November 17, 2010 (Chicago, Illinois) — A long-awaited randomized, controlled trial of a new technique, catheter-based renal denervation, in patients with resistant hypertension shows that this procedure resulted in significant reductions in blood pressure without any major complications .
|Dr Murray D Esler|
TheSymplicity HTN-2 findings support previous uncontrolled investigations that showed similar results, say the investigators, led by Dr Murray D Esler (Baker IDI Heart and Diabetes Institute, Melbourne, Australia). The study was presented by Esler today at the American Heart Association (AHA) 2010 Scientific Sessionsand also published in the Lancet. The procedure offers the tantalizing possibility of a one-off treatment for hypertension, with the caveat that much more research is needed in less severe hypertension; future trials could also extend into other indications, such as heart failure, chronic kidney disease, and cirrhosis with ascites, say Esler et al.
Severe, resistant hypertension that is uncontrolled despite patients taking five or more antihypertensive medications is a big unmet clinical need, with those affected being at increased risk of stroke and renal failure. "There is nowhere to go for these patients," Esler told heartwire in an interview. "We think with this novel approach we can bring many of them under control. I've never seen BP falls as big as this from any other treatment process, which makes the possibility of cure realistic; it might be within reach. It has always been a dream of mine, to come up with a cure for hypertension," he said.
I've never seen BP falls as big as this from any other treatment process, which makes the possibility of cure realistic.
In an accompanying editorial in the Lancet , Dr Michael Doumas (George Washington University, Washington DC) and Dr Stella Douma (Aristotle University of Thessaloniki, Greece) encourage cautious optimism. "Once-and-forever treatment of hypertension represents the holy grail of research in the field. The exciting results of the Symplicity study generate great expectations, and the investigators have paved the way for interventional management of patients with resistant hypertension," they enthuse. However, they point out several limitations of the study and questions that remain to be answered, warning that "overoptimism should be avoided."
At the AHA meeting, the discussant of the study, Dr Suzanne Oparil (University of Alabama, Birmingham), and several other observers were equally excited by these new results, although they also pointed out some important limitations of the trial and stressed that only time will tell whether this approach really will pan out.
|Dr Donald Lloyd-Jones|
"This has the potential for really revolutionizing the way we treat resistant hypertension, which is an enormous clinical need. It's a very dramatic effect," said Oparil. To heartwire she elaborated: "I think it could be very, very helpful because the population is aging, because it's becoming fatter, and there is more insulin resistance and diabetes, so this could be a very important adjunct--in that population of resistant hypertensives--to medical therapy, could reduce the number of medications, and could be very helpful for people who are not very adherent to their medicine."
Dr Donald Lloyd-Jones (Northwestern University, Chicago, IL) told heartwire : "Refractory hypertension is a huge problem. I personally have many patients where BPs are unacceptably high, putting them at extreme risk, particularly for stroke and for heart failure. So we've wanted another piece in our armamentarium. I think this shows remarkable promise. There's more to learn about it, but the fact that it is a relatively easy procedure and appears to be safe is extremely encouraging, and I for one will be looking to see if we can add this at our institution."
An Old Concept Now Adopted by Interventionalists
Renal sympathetic efferent and afferent nerves are crucial for the initiation and maintenance of systemic hypertension and lie within and immediately adjacent to the wall of the renal artery. The concept of denervation of the renal sympathetic nerve to try to reduce BP is old and was attempted, unsuccessfully, by surgical means some years ago.
Both Oparil and Dr Peter Sever (Imperial College, London, UK) are excited about the science behind this procedure. "The pathophysiological role of the renal nerves in essential hypertension has not really been focused on for 20 to 30 years," Sever told heartwire . And Oparil says that whether or not this new approach lives up to the initial promise, it "will stimulate new research on sympathetic mechanisms, which was completely dropped when we got the [renin-angiotensin-system] RAS blockers."
