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Abstract & Commentary
Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco, Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Source: Bhatt DL, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370:1393-1401.
Resistant hypertension, defined as a systolic blood pressure (BP) that remains above
goal despite treatment with at least three complementary antihypertensive agents of different classes at maximally tolerated doses, has become an increasingly common diagnosis in recent years. The prevalence of resistant hypertension is not precisely known, in part due to the use of slightly different definitions, but is widely considered to be at least 10% of the hypertensive population. Renal denervation, an invasive catheter-based procedure involving delivery of radiofrequency energy to the renal arteries, has recently emerged as potential treatment for this problem. Early studies showed great promise, such that the American Heart Association dubbed renal denervation one of the top advances in cardiology in 2012. The Symplicity system from Medtronic was one of the first devices to market, receiving CE mark approval in Europe in 2010, and has been the center of the most rigorous study. The first Symplicity trial (HTN-1), an open-label study of 153 patients undergoing the procedure, recently reported 3-year follow-up data showing reduction in BP of -33/-19 mmHg.1 Symplicity HTN-2, a randomized, controlled trial of 106 patients, showed a similar magnitude of BP lowering in denervation patients at 6 months, with no significant change in controls.2
Bhatt et al now report the results of the Symplicity HTN-3 trial, which sought to overcome the well-recognized shortcomings of earlier studies. To this end, they enrolled 535 adult patients with resistant hypertension from 88 U.S. sites. These patients were randomized in a 2:1 fashion to undergo renal denervation or a sham procedure. Patients who had known secondary hypertension or who were hospitalized more than once in the prior year for hypertensive emergency were excluded, as were patients with anatomic exclusions such as renal artery stenosis. Inclusion criteria were strict, requiring a systolic BP ≥ 160 mmHg at two screening visits, with 2 weeks of ambulatory monitoring also confirming elevated BP. Patient lack of awareness of their treatment assignment was verified by blinding index. Changes to antihypertensive medications during the 6-month follow up were discouraged unless they were considered to be medically necessary. The primary efficacy endpoint was change in office BP at 6 months, with change in ambulatory BP included as a secondary endpoint.
At 6 months, office BPs decreased by a similar amount in the denervation and sham control groups: -14.13 ± 23.93 mmHg in the denervation group and -11.74 ± 25.94 mmHg in the sham group, resulting in a non-significant difference of -2.39 mmHg. Similarly, ambulatory BP decreases were also similar between the intervention and control groups. Further, analysis of diastolic BP, heart rate, renal function, and glycated hemoglobin levels showed no significant effect of renal denervation. The authors concluded that in a blinded, sham controlled study of resistant hypertension patients, renal denervation did not significantly reduce systolic BP after 6 months of follow-up.
This study contradicts the major findings of the majority of published investigations, and in so doing has already altered the fate of renal denervation therapy in the United States. How do we explain the discrepant data? The use of a sham control along with appropriate and measured blinding is certainly the most visible difference, suggesting that some of what was seen in prior investigations could be accounted for by the placebo effect. Sham control procedures are difficult to build into clinical studies, both from an operational and an ethical standpoint, and the authors are to be applauded for using them here. Prior nonrandomized trials did not include a concurrent control group, providing ample opportunities to inflate the observed treatment effect. Regression to the mean has been suggested as another element in this story, accounting for part of the observation that BP lowering in the denervation group was less than was seen in the randomized Symplicity HTN-2 trial,2 while the decrease in the control group was substantially more.
What else was done well in this study? Prospective BPs were evaluated not only in an office setting, but also on an ambluatory basis. Inclusion criteria were overall more stringent than in prior investigations, and exclusions for anatomic criteria were strictly followed. Overall, medical therapy was excellent, including use of spironolactone in a significant proportion of patients. Significantly, the safety endpoint of the study was met, with a low rate of major adverse events.
The trial sponsor has pointed out that the adequacy of the procedure itself was not confirmed in the study. As Dr. Bhatt has said, "Unfortunately, it is not possible to determine definitively whether this trial demonstrated the failure of renal denervation to significantly reduce blood pressure or if there was a failure to achieve adequate renal denervation in these patients." Given that the system used and training procedures were similar to prior Symplicity studies, this observation does not explain the differing results.
The wide range of responses to renal denervation in the study, expressed as the standard deviations of the change in office systolic BP from baseline, suggests the possibility that renal denervation may be more effective in selected populations with increased sympathetic drive. The Medtronic Symplicity catheter, as well as five competing renal denervation systems, continues to be available for clinical use in more than 80 other countries around the world. For now, however, use in the United States awaits definitive evidence for efficacy.
1. Krum H, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: Final 3-year report of the Symplicity HTN-1 study. Lancet 2014;383:622-629.
2. Symplicity HTN-2 investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): A ran-domised controlled trial. Lancet 2010;376:1903-1909.