Research ArticleAn analysis of the blood pressure and safety outcomes to renal denervation in African Americans and Non-African Americans in the SYMPLICITY HTN-3 trial
Introduction
Hypertension prevalence is increasing worldwide.1, 2, 3 In the United States, the age-adjusted prevalence of hypertension is 29%.4 Among African American adults, the prevalence of hypertension is among, though not, the highest in the world.5 African Americans with hypertension have, on average, 7 mm Hg higher systolic blood pressure (SBP) than whites with hypertension.6 African Americans also disproportionately manifest resistant hypertension in comparison with whites.7 Accordingly, African Americans experience substantially greater morbidity and mortality from BP-related complications, such as stroke, heart failure, chronic kidney disease or end-stage renal disease, and retinopathy, than whites.8, 9, 10, 11, 12
The renal sympathetic nervous system is an important contributor to the pathophysiology of hypertension,13, 14, 15 mediated by increased peripheral and renal vasoconstriction, renin release, reductions in renal blood flow, and sodium and water retention. The peripheral venous system is the major (∼80%) location of vascular capacitance, which, when constricted in response to alpha adrenergic stimulation, shifts blood volume from the venous to arterial circulation, thus increasing BP.16, 17, 18 Percutaneous catheter-based renal denervation (RDN) has been proposed as a solution to uncontrolled apparent treatment-resistant hypertension, and the procedure has been previously well described.19
Previous studies with RDN were conducted primarily outside the United States; hence, limited data are available for African Americans. A prespecified objective of the SYMPLICITY HTN-3 study that was conducted solely in the United States was to understand the response to RDN in African Americans. It was previously reported that the difference in the 6-month change in office SBP of RDN versus sham was +2.3 mm Hg (95% confidence interval [CI], −7.3 to 11.8) in African Americans versus −6.6 mm Hg (95% CI, −11.8 to −1.4) in non-African Americans, P for interaction = .09.20 However, the 6-month change in ambulatory 24-hour SBP of RDN versus sham was −0.9 mm Hg (95% CI, −7.2 to 5.4 mmHg) in African Americans versus −2.5 mm Hg (95% CI, −5.9 to 2.4 mm Hg) in non-African Americans, P for interaction = .643.21 A previous analysis of SYMPLICITY HTN-3 found African American race to be independently associated with a larger sham response (estimate −12.0 mm Hg, P = .003).22
We undertook exploratory analyses to more critically examine the prespecified race-specific SBP responses and the safety outcomes to the sham and RDN procedures in the SYMPLCITY HTN-3 cohort; a secondary aim was to determine if the predictors of the sham and RDN SBP response differed by self-reported race. The overarching rationale for this multivariate analysis was to gain insight into the individual-level determinants of the SBP responses in the respective treatment arms that, in turn, influenced the primary study endpoint of SBP response difference between RDN and sham.
Section snippets
Study Design
The SYMPLICITY HTN-3 study design19 and results20, 21 have been published. In summary, the study enrolled 18- to 80-year-old subjects with uncontrolled apparent treatment-resistant hypertension (defined as SBP ≥ 160 mm Hg despite 3 or more antihypertensive medications, including a diuretic, at maximum tolerable dose). Twenty-four-hour ambulatory BP monitoring (ABPM) was used to exclude white coat hypertension (subjects with 24-hour systolic ABPM < 135 mm Hg despite office SBP≥160 mm Hg).
Baseline Characteristics, Medications, and RDN Procedure
Among the 535 subjects randomized in the SYMPLICITY HTN-3 study, 140 (26%) subjects were African American. African American participants randomized to the RDN and sham groups had similar baseline characteristics (Table 1). On the other hand, multiple differences were observed between African American and non-African American participants, including higher baseline office diastolic BP and 24-hour ambulatory SBP and diastolic BP in the former. African Americans were prescribed a greater number of
Discussion
The SBP reduction in RDN compared to sham, though greater in non-African Americans than African Americans, did not meet the primary efficacy endpoint in either race. However, the RDN procedure met its primary safety endpoint in both racial groups. Beyond the initial analysis by efficacy, the present analysis was exploratory by nature and therefore does not provide definitive evidence that the SBP response to RDN differed by race. However, the apparent between-group difference in office SBP
Conclusions
In SYMPLICITY HTN-3, the SBP response to RDN did not differ by race. However, the sham office SBP response was suggestively larger in African Americans than non-African Americans. The sham ambulatory SBP response in both races, and in particular in the African American race, was plausibly explained by a post-randomization treatment effect attributable to improved adherence to prescribed antihypertension medications. Individual-level patient characteristics interacted with African American race
Acknowledgments
The sponsor (Medtronic) designed the study in collaboration with the study co-principal investigators and was responsible for data collection. The overall analysis plan and strategy was developed by the first author (Dr. John M. Flack) in conjunction with the sponsor. Analyses were independently validated by Harvard Clinical Research Institute (Boston, MA). Dr. Flack had full access to all the study data and had final responsibility for the decision to submit. All authors were responsible for
References (36)
- et al.
