Renal denervation: What happened, and why?
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.
Patient demographics?
Is it possible that renal denervation has a differential effect according to race? All previous renal denervation studies were conducted in Europe or Australia; therefore, few data are available on the efficacy of the procedure in other racial groups, such as black Americans. Most of the patients in this trial were white, but approximately 25% were black—a good representation. There was a statistically significant benefit favoring renal denervation in nonblack (mostly white) patients, but not in black patients. This may be related to racial differences in the pathophysiology of hypertension or possibly due to chance alone.
A Hawthorne effect?
A Hawthorne effect (patients being more compliant because physicians are paying more attention to them) is unlikely, since the renal denervation arm did not have any reduction in blood pressure medications. At 6 months, both the sham group and the procedure group were still on an average of 5 medications.
Additionally, while the blood pressure reduction in both treatment groups was significant, the systolic blood pressure at 6 months was still 166 mm Hg in the denervation group and 168 mm Hg in the sham group. If denervation was effective, one would have expected a greater reduction in blood pressure or at least a decrease in the number of medications needed, eg, 1 to 2 fewer medications in the denervation group compared with the sham procedure group.
Regression to the mean?
It is unknown whether the results represent a statistical error such as regression to the mean. But given the run-in period and the confirmatory data from 24-hour ambulatory blood pressure, this would be unlikely.
WHAT NOW?
Is renal denervation dead? SYMPLICITY HTN-3 is only a single trial with multiple shortcomings and lessons to learn from. Since its publication, there have been updates from 2 prospective, randomized, open-label trials concerning the efficacy of catheter-based renal denervation in lowering blood pressure.10,11
DENERHTN (Renal Denervation for Hypertension)10 studied patients with ambulatory systolic blood pressure higher than 135 mm Hg, diastolic blood pressure higher than 80 mm Hg, or both (after excluding secondary etiologies), despite 4 weeks of standardized triple-drug treatment including a diuretic. Patients were randomized to standardized stepped-care antihypertensive treatment alone (control group) or standard care plus renal denervation. The latter resulted in a significant further reduction in ambulatory blood pressure at 6 months.
The Prague-15 trial11 studied patients with resistant hypertension. Secondary etiologies were excluded and adherence to therapy was confirmed by measuring plasma medication levels. It showed that renal denervation along with optimal antihypertensive medical therapy (unchanged after randomization) resulted in a significant reduction in ambulatory blood pressure that was comparable to the effect of intensified antihypertensive medical therapy including spironolactone. (Studies have shown that spironolactone is effective when added on as a fourth-line medication in resistant hypertension.12) At 6 months, patients in the intensive medical therapy group were using an average of 0.3 more antihypertensive medications than those in the procedure group.
These two trials addressed some of the drawbacks of the SYMPLICITY HTN-3 trial. However, both have many limitations including and not limited to being open-label and nonblinded, lacking a sham procedure, using a lower blood pressure threshold than SYMPLICITY HTN-3 did to define resistant hypertension, and using the same catheter as in the SYMPLICITY trials.
