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SPYRAL HTN-OFF MED: Renal denervation lowers BP in unmedicated patients
Catheter-based renal denervation lowered BP in hypertensive patients not treated with antihypertensive medication, according to the results of the SPYRAL HTN-OFF MED trial presented at the European Society of Cardiology Congress and simultaneously published in The Lancet.
"These results are extremely encouraging for the more than 50% of hypertension patients who become nonadherent to their medications within 1 year of initiating therapy," Raymond R. Townsend, MD, director of the hypertension program, University of Pennsylvania, said in a press release issued by Medtronic. "The societal implications are potentially huge as well, as high [BP] contributes more than $500 billion in direct costs to our health care systems globally."
The multicenter, international, single-blind, randomized, sham-controlled, proof of concept trial was conducted to study renal denervation in the absence of antihypertensive medications vs. a sham procedure in order to isolate its effect on BP reduction, as well as to address the confounding factors of the SYMPLICITY HTN-3 trial.
"After SYMPLICITY HTN-3, we learned a lot about the procedure itself, medication adherence and which patients may have less response to the [renal denervation] procedure — these insights have been incorporated into the revised clinical approach in the SPYRAL HTN program," David E. Kandzari, MD, director of interventional cardiology and chief scientific officer, Piedmont Heart Institute, said in the release. "With this new approach and protocol design, coupled with new technology that allows more consistent circumferential treatment and easier access into the distal anatomy, based on these compelling results we are confident that we've appropriately addressed the issues in previous renal denervation trials."
Patients were included in the study if they had an office systolic BP 150 mm Hg and 180 mm Hg, office diastolic BP 90 mm Hg, and a mean 24-hour ambulatory systolic BP 140 mm Hg and 170 mm Hg at second screening underwent renal angiography.
The study findings showed a significant decrease in office and 24-hour ambulatory BP from baseline to 3 months in the renal denervation group:
- 24-hour systolic BP, –5.5 mm Hg (95% CI, –9.1 to –2; P = .0031)
- 24-hour diastolic BP, –4.8 mm Hg (95% CI, –7.0 to –2.6; P < .0001)
- Office systolic BP, –10 mm Hg (95% CI, –15.1 to –4.9; P = .0004); and
- Office diastolic BP, –5.3 mm Hg (95% CI, –7.8 to –2.7; P = 0.0002).
Researchers found no significant changes in the sham-control group:
- 24-hour systolic BP, –0.5 mm Hg (95% CI, –3.9 to 2.9; P = .7644)
- 24-hour diastolic BP, –0.4 mm Hg (95% CI, –2.2 to 1.4; P = .6448)
- Office systolic BP, –2.3 mm Hg (95% CI, –6.1 to 1.6; P = .2381); and
- Office diastolic BP, –0.3 mm Hg (95% CI, –2.9 to 2.2; P = .8052).
The mean difference between the groups favored renal denervation for 3-month change in both office and 24-hour BP from baseline:
- 24-hour systolic BP, –5 mm Hg (95% CI, –9.9 to –0.2; P =. 0414)
- 24-hour diastolic BP, –4.4 mm Hg (95% CI, –7.2 to –1.6; P = .0024)
- Office systolic BP, –7.7 mm Hg (95% CI, –14 to –1.5; P = .0155); and
- Office diastolic BP, –4.9 mm Hg (95% CI, –8.5 to –1.4; P = .0077).
Study findings were similar in baseline-adjusted analyses. There were no major adverse events in either group.
After the results were presented, Medtronic announced that it intends to continue consulting with physician advisors and global regulatory authorities to appropriately move forward with a pivotal trial design.
"Based on the clinical results presented at ESC, we are confident that the SPYRAL HTN-OFF MED Study has successfully demonstrated the treatment effect of [renal denervation]," study presenter Michael Böhm, MD, PhD, chairman, department of internal medicine at University of Saarland in Homburg/Saar, Germany, said in the release. "With consistent and significant drops across ambulatory and office-based [BP] — including both systolic and diastolic measurements — we are confident to be moving forward with a pivotal trial so that doctors and patients may have an alternative approach to lowering [BP]."– by Dave Quaile
References:
Böhm M, et al. Hot Line: Late Breaking Clinical Trials 2. Presented at: European Society of Cardiology Congress; August 26-30, 2017; Barcelona, Spain.
Townsend RR, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)32281-X.
Disclosures: The study was funded by Medtronic. Böhm reports receiving personal fees from Medtronic during the conduct of the study, as well as honoraria for lectures and scientific advice from Abbott, AstraZeneca, Boehringer Ingelheim, Medtronic, Servier and Vifor. Kandzari reports receiving institutional support for conducting clinical trials from Medtronic and research or grant support and honoraria for work unrelated to the study. Townsend reports receiving institutional support for the conduct of clinical trials and consultant fees from Medtronic.
