Despite meeting primary safety endpoints, SYMPLICITY HTN-3 – the pivotal U.S. trial examining renal denervation for treatment-resistant hypertension – has fallen short of its secondary efficacy goals, and failed to reach its primary efficacy endpoint as announced earlier this year by the study's sponsor. The new data was released March 29 as part of ACC.14 in Washington, DC, and simultaneously published in the New England Journal of Medicine (NEJM). 

Click Image to Enlarge. SYMPLICITY HTN-3: Renal Artery Denervation For Resistant Hypertension

The largest study of its kind, and the most rigorously designed – including blinding and a sham treatment in the control arm – SYMPLICITY HTN-3 sought to evaluate the safety and effectiveness of renal denervation with the investigational Symplicity renal denervation system in patients with treatment-resistant hypertension and systolic blood pressure higher than 160 mmHg. Using the Symplicity device, the procedure saw a catheter threaded through arteries to deliver radiofrequency energy that inactivates kidney nerves, consequently interrupting electrical signals to and from the kidney and altering the regulation of a patient's blood pressure.

The study randomly assigned 535 patients with resistant hypertension and systolic blood pressure of 160 mmHg or higher to renal denervation or angiography alone. Both groups remained on treatment regimens of three or more antihypertensive drugs at the highest tolerated doses. Although both study groups statistically exhibited a decrease at six months compared to the baseline (-14.1 mmHg for renal denervation compared to -11.7 mmHg for the sham treatment control), the difference of -2.29 mmHg in office systolic blood pressure between the two arms was not significant.

"That is a fascinating result because it highlights the importance of a properly done, rigorous randomized trial that is both blinded and sham controlled," says Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs, Brigham and Women's Hospital Heart and Vascular Center, professor of medicine at Harvard Medical School, and co-principal investigator. "This is the first blinded trial and sham controlled trial in the field of renal denervation. It seems that these factors really mattered. We saw no added treatment benefit of renal denervation for patients with severe resistant hypertension who were closely monitored and optimally treated with medications."

With more than 77 million Americans and up to 1 billion adults worldwide affected by hypertension and its associated risk for heart attack and stroke, Bhatt advocates that while the trial did not meet its desired endpoint, it has proven to be a huge step in objectively looking at such medical devices.

"The field has really exploded with several devices in clinical practice despite lack of compelling data to support their use. Now we have some definitive data with one device," says Bhatt. "However, we do think research in the field should continue, especially to see if renal denervation is useful in other areas, such as heart failure or with alternative approaches."

A related editorial comment published in NEJM by Franz H. Messerli, MD, and Sripal Bangalore, MD, notes that "the conclusions of the SYMPLICITY HTN-3 study... soberingly state that 'a significant effect on systolic blood pressure was not observed. Further evaluation in rigorously designed clinical trials will be necessary... to confirm previously reported benefits of renal denervation in patients with resistant hypertension.' Should this statement indeed hold true, we will have to come to grips with two facts: the SYMPLICITY studies merely document the natural history of resistant hypertension in clinical trials, and the time has come to turn the page on renal denervation for hypertension but by all means, let's not close the book."

Keywords: Renal Artery, Denervation, Heart Failure, Blood Pressure Determination, Hypertension