In the interventional world, technologies rapidly oscillate between being the high of the “next big thing” and then the low of being “killed off” with the publication of negative trials. Medtronic recently announced that its sham-controlled renal denervation study, SYMPLICITY HTN-3, failed to meet its primary efficacy. Now, Covidien has announced that it is “exiting” the OneShot Renal Denervation Program. Interventional News learns from leaders in the field that the watchword is: “wait for the publication”. “A critical analysis of the full dataset and study design are now imperative before the interventional community leaps to any conclusions about whether renal denervation works or not to control true resistant hypertension,” they say.
Marc Sapoval, professor of clinical radiology and chair of the cardiovascular radiology department at Hôpital Européen Georges-Pompidou in Paris, France, and principal investigator of the French DenerHTN randomised controlled trial (Co-PI Michel Azizi) says: “The interventional community should not to leap to any conclusions before the results are fully published. A press release is not a scientific, peer-reviewed publication and should be treated with caution. We are waiting for among others: appropriate numbers and p values, sub-group analysis, the workflow of patients, the exact number of patients in the denervation group who underwent successful denervation and other important technical and clinical facts such as medical treatment. Of course, if these findings are confirmed in more detail with the publication of the paper, then this should lead to increased caution when using denervation outside of properly designed clinical trials.”
“I did suspect that the results of the trial might fail to meet the efficacy endpoint and attribute it to the high number of non-responders to treatment that we have observed. Based on our own clinical findings, we see that a subset of patients clearly respond to the treatment but that some others do not respond at all. Therefore, when doing renal denervation in the setting of a well-designed randomised controlled trial with a sham control, the possibility that the results are negative even if some patients do benefit from the treatment can be observed,” he explains.
Sapoval also stated that all companies in the field must now be fully conscious of the need for a randomised controlled trial. “This is absolutely mandatory. The French randomised controlled trial, DenerHTN, has completed its recruitment and six months of follow-up with a primary end point on ambulatory blood pressure monitoring, and this data will soon be available,” he says.
Paucity of data
Melvin Lobo, consultant physician, NIHR Barts Cardiovascular Biomedical Research Unit, William Harvey Research Institute, QMUL, London UK, who is part of the team that runs the London Renal Denervation Symposium tells Interventional News that he does not think that the “failure of this study was the end of renal denervation, although it is clearly a major setback.”
Lobo predicts that other device manufactures can expect a much tougher climate in which to launch their technologies. “This is probably a good thing given that a number of devices have been CE marked on the basis of weak first-in-man studies with little supportive data to suggest true efficacy in rigorously screened patients with true resistant hypertension and a striking paucity of randomised controlled trials,” he says. Lobo also clarifies that “There are very few published, well-designed studies in drug treatment of resistant hypertension. We urgently need better designed randomised control studies (for either devices or medicines in resistant hypertension) and also to try to determine which patient might best respond to the treatment through more sophisticated hypertension phenotyping.”
Lobo has had a similar experience as Sapoval to the results of renal denervation. Of the SYMPLICITY HTN-3 efficacy results, Lobo said, “I expected lesser BP reduction than seen in the SYMPLICITY HTN-2 trial and our own experience in the Barts Hypertension Clinic has indicated modest and heterogenous responses to renal denervation in patients with true resistant hypertension. However, there are design flaws with SYMPLICITY HTN-3 and in particular the use of medicines up-titration just two weeks prior to enrolment could have biased the results in favour of the sham treated group. Critical analysis of the full dataset and study design are now imperative. Medtronic have ceased all activity on their global Symplicity programme and this seems appropriate at least until the trial data are published,” Lobo notes.
Back to the basics: Selection criteria
Peter J Blankestijn, Department of Nephrology, University Medical Center Utrecht, Utrecht, The Netherlands, notes that there were several characteristics of SYMPLICITY HTN-3 that need to be taken into account. “First, we have to wait for the official publication and the detailed analyses. I am a nephrologist. In general, nephrologists do not believe in the concept of ‘resistant hypertension’. In most cases, there is an explanation for the fact that blood pressure is not sufficiently controlled despite the fact that multiple drugs are prescribed, non- or poor compliance to medication being a very important one. This is very difficult to take into account. Further, also from a theoretical point of view, there is no reason to believe that ‘resistant hypertension’ patients (according to the inclusion criteria of the trial) are especially likely to benefit. The focus of research should be put on defining selection criteria predicting a beneficial effect. We are only in the very beginning of that,” he says.
Blankestijn believes that a second major issue with the SYMPLICITY HTN-3 trial is the lack of a variable that can be used to monitor the efficacy of the intervention itself. “We simply do not know whether a procedure has successfully affected the nerves. It is quite possible that next generation catheters will be much more effective than the one used in this trial,” he says.