Randomized Trials of Renal Denervation for Uncontrolled Hypertension: An Updated Meta-Analysis

Abstract

Background: Despite optimal medical therapy, a significant proportion of patients' blood pressure remains uncontrolled. Catheter-based renal denervation (RDN) has been proposed as a potential intervention for uncontrolled hypertension. We conducted an updated meta-analysis to assess the efficacy and safety of RDN in patients with uncontrolled hypertension, with emphasis on the differential effect of RDN in patients on and off antihypertensive medications.

Methods and results: Online databases were searched to identify randomized clinical trials comparing efficacy and safety of RDN versus control in patients with uncontrolled hypertension. Subgroup analyses were conducted for sham-controlled trials and studies that used RDN devices that have gained or are currently seeking US Food and Drug Administration approval. Fifteen trials with 2581 patients (RDN, 1723; sham, 858) were included. In patients off antihypertensive medications undergoing RDN, a significant reduction in 24-hour ambulatory (-3.70 [95% CI, -5.41 to -2.00] mm Hg), office (-4.76 [95% CI, -7.57 to -1.94] mm Hg), and home (-3.28 [95% CI, -5.96 to -0.61] mm Hg) systolic blood pressures was noted. In patients on antihypertensive medications, a significant reduction was observed in 24-hour ambulatory (-2.23 [95% CI, -3.56 to -0.90] mm Hg), office (-6.39 [95% CI, -11.49 to -1.30]), home (-6.08 [95% CI, -11.54 to -0.61] mm Hg), daytime (-2.62 [95% CI, -4.14 to -1.11]), and nighttime (-2.70 [95% CI, -5.13 to -0.27]) systolic blood pressures, as well as 24-hour ambulatory (-1.16 [95% CI, -1.96 to -0.35]), office (-3.17 [95% CI, -5.54 to -0.80]), and daytime (-1.47 [95% CI, -2.50 to -0.27]) diastolic blood pressures.

Conclusions: RDN significantly lowers blood pressure in patients with uncontrolled hypertension, in patients off and on antihypertensive medications, with a favorable safety profile. The efficacy of RDN was consistent in sham-controlled trials and contemporary trials using US Food and Drug Administration-approved devices.

Keywords: denervation; hypertension; renal; renal denervation; uncontrolled.

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow diagram showing study selection.

*Others: reasons for the exclusion of major trials published after 2009 are summarized in Table S1.

Figure 2. Change in systolic blood pressure in all randomized clinical trials with patients off antihypertensive medication at primary outcome ascertainment time point.

Primary outcome ascertainment time points: RADIANCE‐HTN SOLO: 2 mo; RADIANCE II: 2 mo; SPYRAL‐HTN OFF MED Pivotal: 3 mo; TARGET BP OFF‐MED: 2 mo; and REDUCE HTN‐REINFORCE: 2 mo. Red stars next to trial name indicate recently published trials that have not been included in previously published meta‐analyses. IV indicates inverse variance; and RDN, renal denervation.

Figure 3. Change in diastolic blood pressure in all randomized clinical trials with patients off antihypertensive medication at primary outcome ascertainment time point.

Primary outcome ascertainment time points: RADIANCE‐HTN SOLO: 2 mo; RADIANCE II: 2 mo; SPYRAL‐HTN OFF MED Pivotal: 3 mo; TARGET BP OFF‐MED: 2 mo; and REDUCE HTN‐REINFORCE: 2 mo. Red stars next to trial name indicate recently published trials that have not been included in previously published meta‐analyses. IV indicates inverse variance; and RDN, renal denervation.

Figure 4. Change in systolic blood pressure in all randomized clinical trials with patients on antihypertensive medication at primary outcome ascertainment time point.

Primary outcome ascertainment time points: RADIANCE‐HTN TRIO: 2 mo; REQUIRE: 3 mo; SPYRAL‐HTN ON MED Expansion: 6 mo; WAVE IV: 6 mo; DENERHTN: 6 mo; SYMPATHY: 6 mo; ReSet: 6 mo; SYMPLICITY HTN‐III: 6 mo; SYMPLICITY HTN‐II: 6 mo; and Desch et al: 6 mo. Red stars next to trial name indicate recently published trials that have not been included in previously published meta‐analyses. IV indicates inverse variance; and RDN, renal denervation.

Figure 5. Change in diastolic blood pressure in all randomized clinical trials with patients on antihypertensive medication at primary outcome ascertainment time point.

Primary outcome ascertainment time points: RADIANCE‐HTN TRIO: 2 mo; REQUIRE: 3 mo; SPYRAL‐HTN ON MED Expansion: 6 mo; WAVE IV: 6 mo; DENERHTN: 6 mo; SYMPATHY: 6 mo; ReSet: 6 mo; SYMPLICITY HTN‐III: 6 mo; SYMPLICITY HTN‐II: 6 mo; and Desch et al: 6 mo. Red stars next to trial name indicate recently published trials that have not been included in previously published meta‐analyses. IV indicates inverse variance; and RDN, renal denervation.

Figure 6. Mean defined daily dose at 6‐mo follow up (A) and antihypertensive medication load index at 6‐mo follow‐up (B) in off antihypertensive medication (OFF‐Med) and on antihypertensive medication (ON‐Med) trials.

In OFF‐Med trials, patients started without medications; antihypertensive medications were initiated after primary outcome assessment (RADIANCE‐HTN SOLO: 2 mo; RADIANCE II: 2 mo; SPYRAL‐HTN OFF MED Pivotal: 3 mo; and TARGET BP OFF‐MED: 2 mo). Red stars next to trial name indicate recently published trials that have not been included in previously published meta‐analyses. IV indicates inverse variance; and RDN, renal denervation.

Figure 7. Mean number of antihypertensive medications at 6‐mo follow‐up (A) and baseline to 6‐mo changes in mean number of antihypertensive medications (B).

In OFF‐Med trials, patients started without medications; antihypertensive medications were initiated after primary outcome assessment (RADIANCE‐HTN SOLO: 2 mo; RADIANCE II: 2 mo; SPYRAL‐HTN OFF MED Pivotal: 3 mo; and TARGET BP OFF‐MED: 2 mo). Red stars next to trial name indicate recently published trials that have not been included in previously published meta‐analyses. IV indicates inverse variance; and RDN, renal denervation.

Figure 8. Forest plots illustrating the efficacy of renal denervation (RDN) in treating uncontrolled hypertension across randomized clinical trials (RCTs), including subgroup analyses of randomized sham‐controlled trials (RSCTs) and contemporary trials using US Food and Drug Administration (FDA)–approved devices.

DBP indicates diastolic blood pressure; OFF‐Med, off antihypertensive medication; ON‐Med, on antihypertensive medication; and SBP, systolic blood pressure.