Efficacy of Renal Denervation Without Antihypertensives (SPYRAL HTN-OFF MED Pivotal)
- Data from the SPYRAL Pivotal trial showed significant reductions in 24-hour and office blood pressure measurements with catheter-based renal denervation compared to a sham procedure in the absence of antihypertensive medications.
- There were no procedural or device-related major adverse events, suggesting an excellent safety profile.
- While the short-term data for renal denervation are quite promising, the long-term efficacy, long-term safety, and impact on cardiovascular event rates are unknown and warrant further research.
More than one third of adults in developed countries suffer from hypertension.1 In 2010, hypertension was the leading cause of death and disability-adjusted life years worldwide.2 Hypertension is associated with increased risk of coronary heart disease, stroke, heart failure, and peripheral artery disease.2 Relative risk reductions for cardiovascular events have been shown to be proportional to the magnitude of blood pressure reduction achieved through treatment.3 However, many patients' blood pressure remains uncontrolled despite numerous safe and effective pharmacologic options, which may be due to physician inertia, patient noncompliance with medical therapy, or resistant hypertension.1 Previous evidence suggest that various neurogenic mechanisms contribute significantly to essential hypertension,4 most notably increased activity of the renal sympathetic efferent and afferent nerves found within the wall of the renal artery.1,5 Ablation of the renal sympathetic nerves has therefore been proposed as a potential treatment for hypertension.
Early proof-of-concept and safety studies showed blood pressure-lowering effects with catheter-based renal denervation.1 However, the randomized, blinded, sham-controlled SYMPLICTY HTN-3 trial showed a statistically significant reduction from baseline in blood pressure in both the renal denervation and sham control groups, without a significant difference between the two groups.6,7 Subsequent analyses suggested significant limitations of the study including high failure rate to complete ablation procedural protocol, inexperienced operators, and medication variability.7,8 Further research is therefore warranted to better understand the potential efficacy of renal denervation as a treatment for hypertension.
The SPYRAL HTN-OFF Med Pivotal Trial is a multicenter, international, prospective, single-blind, randomized, sham-controlled trial designed to assess the efficacy of renal denervation in the absence of antihypertensive medications.9 The trial enrolled 331 individuals with office systolic blood pressures (SBP) ≥ 150 mmHg to < 180 mmHg and a diastolic blood pressure (DBP) ≥ 90 mmHg. Additionally, patients were required to have a mean systolic blood pressure (SBP) ≥ 140 mmHg and < 170 mmHg on a 24-hour ambulatory blood pressure monitor. Patients were randomized in a 1:1 fashion to either catheter-based radiofrequency ablation of the renal sympathetic nerves versus a sham procedure. The primary and secondary outcomes were change in 24-hour SBP and office SBP, respectively, 3 months after the procedure. At 3 months, renal denervation compared to the sham procedure was associated with a 3.9 mm Hg reduction (Bayesian 95% credible interval –6·2 to –1·6) in 24-hour SBP and a 6.5 mm Hg reduction (–9·6 to –3·5) in office systolic blood pressure. DBP was significantly reduced as well. The efficacy of renal denervation was consistent across all subgroups. There were no major procedural or device-related adverse events.
The results of this trial demonstrate significant promise for renal denervation as a therapeutic intervention for individuals with hypertension. Even small changes in blood pressure (1-2 mmHg) can have a significant impact on population rates of cardiovascular disease.2 The 6.5 mmHg reduction in office SBP is significantly larger than what is typically achieved with a single standard antihypertensive medication. Additionally, the effect of renal denervation on blood pressure was consistent across 24-hours, which may give it a therapeutic advantage compared to pharmacologic agents that have varying pharmacokinetics and durations of action. The consistent reduction in blood pressure across sex and other important subgroups suggests that renal denervation could be a beneficial treatment for a large portion of the hypertensive population. However, patients with congestive heart failure, a history of stroke or transient ischemic attack, and atrial fibrillation were excluded from the study as it was felt unethical to withhold certain antihypertensive medications in these populations.
There are several limitations to this trial. First, blood pressure assessment was limited to 3 months for safety reasons, which may have led to an underestimate of the true treatment effect of renal denervation, as prior studies have suggested that blood pressure may continue to decline from 3 to 6 months after intervention. Second, compared to the renal denervation group, about twice as many patients in the sham group resumed medications under protocol defined escape criteria either because of SBPs exceeding 180 mmHg or blood pressure related symptoms or complications. Therefore, increased use of antihypertensive medications in the control group may have decreased the treatment effect seen between the two groups. This observation is also interesting as it suggests that renal denervation, in addition to lowering 24-hour blood pressure, may also decrease the frequency of significant spikes in SBP, thus demonstrating an additional benefit of treatment. Third, the control arm was a sham procedure as opposed to standard of care which is pharmacologic management, thereby complicating clinical application at this time. However, a companion study in patients on antihypertensive medications is ongoing with results expected in < 18 months.
In conclusion, the SPYRAL HTN-OFF MED Pivotal trial showed that catheter-based renal denervation can produce significant reductions in both 24-hour and office blood pressure. The results were consistent across subgroups with no evidence of significant risk associated with the procedure. Rates of control of hypertension in the US and globally are consistently sub-optimal. Additional treatment options for hypertension are needed and the short-term data for renal denervation are promising and clearly support the need for a large randomized trial to evaluate the long-term efficacy and safety of renal denervation and its impact on cardiovascular event rates.
- Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009;373:1275-81.
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Hypertension 2018;71:1269-1324.
- Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 2016;387:957-67.
- Schlaich MP, Lambert E, Kaye DM, et al. Sympathetic augmentation in hypertension: role of nerve firing, norepinephrine reuptake, and angiotensin neuromodulation. Hypertension 2004;43:169-75.
- DiBona GF. Sympathetic nervous system and the kidney in hypertension. Curr Opin Nephrol Hypertens 2002;11:197-200.
- Böhm M, Townsend RR, Kario K, et al. Rationale and design of two randomized sham-controlled trials of catheter-based renal denervation in subjects with uncontrolled hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) and presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications: a novel approach using Bayesian design. Clin Res Cardiol 2020;109:289-302.
- Bhatt DL, Kandzari DE, O'Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370:1393-1401.
- Catheter-based Renal Denervation in the Absence of Antihypertensive Medication: Primary Results from the SPYRAL HTN-OFF MED Pivotal Trial. Presented by Dr. Michael Böhm at the American College of Cardiology Virtual Annual Scientific Session/World Congress of Cardiology (ACC 2020/WCC), March 29, 2020.
- Böhm M, Kario K, Kandzari DE, et al. Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial. Lancet March 2020. [Epub ahead of print].
Keywords: Primary Prevention, Secondary Prevention, ACC Annual Scientific Session, acc20, Blood Pressure, Antihypertensive Agents, Ischemic Attack, Transient, Renal Artery, Control Groups, Atrial Fibrillation, Single-Blind Method, Blood Pressure Monitoring, Ambulatory, Quality-Adjusted Life Years, Cardiovascular Diseases, Risk, Developed Countries, Prospective Studies, Bayes Theorem
< Back to Listings