Clinical Trial Design Principles and Outcomes Definitions for Device-Based Therapies for Hypertension: A Consensus Document From the Hypertension Academic Research Consortium

Abstract

The clinical implications of hypertension in addition to a high prevalence of both uncontrolled blood pressure and medication nonadherence promote interest in developing device-based approaches to hypertension treatment. The expansion of device-based therapies and ongoing clinical trials underscores the need for consistency in trial design, conduct, and definitions of clinical study elements to permit trial comparability and data poolability. Standardizing methods of blood pressure assessment, effectiveness measures beyond blood pressure alone, and safety outcomes are paramount. The Hypertension Academic Research Consortium (HARC) document represents an integration of evolving evidence and consensus opinion among leading experts in cardiovascular medicine and hypertension research with regulatory perspectives on clinical trial design and methodology. The HARC document integrates the collective information among device-based therapies for hypertension to better address existing challenges and identify unmet needs for technologies proposed to treat the world’s leading cause of death and disability. Consistent with the Academic Research Consortium charter, this document proposes pragmatic consensus clinical design principles and outcomes definitions for studies aimed at evaluating device-based hypertension therapies.

Association between high-mobility group box 2 and subclinical hypertension-mediated organ damage in young adults

“… 5 – 7 Subtle HMOD, such as left ventricular hypertrophy (LVH), microalbuminuria, cognitive dysfunction, and thickening of the carotid vessel wall, is detectable early in the development of hypertensive cardiovascular disease (CVD). 8 However, most previous studies of hypertension have focused on older individuals (>50 years), 9 – 11 and few studies have focused on younger individuals with hypertension. Young individuals with hypertension may have distinct characteristics, and the pathophysiologic characteristics of hypertension may differ between older and younger individuals.…”

Effects of Renal Denervation vs Sham in Resistant Hypertension After Medication Escalation

“…Demonstration of the durability of the BP-lowering effect of uRDN in a randomized trial remains a methodological challenge, given the clinical need to add pharmacological treat-ment(s) in the case of persistent, or recurrent, uncontrolled hypertension after more than 2 months of follow-up. 8,9 Prior trials of RDN that enrolled patients with mild hypertension at low risk of hypertension-related complications allowed investigators to maintain stable medication regimens until assessment of the primary BP efficacy end point between 2 6 months. [3][4][5] The risk of a hypertension-related complication within 6 months is much higher for patients with RHTN, 10 as reported at 6 months in the Renal Denervation in Patients with Uncontrolled Hypertension (SYMPLICITY HTN-3) trial.…”

“…The low proportion of hypertension-related complications at 6 months in the TRIO cohort (6.2%) supports our decision to initiate the SSAHT protocol early compared with the SYMPLICITY HTN-3 trial (15.7%) and has been recommended by the Hypertension Academic Research Consortium. 9 However, this study design complicates the ascertainment of the RDN-related BP lowering effects over time, especially if there is an imbalance in antihy- The mean of 7-day home SBP values is shown. The number of patients with available data in each group is shown in parentheses below the x-axis.…”

Data at 36 months for the Symplicity SPYRAL HTN-ON MED pilot

“…There are certain lowincome and middle-income countries, specifically in sub-Saharan Africa, where there is absolutely no primary data. 3 As described in the GBD protocol, a key principle of the GBD study is that it is better to provide estimates with corresponding uncertainty than to not provide any estimation at all. Ours is the first study to report the burden of neck and back pain at the provincial scale in Iran, which can be an asset for policy makers to better evaluate and manage the condition.…”

“…There are admittedly challenges to the analysis of long-term follow-up data in device-based hypertension trials, 3 especially when participants in the control group are permitted to cross over as part of the intention-to-treat principle. As would be expected, people that did cross over from the control group to the renal denervation group typically had significantly higher blood pressure values than those that did not cross over, indicating a lack of blood pressure control from medications alone.…”