Can Biomarkers Predict BP Response with Renal Denervation? Experts Not Convinced

April 15, 2014

BAD NAUHEIM, GERMANY (updated) — A small German study suggests it might be possible to identify responders to sympathetic renal denervation for the treatment of resistant hypertension through the assessment of various markers of endothelial function, vascular remodeling, and hypertension[1].

Among those patients who responded to renal denervation, soluble fms-like tyrosine kinase-1 (sFLT-1), intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) were all significantly higher at baseline than in patients who had no response to treatment.

In the study, published in the May 2014 issue of Hypertension, Dr Oliver Dörr (Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany) and colleagues note that previous investigations have focused on the clinical characteristics of patients when looking to identify responders to treatment. In contrast, their study focuses on biomarkers and identifies "for the first time potential biomarkers that predict whether a patient will be a responder or nonresponder to renal sympathetic denervation–related blood-pressure reduction."

In an editorial[2], however, Dr Markus Schlaich (Baker IDI Heart and Diabetes Institute, Melbourne, Australia) said the study hasn't solved the problem of simplifying and optimizing patient selection for the invasive procedure. The study is too small, and these biomarkers need to be tested in larger cohorts in multiple centers, "ideally in various regions around the globe."

Schlaich points out the cutoff values established by Dörr and colleagues were arbitrary, and there is a fair amount of overlap of biomarker concentrations between the responders and nonresponders. Most critically, however, is that the hypothesized pathophysiological link between elevations in sFLT-1, ICAM-1, and VCAM-1 and a favorable blood-pressure response to renal denervation is weak at best, according to the editorialist.

"Clearly, endothelial dysfunction is a hallmark of many cardiovascular conditions, including hypertension, and antihypertensive drug treatment has been demonstrated to improve endothelium-dependent vasodilation and reduce markers of endothelial dysfunction," writes Schlaich. "In the current study, however, despite substantial blood-pressure reduction in responders, all three biomarkers remained unchanged at six-month follow-up."

Briefly, Dörr and colleagues evaluated 55 patients with resistant hypertension who underwent renal denervation at a single center. Concentrations of sFLT-1, ICAM-1, and VCAM-1 were assessed before and six months after the procedure, and treatment success was defined as a reduction in systolic blood pressure >10 mm Hg six months after renal denervation. In 46 patients, blood pressure was reduced 31.6 mm Hg. In the nine nonresponders, office blood pressure was reduced 4.6 mm Hg. As noted, sFLT-1, ICAM-1, and VCAM-1 levels were all significantly higher in responders than nonresponders at baseline.

The areas under the curve for sFLT-1, ICAM-1, and VCAM-1 were 0.82, 0.75, and 0.68, respectively, "demonstrating prediction of a renal-denervation response," report the investigators.

Biomarkers in Light of Negative Trial

The study results, however, are undermined by the negative SYMPLICITY HTN-3 study. As reported extensively by heartwire , SYMPLICITY HTN-3 was a randomized, sham-controlled renal-denervation study in 535 patients with severe resistant hypertension. After six months, the mean change in systolic blood pressure was not statistically significant when compared with the reduction in patients who underwent the sham procedure.

To heartwire , Dr Sripal Bangalore (New York University School of Medicine, New York), who was not affiliated with SYMPLICITY or the Dörr et al study, agreed with the editorial that there is a need for more trials investigating these and other biomarkers. "Given the results of SYMPLICITY HTN-3, what kind of 'responders' are these biomarkers measuring?" he noted. "Perhaps there would have been similar blood-pressure reduction with the sham procedure."

Also commenting on the results for heartwire , Dr Darrel Francis (Imperial College London, UK) noted that Dörr et al published a study in 2013 showing a 26-mm-Hg reduction in 24-hour ambulatory blood pressure, an early lesson that even meticulous ambulatory monitoring does not get around the need for a blinded randomized control arm. Francis accepts that the researchers found that elevations in sFLT-1, ICAM-1, and VCAM-1 predicted a favorable blood-pressure response, but he believes this finding will not be confirmed when others retest this prospectively.

"The real problem in looking for these baseline markers is that if we look at enough of them, we will often find there are several baseline markers that are different between responders and nonresponders," said Francis. "This might be due to chance alone. I can't see anywhere in the article where they state they tested only for sFLT-1, ICAM-1, and VCAM-1, so it's possible that these were simply the few that showed significant differences among many that might quite rightly be tested by an inquisitive and pioneering group. Therefore, we should not assume that these results here will turn out to be consistent in future research."

In the editorial, Schlaich points out that the reduction in ambulatory blood pressure among responders is approximately 22 mm Hg, which is high compared with historical studies. Moreover, the reduction in ambulatory blood pressure among nonresponders was 7 mm Hg, "which would certainly be considered a clinically relevant blood-pressure reduction and therefore raises the question whether these nine patients can really be classified as nonresponders," he writes.

On the whole, Schlaich said he expects more studies assessing the usefulness of various biomarkers for the prediction of treatment response to renal denervation, although he doubts the search will be easy or quick. Nonetheless, the "journey" is a worthwhile undertaking, he writes.

In general, Francis said, it remains a challenge to identify predictors to treatment response. He cited a paper he published along with Dr Sukhjinder Nijjer (Hammersmith Hospital, London, UK) in 2012 that looked at the inherent difficulties in predicting treatment response with biventricular pacing, because all the response variables had such large spontaneous biological variability over time. Regarding treatment response to renal denervation, there is again large natural variability in the measured variable, in this case blood pressure, as clearly documented in the control arm of SYMPLICITY HTN-3.

"Blood pressure is very variable between one measurement and the next, but we rarely stop to think about what that means for classification of patients as responder vs nonresponder," said Francis. "If for each patient we took two baseline measures of blood pressure a few days apart and again two final measures, we could calculate two completely separate 'responses' to treatment. We might find that these two 'responses' were completely different. What that means is that any process of separating patients into responders and nonresponders includes a large element of chance."

Medtronic, the sponsor of SYMPLICITY HTN-3, said it remains committed to renal denervation and continues to sell the ablation system in Europe where it is approved. At the recent American College of Cardiology Scientific Sessions, physicians were surprised at the negative results given the hype around a procedure that has shown systolic blood pressure reductions as large as 30 mm Hg in trials without sham controls. Some called for a moratorium on renal denervation until there is a better understanding of the procedure, and others said they would be reluctant to treat patients with renal denervation given the negative SYMPLICITY HTN-3 study.

The authors report they have no conflicts of interest. Schlaich is supported by a National Health and Medical Research Council Research Fellowship and has received consulting fees and/or travel and research support from Medtronic, Abbott, Novartis, Servier, Pfizer, and Boehringer-Ingelheim.

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