SPYRAL HTN-ON MED

Published

Kandazi DE, et al. "Effect of renal denervation on blood pressure in the presence of antihypertensive drugs". The Lancet. 2018. 391:2346-55.
PubMed • Full text • PDF

Clinical Question

Among patients with uncontrolled hypertension (office SBP 150-180mmHg and DBP ≥ 90mmHg as well as 24h ambulatory SBP 140-170mmHg) despite 1-3 antihypertensive medications, is renal denervation with medical therapy superior to medical therapy alone in reducing blood pressure?

Bottom Line

Among patients with uncontrolled hypertension (office SBP 150-180mmHg and DBP ≥ 90mmHg as well as 24h ambulatory SBP 140-170mmHg) despite 1-3 antihypertensive medications, the addition of renal denervation to medical therapy results in a significant reduction in blood pressure at 6 months (reduction of 9mmHg in 24h ambulatory SBP and 6mmHg in DBP, with mean difference of -7.4mmHg systolic and -4.1mmHg compared to medical therapy alone, respectively). Medication adherence was about 60% in both groups.

Major Points

The use of renal denervation to modulate sympathethic tone as a means of treating hypertension has been the topic of multiple previous studies. However, trials of variable size, design, and method have demonstrated inconsistent efficacy. Recently, the SPYRAL HTN-OFF MED trial showed significant and meaningful blood pressure reductions in a group of hypertensive patients not receiving medical therapy. However, the potential role of renal denervation as a means to augment blood pressure control in patients with resistant hypertension despite medical therapy - the role in which renal denervation is most likely to be utilized clinically - remains largely unknown.

The 2018 Global Clinical Study of Renal Denervation With the Symplicity Spyral Multi-electrode Renal Denervation System in Patients With Uncontrolled Hypertension on Standard Medical Therapy (SPYRAL HTN-ON MED) trial randomized 80 patients with uncontrolled hypertension (office SBP 150-180mmHg and DBP ≥ 90mmHg as well as 24h ambulatory SBP 140-170mmHg) despite 1-3 antihypertensive medications to renal denervation in addition to medical therapy versus medical therapy alone. Importantly, the study was double-blinded with use of sham control in patients randomized to medical therapy alone (with adequate blinding as assessed using blinding indices). At 6 months, renal denervation was associated with a significant reduction in blood pressure (reduction of 9mmHg in 24h ambulatory SBP and 6mmHg in DBP, with mean difference of -7.4mmHg systolic and -4.1mmHg compared to medical therapy alone, respectively). Reductions in office BP were similarly greater in the renal denervation group. Notably, there was a large amount of nonadherence to antihypertensive medications, about 60% in each group. There were no significant adverse events in either arm.

The results of SPYRAL HTN-ON MED provide encouraging early evidence that renal denervation may lead to additional BP lowering effect even among patients who remain hypertensive despite medical therapy (the population in which adjunctive therapy for HTN is most likely to be used). Large rates of nonadherence to medical therapy (~40%) in each arm limit the ability to draw conclusions regarding the efficacy of renal denervation when added to truly optimal medical therapy (which is likely difficult to achieve in a real world setting). Although the differences in blood pressure observed with renal denervation are considered clinically significant and rival changes observed with addition of additional anti-hypertensive drugs, planned long-term follow up in this population with assessment of cardiovascular outcomes will be critical in establishing whether improved BP control leads to improved clinical outcomes.

Guidelines

As of September 2018, no guidelines have been published that reflect the results of this trial.

Design

• Global, multicenter, double-blinded, randomized, sham-controlled, proof-of-concept trial
• N=80
  • Renal denervation and medical therapy (N=38)
  • Sham control and medical therapy (N=42)
• Setting: 25 centers in North America, Europe, Asia
• Enrollment: July 22, 2015 - June 14, 2017
• Duration follow-up: 6 months
• Analysis: Intention-to-treat
• Primary Outcome: Change in ambulatory blood pressure from baseline to 6 months

Population

Inclusion Criteria

• Age 20-80 years
• Poorly controlled HTN (all of the following)
  • Office SBP 150-180mmHg
  • Office DBP ≥ 90mmHg
  • Mean 24h ambulatory SBP 140-170mmHg
• On 1-3 standard antihypertensive drugs
  • 50% or more of the maximum recommended dose of a thiazide, CCB, ACEi/ARB, or beta blocker

Exclusion Criteria

• Change in antihypertensive regimen within last 6 months
• Nonadherence to screening ambulatory blood pressure monitoring
• Anatomy not suitable for renal denervation upon renal angiogram

Baseline Characteristics

From renal denervation group.

