By Marvin Eng, MD

The eagerly anticipated SYMPLICITY HTN-3 trial was found to have met its primary safety endpoint but had neutral results for its primary efficacy endpoint—6-month office blood pressure. This pivotal trial was to be the basis for Medtronic’s Symplicity^™ Renal Denervation System Food and Drug Administration (FDA) approval. Much to the surprise of the medical community, these negative results starkly contrast the clinically positive findings from prior Medtronic SYMPLICITY clinical studies and St. Jude’s EnligHTN-1.^1-3 In fact, earlier this winter St. Jude halted EnligHTN-IV expecting commercial use of Medtronic’s Symplicity system to compete with clinical trial enrollment.

SYMPLICITY HTN-3 is designed to address oft-mentioned criticisms of renal denervation research, with a sham procedure-control and formal evaluation of ambulatory blood pressure monitoring as a secondary endpoint. Entry criteria included a stable medication regimen of three or more drugs prescribed at fully tolerated doses. The trial enrollment goal of 530 patients was arrived at after aiming for 95% statistical power to detect a mean difference of 15–25 mm Hg between treatment and control groups.⁴ Enrollment for the trial amongst 90 sites was felt to be unexpectedly gradual with completion occurring last May due to stringent entry criteria.

As the clinical community waits for final results from SYMPLICITY HTN-3, speculation abounds as to why the results from the initial positive studies were not replicated. One potential factor: the initial studies utilized the Medtronic Arch^™ catheter, while later studies selected the Flex^™ catheter. The Flex^™ catheter is thought to offer greater freedom of manipulation, while the preformed curve of the Arch^™ catheter applies a default amount of pressure to ensure adequate and consistent contact throughout ablation.

Also, concern has been expressed over medication titration at the beginning of each patient’s enrollment. SYMPLICITY HTN-2 excluded patients who did not meet study entry criteria upon initial evaluation; however, HTN-3 allowed dose escalation for patients to re-qualify for meeting inclusion criteria. Once medications reached maximally tolerable doses, study protocol allowed enrollment after 2 weeks—provided no medication regiment alterations occurred. Some antihypertensives have a delayed onset of action, such as spironolactone, whose blood pressure-lowering effects may not stabilize until 8 weeks from the onset of therapy.⁵ A drifting baseline of blood pressure may confound the findings of both treatment and control arms, as well.

The current reality is that preliminary results from the strict, blinded, randomized controlled SYMPLICITY HTN-3 trial indicate a negative treatment effect for renal denervation. As of now, enrollment in the remaining SYMPLICITY studies, including SYMPLICITY HTN-4, is suspended. Last fall, the 3-year results of SYMPLICITY HTN-1 showed continued declines of systolic blood pressure across each year suggesting that renal denervation had a sustained effect;³ now, though, it is unclear if renal denervation still holds the same therapeutic promise as previously thought.

Preliminary data suggest that treatment effects for alternative renal denervation devices seem to mirror those seen in the first SYMPLICITY trials:

• EnligHTN^™ (St. Jude Medical; St. Paul, Minnesota), Vessix V2^™ (Boston Scientific; Natick, Massachusetts), and OneShot^™ (Covidien; Mansfield, Massachusetts) showed major blood pressure reductions of –26/10,⁶ –25/10,⁷ and –34/138 mm Hg, respectively, in small prospective trials
• Delivery of ultrasonic energy either endovascularly (with Paradise^™; ReCor Medical Inc; Menlo Park, California) or externally (with Kona Surround Sound^™; Kona Medical; Bellevue, Washington) decreased blood pressure –21/9 mm Hg and –29/12 mm Hg, respectively^9,10

Additional clinical development for renal denervation devices may currently be suspended, but reactionary adjustments will likely be made to studying these devices once SYMPLCIITY HTN-3 is further scrutinized.

Finally, the pathophysiological role of heightened sympathetic tone to various diseases expands the potential applications of renal denervation. For instance, a single-center observational trial showed adding renal denervation to radiofrequency pulmonary vein isolation improved the maintenance of sinus rhythm in atrial fibrillation patients.¹¹

Observations of left ventricular regression and improvements in diastolic indices, as well, seem to offer hope in treatment of diastolic heart failure. Again, these are small studies and effects regarding symptomatic improvement or prevention of congestion have yet to be demonstrated.^12,13 Exploration of the therapeutic role of renal denervation outside of hypertension may yet be a fruitful but still unrealized possibility.

Renal denervation for treatment of severe drug-resistant hypertension held considerable promise as a breakthrough in therapeutics for a high-risk subset of patients. Given the recently reported negative results of SYMPLICITY HTN-3, commercial availability of renal denervation will be on hold. Regardless of the outcome, this technology has rejuvenated interest in pathophysiology and a more aggressive stance on treating challenging patients with severe resistant hypertension.

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References

1. Esler MD, Krum H, Schlaich M, et al. Circulation. 2012;126:2976-82.
2. Worthley SG, Tsioufis CP, Worthley MI, et al. Eur Heart J. 2013;34:2132-40.
3. Krum H, Schlaich MP, Bohm M, et al. Lancet. 2013 November 7. [Epub ahead of print]
4. Kandzari DE, Bhatt DL, Sobotka P, et al. Clin Cardiol. 2012;35:528-35.
5. Oxlund CS, Henriksen JE, Tarnow L, et al. J Hypertens. 2013;31:2094-102.
6. Worthley S, Tsioufis C, Worthley M, et al. Abstract presented at the 2013 Transcatheter Cardiovascular Therapeutics Conference. October 28, 2013; San Francisco, California.
7. Sievert H. Abstract presented at the 2013 Transcatheter Cardiovascular Therapeutics Conference. October 29, 2013; San Francisco, California.
8. Ormiston JA, Watson T, van Pelt N, et al. EuroIntervention. 2013;9:70-4.
9. Bonan R. Abstract presented at the 2012 Annual Scientific Sessions of the European Association for Percutaneous Cardiovascular Interventions. May 16, 2012; Paris, France.
10. Neuzil P, Whitbourn RJ, Starek Z, et al. Abstract presented at the 2013 Transcatheter Cardiovascular Therapeutics Conference. October 29, 2013; San Francisco, California.
11. Pokushalov E, Romanov A, Corbucci G, et al. J Am Coll Cardiol. 2012;60:1163-70.
12. Brandt MC, Mahfoud F, Reda S, et al. J Am Coll Cardiol. 2012;59:901-9.
13. Schirmer SH, Sayed MM, Reil JC, et al. J Am Coll Cardiol. 2013 November 25. [Epub ahead of print]

Marvin Eng, MD, is an assistant professor of medicine at the University of Texas Health Sciences Center in San Antonio.

Keywords: Denervation, Heart Failure, Diastolic, United States Food and Drug Administration, Blood Pressure Monitoring, Ambulatory, Hypotension, Spironolactone, Hypertension

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