Esler explained that the renal sympathetic nerves are accessible using an interventional approach through the femoral artery; the procedure is performed bilaterally using radiofrequency ablation with the Symplicity catheter (Ardian, Palo Alto, CA) by either an interventional cardiologist or interventional radiologist and takes around 40 minutes, with four or five sites at each renal sympathetic nerve ablated in a rotational manner to cover the full circumference, but not all in one place, as this might lead to narrowing or aneurysms. Costs are estimated to be similar to those of angioplasty, in the region of $10 000. Esler says that there is a learning curve with this procedure, and he anticipates there could be a "turf war" between radiology and cardiology interventionalists for this indication. The procedure requires an overnight stay in hospital and is painful, so analgesia is employed, he says.
Preliminary data from the patients in Symplicity-HTN2 and from a pivotal trial have been encouraging, but everyone in the field has been eagerly awaiting these final results.
The trial was conducted at 24 centers in Europe, Australia, and New Zealand. In the study, 106 patients with resistant hypertension (systolic BP of >160 mm Hg, or >150 mm Hg for those with type 2 diabetes, despite taking three or more antihypertensive drugs) were randomized on a one-to-one basis to undergo renal denervation with previous treatment (n=52) or to maintain previous treatment alone (control group; n=51). Esler explained that they wanted to "isolate the effect of the denervation," which is why the decision was made to keep the patients' medications uncontrolled.
The control group did not undergo a sham procedure, however, and the data analyzers were not masked to treatment assignment, something the editorialists take issue with. They also lament the fact that secondary hypertension and white-coat hypertension were not defined as exclusion criteria.
84% of Patients Respond; As Yet No Clinical Indicators for Nonresponse
|Catheter-based radiofrequency ablation of renal sympathetic nerves|
The SYMPLICITY-HTN results show that six months after the ablation, average office-based BP in the renal-denervation group was reduced by 32/12 mm Hg (average baseline 178/96 mm Hg), whereas it did not differ from baseline in the control group (change of 1/0 mm Hg from baseline of 178/97 mm Hg). The between-group differences in BP at six months were 33/11 mm Hg (p<0.0001).
Of the patients in the ablation arm, 84% had a 10-mm-Hg or greater drop in systolic blood pressure compared with 35% of controls (p<0.0001). The remaining 16% of those in the ablation arm were considered "nonresponders," because they had only a 0- to 9-mm-Hg drop in BP; Esler said it is not yet clear what is happening in these "nonresponders," and he admitted that the procedure is "a lot to go through for nothing. We don't yet have any clinical predictors for response; we don't know if the denervation wasn't successful in these patients."
The editorialists home in on this: "Meticulous investigation to identify specific predictors of treatment success at baseline should be undertaken in future studies," they observe.
They also point out that only 39% of the ablation group achieved BP "control," which is defined as systolic BP of <140 mm Hg. Esler said this was true "and in a way disappointing," but given that these patients began from such a high baseline BP (average of 178 mm Hg systolic), it is perhaps not surprising, he noted.
Esler also stressed that this is very much an adjunctive therapy: "Severe hypertensives are much better controlled, but it takes a combination of the procedure and drugs. At the moment, the procedure is ancillary to medication in these severe hypertensives." However, he noted that 20% of the patients in the trial were able to reduce either the dose or number of antihypertensives they were taking.
And based on the BP decreases observed, "There could be an up to 60% reduction in strokes or heart attacks," he said, but stressed that this would of course require future outcomes trials "to see to what extent this will translate into clinical benefit."
Questions on Home vs Office BP Measurements, Aldosterone Blockers
|Dr Suzanne Oparil|
In her discussion, Oparil said she would have liked to have seen better use of ambulatory blood-pressure monitoring in the trial, and she noted that the home BP drops seen in the trial were "somewhat less dramatic" than the office-based measurements. Esler told heartwire that ambulatory BP monitoring was employed in only around 20 people in the trial, and he admitted that the home measurements were lower than the office ones, but there was a 20/12-mm-Hg drop in average home BP in those who had the renal denervation procedure, which is still impressive, he said.
