Negative Trial vs Positive Registry
My name is Felix Mahfoud. I'm working at the Saarland University Hospital in Homburg.
I'm at the American College of Cardiology (ACC) Scientific Session in Washington, DC, where Dr. Bhatt presented the SYMPLICITY HTN-3 trial. This was the first randomized controlled trial of renal denervation, where patients with therapy-resistant hypertension were randomized in a 2-to-1 fashion to renal denervation (active treatment) or to a sham procedure. Patients were blinded to whether they received renal denervation or only renal arteriography.
There was no significant difference between both groups 6 months after treatment. Office systolic blood pressure tended to be lower in the renal denervation group, but this was far away from reaching statistical significance, and the 24-hour blood pressure lowering was not significant between both groups.
Today, Professor Boehm presented the Global SYMPLICITY registry, which represents the largest cohort of patients investigated so far under real-world conditions -- that is, patients with uncontrolled hypertension or other disease states characterized by an increased sympathetic activity who underwent catheter-based renal denervation. In that real-world patient population (which is of course an open-label registry), renal denervation significantly lowered office and 24-hour blood pressure. The higher the baseline blood pressure, the greater the drop seen. That held true for office and also for 24-hour blood pressure.
We now have data indicating that the procedure is safe. That was proven by both trials presented at the ACC here. We have conflicting data in terms of efficacy, and we need to understand why the randomized controlled trial didn't meet the primary efficacy endpoint while the real-world scenario nicely showed how effective renal denervation could lower blood pressure.
There seemed to be differences in operator experience with the procedure, and in ethnicities included in both trials. In the SYMPLICITY HTN-3 trial, 30% of the patients were African Americans. We know that those patients tend to differ in terms of pathophysiology.
Adherence to Multiple Medications
Adherence to drug treatment is an issue: In the SYMPLICITY HTN-3 trial, patients were forced to have a maximum-tolerated drug regimen. That was different to the registry, where patients with uncontrolled hypertension were included. In the end, we need more data to convince not only physicians but also patients and health insurance companies to pay for the procedure.
The interesting part of the study is taking a look at the baseline characteristics of the patients. As noted, patients were forced to have a maximum-tolerated antihypertensive drug regimen. Indeed, a high proportion of the patients (40%) were treated with vasodilators, and we all know that these drugs cause serious side effects, and especially in the long term. It is questionable how many patients really take their drugs, and the nonadherence rate will probably be higher over the long term.
We have to learn from SYMPLICITY HTN-3 -- not only the 6-month data, but also long-term follow-up data -- to understand whether there are differences in adherence over time and whether that might change, especially in heavily medicated patients who are treated with vasodilators, which are known to cause serious side effects.
Did Race Play a Role?
There's evidence indicating that African Americans have a different pathophysiology in different disease states. In heart failure, beta-blockers were not as effective in African Americans as in European or Caucasian people. We also know from hypertension trials that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) were less effective compared with calcium-channel blockers, diuretics, and vasodilators in lowering blood pressure.[4,5] Indeed, there seems to be a genetic background indicating that the pathophysiology of hypertension in African Americans is different, and that is one of the interesting hypotheses about SYMPLICITY HTN-3.
We need to further investigate whether ethnicity plays a role in successful renal denervation procedures in terms of blood pressure lowering. We have to learn from SYMPLICITY HTN-3 whether genetic backgrounds play a role.
Talking to Patients
The question inevitably arises of how these competing data affect our clinical practice after ACC; however, we have to ask ourselves about the impact of renal denervation on long-term blood pressure lowering. But we also we have to ask ourselves what alternatives we can offer patients who are heavily medicated, and who have a high risk of having a stroke -- so-called "no option" patients.
I believe that we have to inform patients about the differences in outcomes. When you compare different trials, there is a data set of real-world patients where renal denervation obviously lowered blood pressure. There's a randomized controlled trial performed in the United States where renal denervation did not sufficiently lower blood pressure, and in the end the patient has to decide.
Renal denervation has received CE marking, so it is commercially available in Europe. The US Food and Drug Administration (FDA) did not approve the therapy yet. SYMPLICITY HTN-3 was the investigational device exemption (IDE), so the trial's aim was to get approval for the therapy with a primary objective of showing a significant difference between the sham group and the renal denervation group. That was not met, so it is reasonable that the FDA will not approve renal denervation, given the data that are available at the moment in the United States.
ACC comes to an end. Interesting data have been presented in the field of renal denervation. Many hypotheses have been generated. The field is interesting and too young to close the books. We encourage all investigators to continue their endeavors in getting more information about renal denervation. Thank you.
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Cite this: Registry vs RCT Data on Renal Denervation - Medscape - May 02, 2014.