Is the failure of SYMPLICITY HTN-3 trial to meet its efficacy endpoint the "end of the road" for renal denervation?

Resistant hypertension is a common medical problem that is increasing with the advent of an increasingly older and heavier population. The etiology of resistant hypertension is almost always multifactorial, but the results of numerous studies indicate that renal sympathetic activation is a particularly common cause of resistance to antihypertensive treatment. Consistent with the belief in a pivotal role of renal sympathetic stimulation, there has been a growing interest in renal denervation (RDN) treatment strategies. The long-awaited results of SYMPLICITY HTN-3 study disclosed that the reduction in blood pressure by the SYMPLICITY device did not differ from that in the sham-procedure arm of the study. In the present article, we identify several factors that explain why the study failed to demonstrate any benefit from the intervention. The reasons are multifactorial and include inadequate screening at entry and frequent medication changes during the study. Additional problems include the lack of experience of many operators with the SYMPLICITY device and procedure variability, as attested to by a diminished number of ablation "quadrants." Also a factor was the inability of the first generation Medtronic device to allow four ablations to be performed simultaneously. We recommend that future RDN studies adhere to more rigorous screening procedures, and utilize newer multi-site denervation systems that facilitate four ablations simultaneously. Drug optimization should be achieved by monitoring adherence throughout the study. Nevertheless, we are optimistic about a future role of RDN. To optimize chances of success, increased efforts are necessary to identify the appropriate patients for RDN and investigators must use second and third generation denervation devices and techniques.

Epstein M ，de Marchena E 《-》

Renal denervation.

Renal denervation (RDN) has, within recent years, been suggested as a novel treatment option for patients with resistant hypertension. This review summarizes the current knowledge on this procedure as well as limitations and questions that remain to be answered. The Symplicity HTN-1 (2009) and HTN-2 (2010) studies re-introduced an old treatment approach for resistant hypertension and showed that catheter-based RDN was feasible and resulted in substantial blood pressure (BP) reductions. However, they also raised questions of durability of BP reduction, correct patient selection, anatomical and physiological effects of RDN as well as possible beneficial effects on other diseases with increased sympathetic activity. The long awaited Symplicity HTN-3 (2014) results illustrated that the RDN group and the sham-group had similar reductions in BP. Initial studies demonstrated that RDN in patients with resistant hypertension was both feasible and safe and indicated that RDN may lead to impressive reductions in BP. However, recent controlled studies question the BP lowering effect of RDN treatment. Large-scale registry data still supports the favorable BP reducing effect of RDN. We suggest that, in the near future, RDN should not be performed outside clinical studies. The degree of denervation between individual operators and between different catheters and techniques used should be clarified. The major challenge ahead is to identify which patients could benefit from RDN, to clarify the lack of an immediate procedural success parameter, and to establish further documentation of overall effect of treatment such as long-term cardiovascular morbidity and mortality.

Olsen LK ，Kamper AL ，Svendsen JH ，Feldt-Rasmussen B ... -  《-》

Resistant Hypertension and Renal Nerve Denervation.

Denker MG ，Cohen DL 《-》

Effect of Catheter-Based Renal Denervation on Morning and Nocturnal Blood Pressure: Insights From SYMPLICITY HTN-3 and SYMPLICITY HTN-Japan.

High nighttime and early morning blood pressure (BP) have been associated with greater risk for cardiovascular events than high clinic or daytime BP. BP is typically highest in the rising hours, when morning activities typically begin. We examined the effect of renal denervation on morning (6:00-8:59 AM), daytime (9:00 AM-8:59 PM), and nighttime (1:00-5:59 AM) ambulatory BP. Patient data from 2 prospective, randomized controlled trials of patients with treatment-resistant, uncontrolled hypertension, one conducted in a US population (Renal Denervation in Patients With Uncontrolled Hypertension [SYMPLICITY HTN-3]) and the other in a Japanese population (SYMPLICITY HTN-Japan [HTN-Japan]), were analyzed. Patients in SYMPLICITY HTN-3 and HTN-Japan were prescribed a similar number of baseline antihypertensive medications (5.2±1.4 versus 4.9±1.6, P=0.28), but the classes prescribed and changes in prescription varied by study. Among patients treated with renal denervation, although the number of ablation treatments were similar in both studies (11.2±2.8 versus 11.5±1.9, P=0.55), patients in SYMPLICITY HTN-3 were less likely to receive at least 1 four-quadrant ablation treatment (25% versus 82%, P<0.001). In SYMPLICITY HTN-3, compared with controls (n=159), patients treated with renal denervation (n=325) experienced a significantly greater change in morning (-7.3±19.8 mm Hg, P<0.001) and nighttime (-6.1±18.2 versus -1.6±19.7 mm Hg, P=0.02) but not daytime systolic BP (-7.2±16.2 versus -6.4±18.6 mm Hg, P=0.67). This same trend was observed in the pooled analysis with HTN-Japan. Reduction of BP during these high-risk periods might provide cardiovascular protection in drug-resistant hypertensive patients, although this will need to be proved in future randomized trials. URL: www.clinicaltrials.gov; Unique identifiers: NCT01418261 (SYMPLICITY HTN-3) and NCT01644604 (HTN-Japan).

Kario K ，Bhatt DL ，Brar S ，Cohen SA ，Fahy M ，Bakris GL ... -  《-》

Renal Sympathetic Denervation: A Viable Option for Treating Resistant Hypertension.

Accumulating evidence from mainly uncontrolled clinical studies with various types of ablation catheters have shown that renal denervation (RDN) can be applied safely and is effective in lowering blood pressure (BP) in patients with treatment-resistant hypertension. Sustained BP lowering has been documented up to 3 years. Furthermore, RDN has been associated with regression of target organ damage, such as left ventricular hypertrophy, arterial stiffness, and others. Several studies indicate potential benefit in other common clinical conditions associated with increased sympathetic tone including chronic kidney disease and heart failure. However, the recently published Symplicity HTN-3 study, the largest and most rigorously designed sham-controlled clinical trial, while confirming the safety of the procedure, failed to demonstrate a BP lowering effect beyond that of a sham procedure in patients with resistant hypertension. Efforts to unravel the reasons for the discrepant results from Symplicity HTN-3 have focused on a range of potential confounders including anatomical and procedural aspects. Indeed, data from post-hoc analyses indicate that sufficient RDN may not have been achieved in the majority of patients in Symplicity HTN-3. Furthermore, recent evidence from human postmortem and functional animal studies revealed new insights into the anatomical distribution of renal nerves and their accessibility by intravascular approaches. Initial results from recent clinical trials integrating these important findings indeed seem to confirm that RDN remains a viable option for the treatment of hypertension. Thorough further investigations will be key to determine the true potential of RDN in clinical conditions characterized by increased sympathetic drive.

Schlaich MP 《-》