• Demographics: age 54, male 87%, white 34%
• Comorbidities: BMI 31, DM 13%, smoker 21%, OSA 5%, PAD 0%, CAD 3%, stroke 0%, MI/ACS 0%
• HTN: Office SBP 165, office DBP 100, mean 24h SBP 152, mean 24h DBP 97, office HR 76, 24h HR 75, mean anti-HTN classes 2.2, one anti-HTN 29%, two anti-HTNs 18%, three anti-HTNs 53%
• Medications: diuretic 58%, CCB 71%, ACEi/ARB 82%, BB 11%

Interventions

• Patients randomized 1:1
  • Renal denervation and medical therapy (N=38)
  • Sham control and medical therapy (N=42)
• Following patient enrollment, the first screening visit was done to confirm that patients had been prescribed antihypertensive pharmacotherapy without change in dose for a minimum of 6 weeks and met the office blood pressure criteria for inclusion
• During second screening visit, patients underwent drug screening to assess antihypertensive drug adherence using tandem HPLC and mass spectroscopy of urine and plasma by an independent laboratory
• If office blood pressure, measured using an automatic blood pressure monitor, remained within the required range at the second visit, patients underwent 24h ambulatory blood pressure monitoring
• Patients meeting criteria for inclusion after second screening visit then underwent renal angiogram followed by randomization
• During the procedures (renal angiogram alone or followed by renal denervation), masking was maintained by the use of conscious sedation, blindfolding, music, and patients' lack of familiarity with the procedures
• The blinded trial staff did all follow-up visits and the patient's referring or managing physicians were unaware of a patient's treatment assignment
• Renal denervation was achieved using the Symplicity Spyral multielectrode catheter to provide circumferential RFA treatments in a spiral pattern in the four quadrants of the renal artery and branch vessels between 3-8mm in diameter
• Patients returned for office follow-up visits at 1, 3, and 6 months post-procedure
• No antihypertensive medication changes were allowed through 6 months unless escape criteria were met (office SBP ≥ 180mmHg or < 115mmHg with symptoms of hypotension)
• Analysis of covariance was used to adjust for baseline blood pressure measurements

Outcomes

Comparisons are renal denervation plus medical therapy vs. medical therapy alone

Primary Outcomes

Change in 24h ambulatory SBP

-9.0 vs. -1.6; mean difference -7.4 (95% CI -12.5 to -2.3); p=0.005

Change in 24h ambulatory DBP

-6.0 vs. -1.9; mean difference -4.1mmHg (95% CI -7.8 to -0.4); p=0.03

Secondary Outcomes

Change in office SBP

-9.4 vs. -2.6; mean difference -6.8mmHg (95% CI -12.5 to -1.1); p=0.02

Change in office DBP

-5.2 vs. -1.7; mean difference -3.5mmHg (95% CI -7.0 to 0.0); p=0.048

Adverse Events

• There were noted no procedural or safety events through 6 months of follow-up

Subgroup Analysis

• All patients receiving renal denervation had a significant drop from baseline at 6 months but between group differences were not significant in the adherent patients

Criticisms

• High medical non-adherence rate (~60%) in both arms limits generalizability of results to patients fully adherent to optimal medical therapy for hypertension
• Remains to be seen whether improved BP control translates into improved clinical outcomes

Funding

• The executive committee designed the protocol and identified clinical sites in collaboration with the funder
• The funder was responsible for collection, monitoring, and analysis of the data
• The funder assisted in figure and table generation, copy editing, and formatting