Hypertension bad, normotension good.

The concept is pretty straightforward, so patients hop on a Mobius strip of treatment: lose some weight, exercise a little, take some drugs, stop when it seems to work, and begin again when blood pressure rises. It's a neverending story for some and a nonstarter for others.

No matter what, systemic hypertension remains a serious medical problem, increasing major adverse cardiac and cerebral events. Trial after trial supports the undisputed effects of antihypertensive therapy, but multidrug therapy often fails to produce adequate BP reduction. Even when hypertension is optimally controlled, adverse drug effects often interfere with patients' lifestyles and affect compliance, eventually leading to a return of high BP and its myriad damaging effects.

Treatment-resistant hypertension refers to high BP that persists despite at least three prescription BP medications, including a diuretic. This condition puts approximately 120 million people worldwide at risk of premature death from kidney disease and CV and cerebrovascular events.

Given hypertension's critical influence on morbidity and mortality, new methods have been sought to manage the disease. Recent attention fixes on the sympathetic nervous system (SNS) in the pathogenesis of hypertension and the interruption of the SNS as a therapeutic intervention.

Percutaneous renal sympathetic denervation (RDN) by radiofrequency ablation (RFA) holds the promise to radically change the care of patients with resistant hypertension. A variety of novel renal sympathetic nerve ablation catheters are achieving BP reductions in the range of 28/10 to 32/15 mm Hg at 1 month. Clinical trials of the first such device—the Symplicity single-electrode RFA device—showed a 1-month drop in BP of 14/10 to 20/7 mm Hg in clinical trials. Second-generation devices seem to be improving on both efficacy and safety.

The pivotal trial (SYMPLICITY HTN-3) of the Medtronic device is ongoing; a veritable throng of 50 or more competing devices incorporating strategies for maximizing efficacy and improving patient comfort is crowding the paths of regulatory approval.

Important questions remain. A surprising number of patients do not respond to RDN and, like any intervention, things can go wrong acutely. Long-term follow-up so far is not all that long term. And, if you start looking at the patients who meet the criteria for RDN, let's just say they are a very select population.

Landmark Year
Starting with ACC.12 and going right through the major meetings of the year (EuroPCR, ESC, TCT, and AHA) the data picture on RDN has remained focused and promising. While the number of patients treated within clinical trials remains relatively small, BP reductions are clinically meaningful and durable, and the procedure is safe, although safety questions remain.

SYMPLICITY HTN-2 results presented at ACC.12 by Murray Esler, MD, from Baker IDI Heart and Diabetes Institute, Melbourne, Australia, provided 6-month data; 18-month results went up at ESC later that year. The researchers found that RDN was safe and effective with an average BP reduction at 18 months of –32/–12 mm Hg from baseline. "Up to one-third of hypertensive individuals undergoing therapy are considered resistant to treatment," Dr. Esler told CardioSource WorldNews: Interventions. "It's highly encouraging that RDN shows substantial and sustained blood pressure reduction in treatment-resistant patients." Some patients experience lag time between RDN and BP effect. At ACC.12, Paul A Sobotka, MD, professor of medicine and cardiology, Ohio State University, Columbus, reported SYMPLICITY HTN-1 findings. In a population that at baseline had been receiving a mean of 5.1 antihypertensive medications (and mean baseline systolic BP [SBP] of 176 mm Hg), mean post-procedure BP dropped steadily. The nonresponder rate (<10 mg decrease in SBP) with RDN was 31% at 1 month postprocedure, 10% at 24 months, and 0% at 36 months. The magnitude of responses in late responders was similar to that of early responders—although we need to note that the actual number of patients followed dropped steadily such that only 24 patients were counted at 36 months.

William C. Cushman, MD, chief of the Preventive Medicine Section at the Veterans Affairs Medical Center in Memphis, noted early in the year that while RDN results to date are interesting, he called for more data and studies on long-term effects of RDN on CV outcomes and mortality. He raised doubts, as well, about the extent to which patients had received pharmacotherapy. "I'm not convinced they really had adequate medical therapy," he said.

Willemien L. Verloop, MD, and colleagues from the Netherlands support such suspicions. More than one-third of patients referred for RDN are not so resistant after all, they asserted: their elevated BPs spring from secondary causes of hypertension that have been missed or other issues that argue against intervention. At ESC.12, they presented evidence from a study of 169 patients referred for RDN. Of this group, 64 patients (38%) were suitable for treatment. Among the rest, 21% were excluded due to what could best be described as a white-coat effect: their mean 24-hour ambulatory SBP was <140 mm Hg. Another 13% had a secondary cause of hypertension, such as primary hyperaldosteronism, primary hyperthyroidism, or significant renal artery stenosis. Other patients (about 40%) were either deemed ineligible, opted for medical treatment, or simply decided they did not want to undergo the procedure.

Symple Devices to EnligTHN the Load?
Medtronic's Symplicity device employs a single, monopolar probe that is moved from point to point to perform 6 to 10 denervations per renal artery, a lengthy and painful procedure. The entry from St. Jude Medical, the EnligHTN RF catheter, predictably creates multiple lesions at one time with a basket design and four electrodes, potentially reducing procedure time and, as a consequence, lowering renal toxicity, fluoroscopic exposure, and contrast agent use.