Oparil also questioned why only 17% of the study participants were receiving aldosterone antagonists, a class of drugs that is recognized as particularly effective as add-on therapy in resistant hypertension.
Sever agrees, telling heartwire : "The data are very impressive, and the magnitude of BP fall is considerably greater than you would expect from inhibiting the efferent pathway only, so I think this is telling us the afferent pathway is a critical component of the hypertensive response. My only reservation about the study is that they have not compared the denervation with the most effective add-on drug in patients with resistant hypertension, which is spironolactone."
Lloyd-Jones said: "There is no doubt that adding an aldosterone blocker such as spironolactone or eplerenone is a very effective strategy, and I would like to see these two things go head-to-head, because I'd rather add a medication than do an invasive procedure in most cases. But on the other hand, doing a kind of one-and-done procedure that is minimal risk has real benefits, because we are then not relying on patient adherence."
Esler said, "This is a valid question. Perhaps we should have had all patients in this trial on spironolactone as a base, but we left it to the individual centers, which were all certified centers of excellence in hypertension care." But he also noted that spironolactone "is a powerful drug, but it's not totally benign, and it commonly causes side effects that can be quite severe. It puts potassium up and can cause very pronounced lowering of serum sodium, which is a significant problem."
Procedure Appears Safe and Long-Lasting: US Trial to Start in 2011
Encouragingly, the renal sympathetic nerve denervation does not appear to cause any adverse effects, Esler said. Imaging of renal arteries for damage showed no evidence of renal artery stenosis or aneurysmal dilatation during the six-month follow-up and no changes in renal function were seen, even in those with mild to moderate renal failure.
Also, the procedure appears to be long-lasting. It was thought initially that sympathetic-nerve regrowth might mitigate the treatment effect, said Esler, but in the patients treated in the pilot studies, no loss of antihypertensive effect has been seen with follow-up of two years.
Esler says the Symplicity catheter is approved for clinical use in the EU and Australia; Oparil commented on the "potential hazards when this procedure moves to the local cath lab." But Esler stressed the introduction to clinical care "will be careful and measured and restricted to sites that participated in the trial. It's going to happen slowly, and the next step will be to set up registries."
Also, a trial is about to start in the US for regulatory purposes. There has been huge interest in this study, he says, with more than 200 centers wanting to participate. Around 300 patients will be enrolled in the US trial, which it is hoped will begin in early 2011.
However, much more research needs to be done to extend this concept to other forms of hypertension and to look at the efficacy in subgroups of patients with hypertension and possibly in other indications, "because stimulated sympathetic nerves are important in other diseases," such as heart failure, Esler says, noting that one study of denervation in human heart failure is under way.
Oparil commented: "Whether it's going to be useful and cost-effective in a broader population of patients" remains to be seen. "Theoretically, when we did experiments in rats, if you got rid of the renal nerves, they never got hypertension, you totally prevented it. We don't have very good evidence that medical therapy for so-called prehypertension really changes the development of hypertension. If this procedure totally prevented this inexorable increase in systolic BP with time, or if it blunted the increase, it would be of tremendous benefit to the population."
Questions such as this one will require clarification of the pathological mechanisms that mediate the reductions in blood pressure and the resultant effects on target organs, say Doumas and Douma. "Only the future can tell whether renal denervation will change the way we treat hypertension in everyday clinical practice."
Esler has received consulting fees and travel expenses from Ardian; his institution has received a research grant from the company. Disclosures for the coauthors are listed in the paper. Oparil has received grants and honoraria and is a consultant for a variety of companies that market antihypertensives; she has no relationship with Ardian. The editorialists have no conflicts of interest.
Heartwire from Medscape © 2010 Medscape, LLC
Cite this: A Revolutionary Road for Resistant Hypertension? Renal Denervation in Symplicity HTN-2 - Medscape - Nov 17, 2010.