Renal denervation bounces back in 3-year follow-up study
Following negative primary results, the final follow-up of the SYMPLICITY HTN-3 trial takes a turn for the better, demonstrating significant blood pressure (BP) reductions with renal denervation (RDN) in patients with uncontrolled hypertension (HTN).
“[The trial] did not meet its primary 6-month efficacy endpoint [ie, office systolic BP (SBP) change from baseline], raising an unprecedented wave of scepticism about RDN,” noted Drs Elvira Fanelli and Alexandre Persu from the Cliniques Universitaires Saint-Luc, Woluwe-Saint-Lambert, Brussels, Belgium, in an editorial. “[However, the current results] show a surprisingly large benefit.” [Lancet 2022;doi:10.1016/S0140-6736(22)01788-3]
A total of 535 individuals with treatment-resistant HTN (mean age 57 years, 63 percent male, mean office SBP 180 mm Hg) were randomized 2:1 to receive RDN or sham control. Participants were on maximum tolerated doses of ≥3 antihypertensives, including a diuretic. Following the 6-month primary endpoint evaluation, 101 patients in the sham control arm crossed over to the RDN arm (crossover arm). [Lancet 2022;doi:10.1016/S0140-6736(22)01787-1]
At 3 years, the drops in SBP were greater with RDN vs sham (–26.4 vs 5.7 mm Hg; p<0.0001 [office] and –15.6 vs –0.3 mm Hg; p=0.0001 [24-hour ambulatory]).
These findings were a remarkable jump from the nonsignificant 6-month results, both in terms of office (absolute difference, –2.4; p=0.26) and ambulatory SBP (–1.1; p=0.52 [daytime] and –3.3; p=0.06 [nocturnal]). [N Engl J Med 2014;370:1393-1401; J Am Coll Cardiol 2014;64:1071-1078]
Other BP parameters that improved significantly at 3 years with RDN vs sham were office diastolic BP (DBP) and 24-hour SBP and DBP (p<0.0001 for all).
Despite the impressive current results, lead investigator Dr Deepak Bhatt from Brigham and Women’s Hospital, Boston, Massachusetts, US, underlined the “need to be cautious” during a press conference at TCT 2022. “SYMPLICITY HTN-3 was the most rigorous, sham-controlled trial to date, but it probably provided an underestimate of the actual treatment effect because of [several] confounding factors.”
“[The initial results] did not show any benefit in the overall trial … When the primary endpoint is negative, you do not want to make too much of it,” he continued. “[However,] I do think there is something there with RDN … The initial HTN-1 and HTN-2 trials with the Symplicity Flex catheter were very positive, large effects, but there were some methodologic limitations.”
Safety-wise, at 36 months, the incidence of the composite safety endpoint* was similar across arms (12, 12, and 14 percent for the respective RDN, crossover, and sham arms). This correlates with the primary results showing similar rates of major adverse events, mortality, serum creatinine elevation >50 percent, and new renal artery stenosis between the RDN and sham arms.
“This is the longest safety analysis of the RDN procedure in a randomized trial setting and highlights the procedure’s overall safety,” said Bhatt.
Time to re-mobilize the ‘train’?
In the editorial accompanying the initial report on SYMPLICITY HTN-3, the experts noted that the study “brings the [RDN] train to a grinding halt”. [N Engl J Med 2014;370:1454-1457] But given the current results, plus those of other randomized trials** supporting the benefit of RDN for resistant HTN, it appears the brakes could still be released for the 'RDN train' to move forward.
“[The current] data support the growing body of evidence of favourable, durable, and safe long-term results of RDN, with the potential for larger reductions in BP with longer durations of follow-up,” said Bhatt. “RDN might offer an additional treatment option for patients with uncontrolled, resistant HTN outside of lifestyle modification and use of maximally tolerated antihypertensive medications.”
Fanelli and Persu however underscored the need for further investigation “to better define the efficacy of this technique over time, and to predict patients who will benefit most from it”.