well.32 The overall sentiment at an ASH co-sponsored collaborative think tank that led to the Scientific Statement discussed next was that SYMPLICITY HTN-3 should not be regarded as a failure of RDN as a therapeutic modality; rather, it underscored the need to determine how both nonclinical and clinical investigations should be conducted going forward.5 This paper provides a summary of presentations and discussions at a cardiovascular think tank co-sponsored by ASH, the US Food and Drug Administration (FDA), and the National Heart, Lung, and Blood Institute (NHLBI) held in June 2014. It reviews the present status of nonclinical safety and efficacy models of RDN, discusses the design and rationale of a controlled phase II (proof-of-concept) RDN trial in human hypertension not confounded by antihypertensive drug therapy, and considers the most appropriate phase III pivotal trial designs for future device trials in severe and/or RH. The primary objective for this proof-of-concept approach would be assessment of BP changes from baseline at week 8, preferably using ambulatory BP monitoring (ABPM). Sample size estimation suggests that approximately 160 participants randomized would be sufficient, ie, 80 per treatment group in a 1:1 randomization scheme.5 A recommended design for phase III is a blinded, sham-procedure controlled, randomized study to ensure that assessment of BP-lowering by RDN is compared with that by an appropriate control. Rigorous screening for participants correctly meeting the inclusion criteria is essential. Certainly, sham-procedure control is not equivalent to optimal clinical care of severe or uncontrolled hypertension, but it is nonetheless necessary since “both a ‘placebo-like’ effect and changes in individuals’ behavior during the course of the follow-up period are expected in a hypertension trial.” Other design considerations include uniform treatment strategies in the sham-procedure treatment arm to minimize variation in pharmacologic regimens, and employment of a blinded early efficacy interim analysis for futility. The primary objective would be assessment of BP changes from baseline at month 6, preferably using ABPM. Sample size estimation suggests that approximately 600 participants would need to be randomized in a 2:1 randomization scheme, ie, 400 in the RDN treatment arm and 200 in the sham-procedure treatment arm.5 The smaller and shorter phase II trial could either be completed prior to exposing a larger participant sample to the investigational device in a pivotal phase III trial or nested within an adaptive-design pivotal study: a planned safety assessment would be conducted before continuing to enroll the full participant sample. This would allow sponsors and investigators to obtain an understanding of procedural performance and safety, assess initial efficacy data, conduct potential biomarker studies pertaining to efficacy, and start to develop the clinical component of an integrated safety data portfolio. While the focus of this commentary lies with the two ASH Scientific Statements that have been summarized, the fundamental agreement between the contents of the second Statement and a recent Editorial36 is encouraging, especially since the authors of the Editorial are actively involved in the next generation of RDN clinical trials. Areas of agreement include the following. First, while acknowledging that while there are notable differences when testing drugs and devices, we can learn from trial designs that have been successfully employed in antihypertensive drug development programs. Second, it is important to determine more rigorously whether RDN is efficacious alone, and, if so, whether it is helpful as an adjunctive therapy for patients receiving antihypertensive medications. Third, ABPM is an important methodology.37 Fourth, assessment of long-term safety is required. Since RDN is not currently approved by the FDA, the management of severe hypertension and RH in the foreseeable future will be through “careful evaluation for pseudo-resistance using careful clinical and ambulatory BP measurements and comprehensive evaluations for secondary forms of hypertension, including primary aldosteronism, renal vascular disease, and volume excess syndromes,” prior to implementation of appropriate combination pharmacologic therapy facilitated by hypertension specialists for patients with true RH.5 Regulatory review of future RDN clinical trials using more sophisticated technology, more appropriate study designs, and more careful selection of appropriate study populations most likely to benefit from RDN will determine whether this interventional procedure will become approved for clinical practice in the United States. The authors report no specific funding in relation to the preparation of this commentary. No editorial support was used.