Interpreting Key Trials

Renal denervation: What happened, and why?

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ABSTRACT

Despite promising results in initial trials, renal denervation failed to achieve its efficacy end points as a treatment for resistant hypertension in the SYMPLICITY HTN-3 trial, the largest trial of this treatment to date (N Engl J Med 2014; 370:1393–1401). Is renal denervation dead, or will future trials and newer technology revive it?

KEY POINTS

  • Renal denervation consists of passing a catheter into the renal arteries and ablating their sympathetic nerves using radiofrequency energy. In theory, it should lower blood pressure and be an attractive option for treating resistant hypertension.
  • SYMPLICITY HTN-3 was a blinded trial in which patients with resistant hypertension were randomized to undergo real or sham renal denervation.
  • At 6 months, office systolic blood pressure had failed to fall more in the renal denervation group than in the sham denervation group by a margin of at least 5 mm Hg, the primary efficacy end point of the trial.
  • Methodologic and technical shortcomings may explain the negative results of the SYMPLICITY HTN-3 trial, but most device manufacturers have put the brakes on future research into this novel therapy.
  • Today, renal denervation is not available in the United States but is available for routine care in Europe and Australia.


 

References

Many patients, clinicians, and researchers had hoped that renal denervation would help control resistant hypertension. However, in the SYMPLICITY HTN-3 trial,1 named for the catheter-based system used in the study (Symplicity RDN, Medtronic, Dublin, Ireland), this endovascular procedure failed to meet its primary and secondary efficacy end points, although it was found to be safe. These results were surprising, especially given the results of an earlier randomized trial (SYMPLICITY HTN-2),2 which showed larger reductions in blood pressures 6 months after denervation than in the current trial.

See related editorial

Here, we discuss the results of the SYMPLICITY HTN-3 trial and offer possible explanations for its negative outcomes.

LEAD-UP TO SYMPLICITY HTN-3

Renal denervation consists of passing a catheter through the femoral artery into the renal arteries and ablating their sympathetic nerves using radiofrequency energy. In theory, this should interrupt efferent sympathetic communication between the brain and renal arteries, reducing muscular contraction of these arteries, increasing renal blood flow, reducing activation of the renin-angiotensin-adosterone system, thus reducing sodium retention, reducing afferent sympathetic communication between the kidneys and brain, and in turn reducing further sympathetic activity elsewhere in the body, such as in the heart. Blood pressure should fall.3

The results of the SYMPLICITY HTN-1 and 2 trials were discussed in an earlier article in this Journal,3 and the Medtronic-Ardian renal denervation system has been available in Europe and Australia for clinical use for over 2 years.4 Indeed, after the SYMPLICITY HTN-2 results were published in 2010, Boston Scientific’s Vessix, St. Jude Medical’s EnligHTN, and Covidien’s OneShot radiofrequency renal denervation devices—albeit each with some modifications—received a Conformité Européene (CE) mark and became available in Europe and Australia for clinical use. These devices are not available for clinical use or research in the United States.3,5

Therefore, SYMPLICITY HTN-3, sponsored by Medtronic, was designed to obtain US Food and Drug Administration approval in the United States.6

SYMPLICITY HTN-3 DESIGN

Inclusion criteria were similar to those in the earlier SYMPLICITY trials. Patients had to have resistant hypertension, defined as a systolic blood pressure ≥ 160 mm Hg despite taking at least 3 blood pressure medications at maximum tolerated doses. Patients were excluded if they had a glomerular filtration rate of less than 45 mL/min/1.73 m2, renal artery stenosis, or known secondary hypertension.

A total of 1,441 patients were enrolled, of whom 364 were eventually randomized to undergo renal denervation, and 171 were randomized to undergo a sham procedure. The mean systolic blood pressure at baseline was 188 mm Hg in each group. Most patients were taking maximum doses of blood pressure medications, and almost one-fourth were taking an aldosterone antagonist. Patients in both groups were taking an average of 5 medications.

The 2 groups were well matched for important covariates, including obstructive sleep apnea, diabetes mellitus, and renal insufficiency. Most of the patients were white; 25% of the renal denervation group and 29% of the sham procedure group were black.

The physicians conducting the follow-up appointments did not know which procedure the patients underwent, and neither did the patients. Medications were closely monitored, and patients had close follow-up. The catheter (Symplicity RDS, Medtronic) was of the same design that was used in the earlier SYMPLICITY trials and in clinical practice in countries where renal denervation was available.

Researchers expected that the systolic blood pressure, as measured in the office, would fall in both groups, but they hoped it would fall farther in the denervation group—at least 5 mm Hg farther, the primary end point of the trial. The secondary effectiveness end point was a 2-mm Hg greater reduction in 24-hour ambulatory systolic blood pressure.

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Renal denervation: Are we on the right path?

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