Predictors of BP Response in the Symplicity HTN-3 Trial
Predictors of BP Response in the Symplicity HTN-3 Trial
Aims The SYMPLICITY HTN-3 randomized, blinded, sham-controlled trial confirmed the safety of renal denervation (RDN), but did not meet its primary efficacy endpoint. Prior RDN studies have demonstrated significant and durable reductions in blood pressure. This analysis investigated factors that may help explain these disparate results.
Methods and results Patients with resistant hypertension were randomized 2 : 1 to RDN (n = 364) or sham (n = 171). The primary endpoint was the difference in office systolic blood pressure (SBP) change at 6 months. A multivariable analysis identified predictors of SBP change. Additional analyses examined the influence of medication changes, results in selected subgroups and procedural factors. Between randomization and the 6-month endpoint, 39% of patients underwent medication changes. Predictors of office SBP reduction at 6 months were baseline office SBP ≥180 mmHg, aldosterone antagonist use, and non-use of vasodilators; number of ablations was a predictor in the RDN group. Non-African-American patients receiving RDN had a significantly greater change in office SBP than those receiving sham; –15.2 ± 23.5 vs. –8.6 ± 24.8 mmHg, respectively (P = 0.012). Greater reductions in office and ambulatory SBP, and heart rate were observed with a higher number of ablations and energy delivery in a four-quadrant pattern.
ConclusionsPost hoc analyses, although derived from limited patient cohorts, reveal several potential confounding factors that may partially explain the unexpected blood pressure responses in both the sham control and RDN groups. These hypothesis-generating data further inform the design of subsequent research to evaluate the potential role of RDN in the treatment of resistant hypertension.
The recognition of the importance of the renal sympathetic and somatic nerves in modulating blood pressure and the development of a novel procedure intended to selectively interrupt the sympathetic contribution to hypertension has introduced an opportunity to provide meaningful benefit to patients with resistant hypertension. Early experience with surgical sympathectomy demonstrated positive reductions in blood pressure for some patients, but such procedures were abandoned because, in part, they had serious side effects. Additionally, the demonstration of high renal norepinephrine spill over into plasma of patients with untreated essential hypertension provides key evidence for the central role of renal sympathetic activation in the pathogenesis of hypertension. More recently, preclinical and early phase human evaluations of a catheter-based approach to renal denervation (RDN) have mechanistically correlated afferent sensory and sympathetic efferent denervation with decreased renal norepinephrine spill over, halving of renin activity and increased renal plasma flow. In parallel, RDN has also demonstrated clinically significant, sustained reductions in office systolic blood pressure (SBP) of ~25 mmHg in unblinded studies. Furthermore, observed reductions in blood pressure in a real-world, less-selected patient population have been substantive across a broader range of baseline blood pressures and confirm the safety of radiofrequency RDN. These early promising results in patients with resistant hypertension led to the rapid adoption of this therapy and its inclusion as a potential treatment option in published guidelines.
The recent results of the SYMPLICITY HTN-3 trial have challenged preclinical science, clinical anecdote, and the consistency observed across early phase trials. Although the trial demonstrated the safety of RDN, among 535 patients identified with treatment-resistant hypertension the difference in 6-month blood pressure decline between RDN and sham-treatment groups was not significantly different for office or ambulatory measures. Given such discordant findings between SYMPLICITY HTN-3 and prior experience, we investigated key factors that could have contributed to the greater than expected drop in blood pressure after a sham procedure and the less than expected blood pressure drop in the patients receiving RDN. Based on the results of multivariable analysis to identify predictors of SBP change, and analysis of pre-specified and post hoc subgroups to identify potential confounding factors that may have affected the trial results, three areas of investigation were pursued: (i) changes in antihypertensive medications, (ii) outcomes in selected subgroups, and (iii) detailed assessment of procedural data that may have impacted the delivery of effective RDN.
Abstract and Introduction
Abstract
Aims The SYMPLICITY HTN-3 randomized, blinded, sham-controlled trial confirmed the safety of renal denervation (RDN), but did not meet its primary efficacy endpoint. Prior RDN studies have demonstrated significant and durable reductions in blood pressure. This analysis investigated factors that may help explain these disparate results.
Methods and results Patients with resistant hypertension were randomized 2 : 1 to RDN (n = 364) or sham (n = 171). The primary endpoint was the difference in office systolic blood pressure (SBP) change at 6 months. A multivariable analysis identified predictors of SBP change. Additional analyses examined the influence of medication changes, results in selected subgroups and procedural factors. Between randomization and the 6-month endpoint, 39% of patients underwent medication changes. Predictors of office SBP reduction at 6 months were baseline office SBP ≥180 mmHg, aldosterone antagonist use, and non-use of vasodilators; number of ablations was a predictor in the RDN group. Non-African-American patients receiving RDN had a significantly greater change in office SBP than those receiving sham; –15.2 ± 23.5 vs. –8.6 ± 24.8 mmHg, respectively (P = 0.012). Greater reductions in office and ambulatory SBP, and heart rate were observed with a higher number of ablations and energy delivery in a four-quadrant pattern.
ConclusionsPost hoc analyses, although derived from limited patient cohorts, reveal several potential confounding factors that may partially explain the unexpected blood pressure responses in both the sham control and RDN groups. These hypothesis-generating data further inform the design of subsequent research to evaluate the potential role of RDN in the treatment of resistant hypertension.
Introduction
The recognition of the importance of the renal sympathetic and somatic nerves in modulating blood pressure and the development of a novel procedure intended to selectively interrupt the sympathetic contribution to hypertension has introduced an opportunity to provide meaningful benefit to patients with resistant hypertension. Early experience with surgical sympathectomy demonstrated positive reductions in blood pressure for some patients, but such procedures were abandoned because, in part, they had serious side effects. Additionally, the demonstration of high renal norepinephrine spill over into plasma of patients with untreated essential hypertension provides key evidence for the central role of renal sympathetic activation in the pathogenesis of hypertension. More recently, preclinical and early phase human evaluations of a catheter-based approach to renal denervation (RDN) have mechanistically correlated afferent sensory and sympathetic efferent denervation with decreased renal norepinephrine spill over, halving of renin activity and increased renal plasma flow. In parallel, RDN has also demonstrated clinically significant, sustained reductions in office systolic blood pressure (SBP) of ~25 mmHg in unblinded studies. Furthermore, observed reductions in blood pressure in a real-world, less-selected patient population have been substantive across a broader range of baseline blood pressures and confirm the safety of radiofrequency RDN. These early promising results in patients with resistant hypertension led to the rapid adoption of this therapy and its inclusion as a potential treatment option in published guidelines.
The recent results of the SYMPLICITY HTN-3 trial have challenged preclinical science, clinical anecdote, and the consistency observed across early phase trials. Although the trial demonstrated the safety of RDN, among 535 patients identified with treatment-resistant hypertension the difference in 6-month blood pressure decline between RDN and sham-treatment groups was not significantly different for office or ambulatory measures. Given such discordant findings between SYMPLICITY HTN-3 and prior experience, we investigated key factors that could have contributed to the greater than expected drop in blood pressure after a sham procedure and the less than expected blood pressure drop in the patients receiving RDN. Based on the results of multivariable analysis to identify predictors of SBP change, and analysis of pre-specified and post hoc subgroups to identify potential confounding factors that may have affected the trial results, three areas of investigation were pursued: (i) changes in antihypertensive medications, (ii) outcomes in selected subgroups, and (iii) detailed assessment of procedural data that may have impacted the delivery of effective RDN.