Five Lessons to Be Learned From the Fall of Renal Denervation

John Mandrola


January 14, 2014

These are tough times for cardiology. Bad news seems like a new rule. The latest game-changing innovation to fall from grace: renal denervation for the treatment of hypertension.

The stakes were huge. High blood pressure affects millions. Renal denervation was billed as an easy and safe procedure. Preliminary data looked promising. Among the winners—patients, cardiologists, and medical-device makers—hope was palpable. Electrophysiologists and interventionalists were fixing to fight for the treasure.

Then came the press release. Medtronic announced that its pivotal renal-denervation study, SYMPLICITY HTN-3 , failed to meet the primary efficacy end point—reduction of blood pressure at six months. The translation: when renal denervation was studied in larger numbers of patients and with proper controls (sham procedures in the control group), it didn't work.

This is huge. Mark my words, the failure of SYMPICITY HTN-3 will make the 2014 top-10 lists of big stories.

Journalist Mike O'Riordan has the full story on heartwire . It's important to note that the actual data have not been presented. So it would be unfair to dismiss neural modulation as a treatment for hypertension on the basis of a single press release. There may be useful information in the details. Also, the specific technique of renal denervation may be important. Different companies make slightly different devices, and SYMPLICITY HTN-3 used only one system.

But even with these caveats, the news is grim. Both Medtronic and St Jude Medical have suspended ongoing renal-denervation trials.

I see five major lessons to be learned.

Lesson 1: Too Good to Be True Means . . .

Implausibility is not just relevant in sport; it is also relevant for interpreting science. Influential academic cardiologist Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA) said it best:

"I  mplausibly large treatment effects observed in uncontrolled and unblinded studies are typically unreliable and seldom replicable in rigorously controlled randomized trials. That is the major lesson from the SYMPLICITY HTN-3 trial. If the data are too good to be true, they usually are! It is too soon to abandon this procedure. We need to scrutinize the data first. If the treatment effect is attributable entirely to a sham effect, then it is difficult to see a future for renal denervation."

Lesson 2: The Fog of Hype

After publication of the SYMPLICITY HTN 2 trial in late 2012, the American Heart Association (AHA) published a press release that exuded extravagantly intensive publicity. As journalist Lisa Nainggolan reported in this heartwire story, the AHA overreached in its enthusiasm. The press release contained this quote from lead investigator Dr Murray Esler (Baker IDI Heart and Diabetes Institute, Melbourne, Australia): "Studies will soon determine whether this procedure can cure mild hypertension, producing permanent drug-free normalization of blood pressure. Based on the blood-pressure declines achieved, reduction in heart attack and stroke rates of more than 40% is anticipated."

Hindsight is sharp but those two sentences deserve emphasis. To give the impression—from preliminary data—that mild high blood pressure (and subsequent CV outcomes) could someday be zapped, cured, ablated, or controlled with a simple procedure is at best dubious and at worst egregious.

The AHA was not alone in its hopeful speculation. The American College of Cardiology listed renal denervation on its top cardiovascular stories to watch for in 2014. And any cardiology-meeting attendee can testify that renal denervation has been a hot topic in the past two years. Hype has also influenced European regulators, as multiple renal-denervation systems have earned CE Mark approval in Europe.

Lesson 3: Simple Is Good, Except When Treating Disorders of Lifestyle

Most doctors have seen the thin, often wiry, often tachycardic, sometimes red-faced patient, who, despite taking four blood-pressure medicines and using sleep-apnea therapy, remains hypertensive. These hypersympathetic patients represent a tiny minority of patients with high blood pressure. Any regular doctor knows this.

The truth with hypertension is sobering. It's largely an acquired disease of disordered lifestyle choices, a chronic problem accumulated over years. Treating hypertension is a team sport, one that requires patients to take active roles in their care. If the goal is improving outcomes, not just moving surrogate numbers, relying on drugs or procedures is a losing strategy. Simpler tools—a pair of sneakers, the willpower to carve out time to exercise, to make good food choices, and to pay attention to sleep disorders—lie at the core of successful BP treatment. Basic stuff. Unlike ablating portions of the autonomic nervous system.

Taken together, the failure of renal denervation, renal stenting, nonstatin cholesterol-lowering drugs, fish oil, multivitamins, and the like are metaphors for the idea that heart health comes not from doctors but from patients. When that simple truth becomes the norm, then we will see true progress in cardiovascular disease.

Lesson 4: The Minimal-Disruption Rule

What follows may sound silly coming from a doctor whose primary procedure involves burning healthy myocardial cells. That said, it seems right to question the wisdom of denervating anything. The sympathetic nervous system evolved for a reason, didn't it?

Perhaps the strategy of AV node ablation with permanent pacing is an appropriate analogy. In this case, the problem is rapid ventricular rates during AF. Similar to renal denervation, creating AV block is easy, and pacemakers are reliable. Selected AF patients do well with palliative iatrogenic AV block and pacing. The key words being "selected" and "palliative."

The inherent problem with ablation is that it is permanent. Burns can't be undone, and therefore, it makes sense to tread lightly when destroying normal physiologic structures and function. Permanent modulation of the autonomic nervous system is not like a cholecystectomy or appendectomy. Think biologic effects: one pill (or one procedure) designed to move one surrogate (lowering BP) is destined to have complex effects in the human body. Even if renal denervation were successful in lowering BP, would this have translated to improved CV outcomes? Or would there have been significant trade-offs?

Lesson 5: Being Mindful of Intervention Bias

When faced with a bad situation, a patient with high blood pressure for instance, doctors are trained to help. But doctors aren't computers or robots. Human aid comes with preconceived notions and experiences—or bias.

Here, in the case of considering permanent destruction of tissue with radiofrequency power, it's useful to look inward. Can we see our own intervention bias? Smart people attribute the do-something-doctor tendency to self-interest bias and confirmation bias. Human doctors are hardwired to intervene.

The do-something philosophy works well in STEMI care, trauma, and general surgery. Assess, decide, and intervene are necessary strategies for acute care. Treating chronic disease, however, is another matter. Acquired disorders like hypertension, obesity, inactivity, and atrial fibrillation are not so amenable to single physician-led interventions.

In fact, in many cases, the patient with chronic disease finds himself or herself in as much danger from our treatment as from the disease itself. Antiarrhythmic drugs for atrial fibrillation, NSAIDs for arthritis, and fenfluramine/phentermine for obesity are just a few of many examples. The medical-harm list is a long one.

Doctors experienced in radiofrequency ablation for arrhythmia have learned the intervention-bias lesson the hard way. We now know ablation cuts both ways—and that less is almost always more.

The Take-Home

Renal denervation is an interesting idea that deserves further study. There may indeed be small groups of patients that benefit. But ablation of renal nerves as a treatment for high blood pressure looks more like a sacrifice bunt than a home run.

That's not surprising. In the treatment of chronic diseases acquired through disordered lifestyle choices, doctors will offer few easy solutions.



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