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BARCELONA - Renal denervation is back from the dead, but only as a faint shadow of its former self.
Initial interim results of the study suggest that the new and improved version of renal denervation (RDN) produces a real but very modest reduction in blood pressure. The findings were presented here at the European Society of Cardiology meeting and .
The trial was started in an effort to reboot RDN after the near -level disaster of the SYMPLICITY-3 HTN trial. Prior to that trial, RDN was widely expected to deliver a spectacular 20-30 mm Hg systolic blood pressure reduction, a magnitude of effect unrivalled by drugs. But the trial, the first rigorous, well-controlled test of RDN, was unable to prove that RDN was better than a sham procedure. This led Medtronic, the sponsor of the trial, to go back to the drawing board to develop a new and improved device.
SPYRAL HTN-Off Med provides the first look at that device, the Symplicity Spyral multielectrode renal denervation catheter. Trial participants were enrolled after withdrawal of antihypertensive therapy and randomized to RDN or a sham procedure.
The trial is one of two ongoing initial trials with the device. The second trial, SPYRAL-HTN-ON-Med, has a similar design but is testing the device in patients treated with antihypertensive drug therapy.
The new data focuses on blood pressure reduction and major safety events at the 3 month evaluation of the first 80 patients randomized. SPYRAL HTN-Off Med is an ongoing proof-of-concept trial intended to inform and support a larger pivotal trial.
The main finding to date is a small but apparently real reduction in blood pressure. The 24-hour systolic blood pressure was reduced by 5.5 mm Hg in the treatment group compared with a 0.5 drop in the sham control group. Office systolic BP was reduced by 10 mm Hg in the treatment group versus 2.3 mm Hg in the sham group. There were no major safety or procedural concerns.
"These data provide biological proof of principle that renal denervation as done in this trial lowers blood pressure in untreated hypertensive patients," the authors wrote in the Lancet. The magnitude of blood pressure reduction is "clinically meaningful," they wrote. "Blood pressure reductions of similar magnitudes have been associated with reduced rates of cardiovascular death, coronary death, and stroke."
In an accompanying editorial, Michel Azizi (University Paris Descartes) raised a number of doubts and concerns about the trial, but acknowledged that the trial "might open a new paradigm for the treatment of hypertension." He pointed out that "early reporting of an interim analysis ... tends to overestimate the treatment effect and underestimate the risk of adverse events. Additionally, p values for between-group differences in blood pressure should be interpreted with caution because the study was not powered for any endpoint."
He further noted that, because only 38 patients were randomized to the device, the safety profile remains open to question. "Even a very small risk of adverse events (ie., one in 1000 patients), which could not be detected in this trial, would be unacceptable for patients with mild hypertension."
Finally, he pointed out that there was a large variation in response to RDN, "suggesting that renal denervation ... even by trained interventionalists, might not be a suitable therapeutic alternative for all patients with mild-to-moderate hypertension."
Outside experts not involved with the trial discussed the significance of the trial:
Sripal Bangalore (NYU) said that "the degree of BP reduction, although modest, is no different than other antihypertensive drugs in patients with mild-moderate HTN." He also expressed concern about the variability of response, and speculated that newer devices under development might have less variability.
More importantly, Bangalore said that he sees a feasible role for RDN in that "if you give patients a choice -- one pill for 10 years versus a procedure with minimal risk -- most would likely choose the later."
Franz Messerli (Mount Sinai) said that the degree of blood pressure reduction was comparable to that seen with hydrochlorothiazide (HCTZ). "Most physicians would say that HCTZ is a good and useful antihypertensive agent!" On the other hand, he pointed out that "we still don't know whether RDN-associated decrease in BP will reduce outcome." Denervation of the renal nerve lowers blood pressure by reducing sympathetic activity. This is the same pathway used by beta blockers, which have "a poor track record in reducing hard endpoints. Obviously, an outcome study is needed to answer this question."
Sanjay Kaul said he agreed with the concerns raised in the editorial. "The treatment effect, modest to begin with, is likely to be overestimated because of early interim analysis ('random high'). Safety might be underestimated ('random low')." Further, he argued, "the unmet need is in patients with refractory hypertension, not mild to moderate hypertension, which was the cohort evaluated!"
David Kandzari (Piedmont Heart Institute), a SPYRAL trial investigator, argued in favor of the trial. "First," he said, "a reduction in ABPM [ambulatory blood pressure measurement] of at least 3 mm Hg has been considered by the medical community as clinically meaningful, although ABPM measurements are unfortunately unfamiliar to many U.S. practitioners. These reductions exceed that standard. Second, among trials with moderate, uncontrolled hypertension, recall that absolute and relative treatment differences are more modest than those observed in severe, treatment resistant hypertension. And, in this former group, the reductions in ABPM and office SBP are numerically more similar."
In addition, said Kandzari, the findings at 3 months may not reflect the full benefits of the procedure. "There is reason to believe that the blood pressure may further decline in patients treated with RDN, although the design of this study will not exactly address this issue." But, he argued, in the end, "the data are compelling enough to move forward with a pivotal trial based on lessons learned from both prior clinical trials and preclinical experience."