An experimental device that had shown promise and raised hopes for controlling stubbornly and dangerously high blood pressure is not effective, a new study involving Cleveland Clinic cardiologists and patients shows.
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The device, known as the Symplicity System and made by Minneapolis-based Medtronic, Inc., is a generator that delivers jolts of radiofrequency energy through a special catheter into the kidney’s main artery. The pulses damage nerves that connect the kidney and the brain. That is supposed to disrupt malfunctioning circuitry that keeps blood pressure abnormally high.
Early excitement for renal denervation
The disruptive process is called renal denervation, and it has been the focus of much recent excitement in the medical world. Small studies showed encouraging early evidence – enough that renal denervation was available for regular clinical use in patients in parts of Europe, Asia, Africa, Australia and the Americas, though not in the United States. In 2012, then American Heart Association President Gordon Tomaselli, MD, a Johns Hopkins cardiologist, told the New York Times that renal denervation “has the potential to change the way hypertension is managed in this country and around the world.”
But earlier this month, Medtronic made a surprising announcement. The company said that a clinical trial conducted in patients at Cleveland Clinic and dozens of other U.S. medical centers during the past two years to test the effectiveness and safety of the Symplicity renal denervation device found that it did not lower blood pressure as expected.
No better than placebo
The rigorous testing, which Medtronic had hoped would convince the federal Food and Drug Administration to OK its Symplicity device and renal denervation for non-experimental U.S. use, showed that the blood pressure of patients who underwent the nerve-zapping surgery wasn’t significantly lower than patients who had undergone a sham operation, and whose renal nerves remained intact. In other words, the treatment results were no better than a placebo.
The device’s ineffectiveness and the doubts it raises about renal denervation were “a huge surprise and disappointment,” said interventional cardiologist Mehdi Shishehbor, DO, MPH, PhD, who with nephrologist George Thomas, MD, supervised Cleveland Clinic’s portion of the testing. “But this is why we participate in these trials – to ensure efficacy and patient safety.”
Millions have stubbornly high blood pressure
Resistant hypertension – the condition that doctors hoped renal denervation could successfully treat – is a major medical problem. An estimated 9 million Americans, and perhaps 120 million people worldwide, have blood pressure that remains dangerously high, 140/90 mm Hg or above, despite taking three or more antihypertensive medications. Their elevated blood pressure puts these people at heightened risk of stroke, heart attack, kidney disease and death. They endure anxiety, the expense of medical care, and the aggravation of taking pills several times a day.
That’s why there has been such interest in a new way to tackle resistant hypertension.
High blood pressure is a complicated disease with multiple triggers. There’s good evidence that one of them is an overactive sympathetic nervous system. Normally, among many other jobs, the sympathetic nerves regulate the amount of sodium and water our bodies retain, control blood flow to and from our kidneys, and unleash chemicals that raise or lower blood pressure. The power of this system is apparent when we’re startled. The brain and sympathetic nerves orchestrate our “fight-or-flight response,” readying the body for exertion by rocketing up blood pressure and heart rate. It’s not hard to imagine how a sympathetic nervous system stuck in overdrive would contribute to hypertension.
Rise, fall and rise of nerve disruption
In the late 1940s, surgeons experimented with removing some of the sympathetic nerves as a way to control severe high blood pressure. Though there appeared to be some success, unwanted side effects and the development of new hypertension drugs caused the procedure to be abandoned barely a decade later.
But resistant hypertension remained a problem. The development of minimally invasive surgery, and of precise equipment to disrupt nerves with energy pulses, recently revived the concept of denervation as a possible hypertension treatment.
Promising initial results
Medtronic began testing its Symplicity renal denervation system in 2007 at medical centers in Australia, Europe and the United States. Patient volunteers underwent minimally invasive surgery in which a special catheter was inserted into an artery in the thigh and threaded into the kidney, where low-power radiofrequency bursts deactivated the renal nerves. In March 2012, Medtronic announced that its first two rounds of clinical trials showed Symplicity had produced “significant and sustained” blood pressure reduction in patients – an average drop of 33/19 – for as long as three years. A larger study, begun in August 2011, was intended to pave the way for U.S. approval of the Symplicity device and the renal denervation procedure.
Then came the startling announcement that the larger study had shown Symplicity was ineffective.
While Medtronic has not released detailed results of the study, Dr. Shishehbor said several factors could explain the conflicting results:
- The latest clinical trial, involving 535 patients in 87 medical centers, was more than five times larger than the biggest previous randomized renal denervation study. The blood pressure drops seen in those smaller studies of less diverse patients could be a statistical fluke, not a result of the renal denervation procedure itself.
- Most of the previous tests were not “randomized” clinical trials – the gold standard in medical testing – meaning they did not compare hypertension patients who were randomly picked to have the renal denervation procedure with similar patients who didn’t have the procedure. In the just-ended clinical trial, the FDA took the unusual extra step of requiring an ultra-realistic “apples to apples” comparison. Outcomes of patients who underwent the renal denervation procedure were compared with patients who had a catheter threaded into their kidney but whose nerves weren’t zapped. The degree of similarity in the two patient groups being compared makes the results more reliable. In this case, there were no significant differences in the two groups’ blood pressures six months after their procedures.
Importance of clinical trials
Dr. Shishehbor said the Symplicity study findings, though disappointing, show the value of randomized trials and a thorough review. “This trial is important because it was a strong, sham randomized clinical trial that showed us that this device is not effective,” he said. “We would never have learned that if we did not do a trial designed like this.”
Eleven of the 13 Cleveland Clinic patients who volunteered to take part in the testing had renal denervation, while two were in the sham group, Dr. Shishehbor said. The study found that, though the procedure wasn’t effective at lowering blood pressure, there were no harmful short-term effects. All of the patients will be followed closely for the next 5 years, he said.
Whether the Symplicity technology is specifically at fault, or whether it is the overall renal denervation approach that is ineffective, remains to be determined. “I think we need to go back to the drawing board and try to understand why that particular device failed, and what that means for the field of renal denervation,” Dr. Shishehbor said.
Additional research will attempt to answer those questions. “It is quite possible that, although one renal denervation technology does not achieve the expected outcome, another device may effectively denervate the blood vessel,” said Cleveland Clinic vascular surgeon Lee Kirksey, MD, MBA.
Boston Scientific Corp. had planned to launch testing of its Vessix™ renal denervation device by July at Cleveland Clinic and other U.S. sites. But the company announced on Jan. 16 that it will delay the clinical trial until it can analyze Medtronic’s failure and discuss its research plan with the FDA. If disrupting the kidneys’ nerve connections ultimately doesn’t pan out as a resistant hypertension treatment, there are other possibilities manipulating blood pressure switches elsewhere in the body.
Special nerves called baroreceptors in the carotid arteries keep watch on the crucial blood supply to the brain, and can trigger a rise or fall in blood pressure. In September 2013, a California company called Vascular Dynamics, Inc., began human testing of its MobiusHD™ device, surgically implanted in the carotid, that is supposed to signal the baroreceptors to lower blood pressure. Dr. Shishehbor said Cleveland Clinic is one of the few sites where the clinical trial – known as CALM-FIM (Controlling and Lowering Blood Pressure with the MobiusHD – First In Man) – is underway.