SNOWMASS, COLO. – Reports of the demise of catheter-based renal denervation therapy for resistant hypertension in light of the disappointing SYMPLICITY HTN-3 trial results are greatly exaggerated, according to Dr. Bernard J. Gersh.
“I think what we can say about renal denervation is that the initial enthusiasm has been tempered and the number of unanswered questions is not decreasing. But the concept, I assure you, still maintains its promise,” the cardiologist said at the annual Cardiovascular Conference at Snowmass.
Dr. Bernard J. Gersh
Expectations for SYMPLICITY HTN-3 were sky high in the cardiology and business worlds on the basis of the prior unblinded SYMPLICITY HTN-1 and -2 studies showing renal denervation (RDN) achieved spectacular reductions in systolic blood pressure of 25-30 mm Hg in patients with multidrug-resistant hypertension. As the chair of the SYMPLICITY HTN-3 data safety monitoring board, he knew the outcome prior to release of the results, and he was struck that during that period the talk at cardiology conferences was only of next-generation RDN catheters and expanded indications, such as heart failure and even metabolic syndrome. Absolutely no one seemed to entertain the possibility that the results wouldn’t be positive.
So the general reaction to the SYMPLICITY HTN-3 results was profound, crushing disappointment. The trial, which was the first blinded, controlled study of RDN, showed significant reduction in blood pressure at 6 months in the RDN recipients, but a similar reduction in medically managed controls who underwent a sham RDN procedure, making for a neutral study outcome (N. Engl. J. Med. 2014;370:1393-59).
Yet the physiologic basis remains strong for RDN as a treatment for hypertension, heart failure, and perhaps other cardiovascular disorders in which sympathetic nervous system activation plays a crucial role, according to Dr. Gersh, who chaired the data safety monitoring board for SYMPLICITY HTN-3 and is a professor of medicine at the Mayo Clinic in Rochester, Minn.
He cited a recommended review written by a pioneer in the field, Dr. Murray Esler of Australia, who observed that increased renal sympathetic nervous system activity increases the secretion rate of renin, reduces renal blood flow, and boosts renal tubular sodium reabsorption while reducing urinary sodium excretion, all actions that contribute to hypertension (Exp. Physiol. 2011;96:611-22).
Dr. Gersh ticked off many potential explanations for the neutral outcome in SYMPLICITY HTN-3, including the placebo effect; regression to the mean; operator inexperience; limitations of the current technology; and the likelihood that a fair number of study participants didn’t have true treatment-resistant hypertension, but were merely resistant to taking their medication until they entered a structured, supervised randomized trial setting. The power of a placebo procedure is not to be underestimated, the cardiologist emphasized. He cited a striking illustration from another field of medicine, in which a recent meta-analysis of 137 controlled studies in more than 33,000 patients with knee osteoarthritis showed that intra-articular placebo injections outperformed oral naproxen, celecoxib, and placebo in terms of pain relief (Ann. Intern. Med. 2015;162:46-54).
Regression to the mean definitely occurred in SYMPLICITY HTN-3, as evidenced by the fact that reductions in office systolic blood pressure (SBP) averaged 25.7 and 19.7 mm Hg, respectively, in RDN recipients and controls with a baseline greater than 184 mm Hg, compared with 13.8 and 9.8 mm Hg in those with a lower baseline SBP, of 170-184 mm Hg, Dr. Gersh continued.
Operator inexperience was likely a factor in the study outcomes: Nearly one-third of the operators dad done just one procedure. And while the study protocol called for four to six ablations per side, a recent secondary analysis of SYMPLICITY HTN-3 showed that the greater the number of ablations, the greater the drop in SBP. Patients who received at least seven ablations per side averaged a nearly threefold larger blood pressure reduction at 6 months, compared with those who got five or six per side (Eur. Heart J. 2015;36:219-27).
Some 39% of study participants had a medication change because of side effects during the 6-month trial. This confounds attempts to assess the true impact of RDN. To answer this question, the Food and Drug Administration recently granted Boston Scientific approval to test RDN in a sham-controlled trial in patients with mild to moderate hypertension after a 4-week medication washout period. The 6-month trial is due to start shortly. This is an important study because it will demonstrate whether RDN in its present form actually works.
“Clearly, what we’ve learned in SYMPLICITY HTN-3 is ‘resistant’ hypertension is amenable to expert pharmacologic control. This raises an interesting question: If renal nerve denervation works, could we offer it as an alternative to taking two or three drugs for the next 10 or 20 years? That might be, in certain patient populations, a very attractive option. That’s why we’ve got to show whether this procedure works well,” according to Dr. Gersh.