The first-in-human EnligHTN I (ARSENAL) trial, a prospective, multicenter study of this system presented at TCT by Vasilious Papademetriou, MD, of Georgetown University, Washington, DC, included 46 patients who were taking a mean of four medications (98% including a diuretic) and had mean baseline BP of 176/96 mm Hg. Median procedure time was 34.0 minutes (mean 15.1 ablations). Office BP changes at 1 month stood at –28/–10 mm Hg; at 3 months, they were similar at –27/–10 mm Hg. Ambulatory BP changes were identical at 1 and 3 months, and the responder rate (defined as a reduction of 10 mm Hg SBP or more) was 80%, with 37% of patients reaching the SBP goal of <140 mm Hg.

With no reported renal artery dissections, aneurysms, or new stenosis, Dr. Papdemetriou concluded, "The EnligHTN system delivers a promising therapy for the treatment of patients with resistant hypertension." The 6-month results he reported at the 2012 AHA meeting also indicated sustainable BP lowering, with a 26 mm Hg reduction in SBP and 76% of patients responding to therapy.

With RDN, Is Sham a Sham?
At TCT 2012, Darrell Francis, MD, from St. Mary's and Hammersmith Hospital, London, weighed in with the "pro" position in the debate: SYMPLICITY Results Are Too Good to Be True: That's Why We Need a Sham Trial Design! The opposing position was assigned to Deepak Bhatt, MD, MPH, professor of medicine at Harvard Medical School and a co-principal investigator on SYMPLICITY HTN-3.

Dr. Francis noted that huge differences between BP changes emerged, depending on where they were measured. Granted, such large differences between office-based BP and ambulatory BP are not unique to RDN trials; similar "exaggerations" as Dr. Francis called them, occur as well with drug therapy (e.g., valsartan/amlodipine).

He told the TCT attendees, "Scientists like you and me should keep our expectations nearer to the bias-resistant levels of ambulatory BP," noting those reductions are not nearly as impressive as the SYMPLICITY HTN-2 headlines, but are more in line with highly effective drug therapy. So, he said, "Don't cry when scientific (i.e., blinded) clinic blood pressure reductions in SYMPLICITY HTN-3 are less than 33/11." (We explain why in a moment.)

So, are sham trials needed? Dr. Bhatt made clear early on he disagreed with his side of the argument, titling his presentation Sham Trials are Burdensome and Introduce Their Own Errors! Nonetheless, taking up the task, he stated that sham controls violate primum non nocere in that "patients being subjected to the sham treatment cannot possibly benefit, but they are still subject to the risks, which are not trivial." With RDN, the risks include bleeding, vascular complications, atheroembolism, and renal artery dissection. Furthermore, the notion that a denervation procedure could result in a placebo effect on BP measurement, in the same way as with subjective measures like angina relief and quality of life, is "ridiculous."

Dr. Bhatt said further that patients' hatred of sham controls not only makes enrollment much more challenging and time-consuming, it also delays the ultimate availability of the therapy. Moreover, the resulting super-selected population makes results less generalizable. The pain caused in many patients by denervation tips off patients that they got the active therapy, reducing the blinding's validity, as well. Lastly, after reviewing the SYMPLICITY HTN-2 home and 24-hour ambulatory and office BP changes through 36 months (–33/–19 mm Hg in 24 patients), he pointed out that ambulatory BP cannot be "faked," and placebo effects are not durable.

He closed with a confession: "I actually believe in sham controls and was a strong proponent for it in the SYMPLICITY HTN-3 trial design." How that translates in SYMPLICITY HTN-3: more than 500 patients with refractory hypertension will be randomized 2:1 to RDN with the Medtronic device or a blinded sham treatment. After 6 months, eligible control group patients will be offered active treatment.

So can we forget about shams and just go with BP as an endpoint? Dr. Sobotka, who moderated the sham/no sham debate, had supported just that view in a prior TCT session, saying that, while ambulatory BP monitoring identifies the ~20% of individuals with white-coat hypertension, "Ambulatory BP monitoring, home electronic BP monitoring, and repeated office electronic measurements may all have the same predictive accuracy. The value is the repeated measures; any measure that is reproducibly performed is an adequate endpoint."

He further underscored that awakening patients every 15, 30, or 45 minutes throughout the night for ambulatory BP monitoring does not replicate normal sleep.

In a subsequent interview, Dr. Sobotka said the arguments against sham trials in RDN are simple: While sham trials are critical for analysis of subjective endpoints that can be influenced by placebo effects, blinded BP measures, especially ambulatory BP monitoring and endpoints beyond 6 months, have not been reported to be influenced by placebo effects.

Any health risk experienced by a patient allocated to a control arm must certainly outweigh the scientific merit derived by incorporating the sham.