Editor’s Note: This article was updated on August 28, 2017 to clarify Medtronic’s actions after presentation of the results.
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In recent years, the purported benefits of bivalirudin over unfractionated heparin in PCI have come into question. The VALIDATE-SWEDEHEART trial provides further data to assess both anticoagulation strategies in the setting of modern PCI practices. What strikes me most about this study is the almost universal adoption of transradial access amongst operators and the requirement of high-potency P2Y12 inhibitors. This may limit the generalizability of the trial in a country like the U.S., where transfemoral procedures are still performed more commonly than in many other countries in the world.
However, for those operators performing transradial PCI for STEMI and non-STEMI, VALIDATE-SWEDEHEART suggests strongly that there is no significant benefit in using one agent over the other. Thus, in our cost-conscious climate, it would seem difficult to justify the routine use of bivalirudin given its higher cost. For those patients receiving clopidogrel for P2Y12 inhibition, it is not clear that this study provides clear guidance, but it does fall in line with other recent studies. Patients receiving bivalirudin also were strongly recommended to receive a prolonged infusion post-PCI. This also likely does not reflect general clinical practice, given that initial trials of bivalirudin did not require prolonged therapy.
Overall, this study supports the reasoning that has pushed many operators to switch back from bivalirudin to unfractionated heparin as their default anticoagulation regimen in PCI. Future studies will need to demonstrate if there remain selected high-risk populations that stand to benefit from bivalirudin in the modern PCI practice.
Perspective
Back to TopHypertension is the leading cause of death and disability worldwide. Patients often require several classes of medications to control their BP, increasing the risk of nonadherence, intolerance and cost. Though initially touted as a game-changing procedure, the role of renal denervation for the treatment of hypertension remains undetermined. After many initial positive trials, the negative results of the SYMPLICITY HTN-3 trial appeared to almost be the end of this approach. Review of this pivotal trial identified challenges with the procedure, trial conduct and study population, and subsequent preclinical studies have informed the performance of renal denervation and design of new technologies.
Now, we have a small but well-designed trial of 80 patients which infuses new life into renal denervation. SPYRAL HTN-OFF MED examined the use of renal denervation vs. a sham procedure in patients with uncontrolled hypertension in the absence of antihypertensive therapy. This small study examined both ambulatory and office BP measurements. There was no significant difference between the groups with respect to baseline BPs (average systolic BP, 162 to 163 mm Hg). There were many more sites of renal denervation in this trial (n=44) compared with SYMPLICITY HTN-3, including the extension of renal denervation to the more distal renal artery branches. No major adverse events or procedural-related complications were identified in either treatment group.
This feasibility trial showed superiority of renal denervation with a change in ambulatory systolic BP of –5.5 mm Hg in the renal denervation group versus –0.5 mm Hg in the sham group (P = .04). The office systolic BP also decreased compared with baseline more in the renal denervation group compared with the sham group, i.e. -10,0 mmHg vs. -2.3 mmHg, p=0.02).
SPYRAL HTN-OFF MED highlights that perhaps the negative results of SYMPLICITY HTN-3 were indeed the result of suboptimal renal denervation technique, trial design and technology. The impact of renal denervation against the background of antihypertensive therapy in moderate, uncontrolled HTN are also awaited in the soon completed SPYRAL ON MEDS program. These results inform the design and conduct of a large, multicenter, randomized ongoing trial of renal denervation in uncontrolled hypertension.
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This study and the SPYRAL HTN-ON MED study are proof-of-concept studies. They are performed in order to design a larger trial of renal denervation for Medtronic. By comparing renal denervation in hypertensive patients with hypertensive patients on no medication, this study suggests that the concept of a catheter-based renal denervation procedure is feasible. This study is not powered to prove efficacy even though there was a significant P value. The results were looked at incrementally as patients accrued, and when a significant difference was detected, the results were reported.
As this study was not powered sufficiently to prove efficacy, it cannot prove that renal denervation will be beneficial to patients. But the significant P value suggests that the concept should bear out in a larger, appropriately powered study.
I would like to see a large multicenter, sham-controlled study of hypertensive patients on no medications with and without renal denervation. Although this group is currently well treated with medications, such a study will help confirm the physiologic effect of renal denervation. With no medications in the control group, it should reduce the confounder of variable medication adherence in the control group. People in a research study are usually more adherent than is generally seen in practice.
A second study of the patient with resistant hypertension undergoing renal denervation in a multicenter, blinded, sham-controlled study will also be important. This group is not currently well-treated. The addition of renal denervation may provide another weapon in the armamentarium. As opposed to the SYMPLICITY HTN 3 study, the control group must be monitored better for medication adherence. Changes in the pharmacologic regimen also must be better controlled.