Selected major risk factors and global and regional burden of disease
Lancet
(2002) - et al.
Ethnicity and renal disease: lessons from the multiple risk factor intervention trial and the treatment of mild hypertension study
Am J Kidney Dis
(1993) Autonomic control of the venous system in health and disease: effects of drugs
Pharmacol Ther
(2001)- et al.
Impact of renal denervation on 24-hour ambulatory blood pressure: results from SYMPLICITY HTN-3
J Am Coll Cardiol
(2014) - et al.
A systematic review of the associations between dose regimens and medication compliance
Clin Ther
(2001) - et al.
Regional variations of blood pressure in the United States are associated with regional variations in dietary intakes: the NHANES-III data
J Nutr
(2003) - et al.
Salt sensitivity: a review with a focus on non-Hispanic blacks and Hispanics
J Am Soc Hypertens
(2013) - et al.
Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study
Lancet
(2009) - et al.
Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the SYMPLICITY HTN-1 study
Lancet
(2014) - et al.
Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure
Hypertension
(2003)
Resistant hypertension: a frequent and ominous finding among hypertensive patients with atherothrombosis
Eur Heart J
Hypertension among adults in the United States: National Health and Nutrition Examination Survey, 2011-2012
NCHS Data Brief
An international comparative study of blood pressure in populations of European vs. African descent
BMC Med
Racial disparity in hypertension control: tallying the death toll
Ann Fam Med
Prevalence of resistant hypertension in the United States, 2003-2008
Hypertension
Differences in the incidence of congestive heart failure by ethnicity: the multi-ethnic study of atherosclerosis
Arch Intern Med
Executive summary: heart disease and stroke statistics–2010 update: a report from the American Heart Association
Circulation
State of disparities in cardiovascular health in the United States
Circulation
Cited by (33)
The Rise and Fall and Rise of Renal Denervation
2022, Journal of the American College of CardiologyRenal Denervation for Treating Hypertension: Current Scientific and Clinical Evidence
2019, JACC: Cardiovascular InterventionsCitation Excerpt :In addition, it will be important to determine if RDN can reduce the number of drugs (or drug dosages) needed for long-term BP control. Patients with isolated systolic HTN were initially thought not to respond to RDN (22) and have been excluded from several RCTs; however, a recent study indicated that RDN was effective in lowering BP in patients with isolated systolic HTN who did not have elevated pulse wave velocity (58), and this issue should be addressed in the future. Although there are no hard endpoint data with the use of RDN, a recent meta-analysis of relevant intermediate markers reported that RDN is associated with regression of left ventricular hypertrophy and a reduction in pulsed wave velocity (59).
Device Therapies
2018, Hypertension: A Companion to Braunwald's Heart DiseaseHigh screen failure rate in patients with resistant hypertension: Findings from SYMPLICITY HTN-3
2017, American Heart JournalCitation Excerpt :The reason for this racial difference is uncertain. However, demographic differences between the African American and non-African American trial subpopulations were noted previously14: The African American cohort was younger, included more women, had higher 24-hour mean SBP and higher body mass index, and was also prescribed more medication classes with a different distribution of specific prescribed antihypertensive agents. Furthermore, both of these minority populations, as well as smokers, have been known to have lower medication adherence and thus may have had a greater opportunity to improve their adherence during the screening process because of the study effect,15 leading to a lower SBP at SV2 than SV1.
Can we predict the blood pressure response to renal denervation?
2017, Autonomic Neuroscience: Basic and Clinical
Funding: See last page of article.