The FDA's regulatory responsibility to use "the least burdensome appropriate means of evaluating a device's effectiveness" with respect to devices poses the question: Is this treatment strategy effective in reducing BP for all our patients, and not just those who can access super-specialized care who can remain compliant with lifelong polypharmacy? The populations treated in current RDN trials, he added, "are not representative of the patients we as clinicians and health care providers must target for reduction of CV risk in the United States."

Finally, "asking if RDN helps refractory BP in patients who have been compliant with polypharmacy is elegant but perhaps irrelevant. The more enlightened approach, I believe, would be to ask: 'Given your current therapy, will a strategy of renal denervation meaningfully improve blood pressure control?'"

Adieu to Adherence Problems?
One argument for RDN: the issue of adherence shrinks. "The benefit [of RDN] to people who won't take their medications is potentially huge, because you do the procedure once and blood pressure stays down for years," said John Flack, MD, professor of medicine and physiology at Wayne State, Detroit. Dr. Flack noted that refractory or resistant hypertension is more common in African-American populations, and they will be disproportionately eligible for RDN procedures if the catheter is approved.

He suspects, having been on the FDA's cardiorenal panel, that the Medtronic device will be reserved for patients with SBP of ≥160 mm Hg taking three or more antihypertensive medications (including a diuretic).

"The real key will be if SYMPLICITY HTN-3 benefits parallel those in HTN-1 and -2," Dr. Flack said. Then, after, approval, post-marketing surveillance will have to show continued safety and patients with lower BP levels will have to be enrolled. Ultimately, Dr. Flack said, RDN use will naturally migrate to lower-risk populations.

Dr. Flack noted, as well, that he is impressed by ancillary benefits shown with the Symplicity catheter, which include postprocedure improvements in glycemic control and reductions in obstructive sleep apnea.

RDN in Real Life
While some are looking forward to the extension of RDN benefits to wider populations, the question as to how many patients will ultimately be eligible for the procedure remains unsettled. Right now, it is a select population indeed. In a letter to the editor of JACC, Michael Azizi, MD, PhD, Vascular Medicine and Hypertension Unit, Hôpital Européen, Paris, France, and colleagues noted that 36 of the 190 patients screened in the SYMPLICITY HTN-2 trial failed to meet the BP inclusion criteria and 30 were excluded for renal artery anatomy incompatible with RDN.

So how does that work in the real world? Azizi et al. reviewed 3,067 consecutive patients referred to their tertiary hypertension center during 2011. They conducted a detailed study of the 1,209 of these patients who were hospitalized for their work-up, excluding 175 off the top due to criteria such as age (<18 or 80 years or older), pregnancy, incomplete evaluation, or evaluations that revealed no hypertension. From the remaining 1,304 patients, only 200 met the European Society of Hypertension criteria for resistant hypertension and only 87 of these patients were diagnosed with essential resistant hypertension.

But they weren't done there. Among these, only 31 fulfilled the office systolic RDN criteria, but 7 of these patients failed to meet out-of-office and eGFR criteria, leaving 24. Finally, after dramatically paring the field, only 15 had appropriate renal artery anatomy and were RDN eligible.

Of these, the authors added, only a small proportion (about one-fourth) had received spironolactone, which has been proven effective in resistant hypertension. Dr. Azizi concluded, "Our findings demonstrate that percutaneous RDN, whether for clinical trials or specific patients, is limited to a highly selected fraction of patients with resistant hypertension—even in a specialist hypertension unit." Furthermore, a thorough diagnostic work-up is essential for appropriate patient selection.

It may be a very select group of patients eligible for intervention at the present time, but that has not stopped a growing competitive field. Sources estimate that more than 50 RDN devices are under development. These include various balloon and irrigated balloon catheters, as well as ultrasonic and tissue-directed pharmacological ablation technologies that may provide a noninvasive alternative.

Sampling the Smorgasbord
Commenting on what he called "a smorgasbord" of alternative devices and energy delivery strategies, Dr. Sobotka said, "They are basically all converging at about the same blood pressure reduction and responder rates, showing that renal denervation is working well across all of the devices. Any outcome differences are likely to be unrelated to the catheter."

He added, "There may be a biological limit to the effect and the Symplicity catheter is very close to it. It has such a long track record of low adverse events and complications that it will be hard to show superiority in safety for other devices."

At present, data are insufficient to support any judgments on claims of reduced cath lab time or lower contrast use for any devices, Dr. Sobotka noted.

So while we have a menu of devices in the works, we still need the FDA to put at least one on our plates. But when it does and we can determine which of our treatment-resistant hypertensive patients will benefit the most from RDN, we can stop their trek on the Mobius strip of therapy and reduce the stress of the pressure problems in their lives.

Keywords: Follow-Up Studies, Denervation, Ultrasonics, Embolism, Cholesterol, Imidazoles, Mortality, Premature, Sympathectomy, Niacin, Dihydrotachysterol, Hypertension, Sleep Apnea, Obstructive, Carbamates, Diuretics, Hyperthyroidism, Pyrazoles, Constriction, Pathologic, Spironolactone, Tetrazoles, Drug Combinations, Kidney Diseases, Renal Artery Obstruction, Hyperaldosteronism, Quality of Life, White Coat Hypertension, Amlodipine, Diabetes Mellitus

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