They say the way to a man’s heart is through his stomach. Not so, at least when it comes to cardiac care. Recent research and clinical practice point to the kidneys as a pathway for treating cardiovascular diseases. Using a percutaneous, catheter-based technique to disrupt overactive renal sympathetic nerves, specialists have been able to lower blood pressure in patients with drug-resistant hypertension. And they aren’t stopping there. Early studies show the approach may be effective for treating atrial fibrillation (AF) and heart failure (HF) as well.
An unnerving scenario
The heart is one of several organs that in concert regulate blood pressure. The kidneys also play an important role, assisted by the renal sympathetic efferent and afferent nerves within and adjacent to the walls of the renal artery. If the nerves that feed into the sympathetic nervous system go into overdrive, then they may precipitate hypertension. Systemic hypertension, in turn, can cause organ damage and put hypertensive people at risk for major cardiovascular events such as stroke.
One-third of U.S. adults are hypertensive, according to the American Heart Association. Worldwide, that estimate grows to approximately one-quarter of adults, with prevalence expected to rise in developing countries. For many patients, medications can control their hypertension and reduce the risk of stroke. But some patients cannot achieve target blood pressure even when treated with many drug therapies at the highest tolerated doses.
Renal denervation, an approach that uses percutaneous catheters and radiofrequency energy to disrupt renal nerve signaling, may prove to be an option for people with treatment-resistant hypertension. Because poorly controlled hypertension also is a risk factor for AF, electrophysiologists are exploring the use of renal denervation to reduce AF occurrences. Poor cardiac function also sets the sympathetic nervous system into overdrive, a condition that has cardiologists viewing renal denervation as a therapy in HF.
“In medical school, we are taught that all of these diseases have separate etiologies; they all come from different sources,” says Justin E. Davies, MBBS, PhD, of the International Centre for Circulatory Health at the National Heart and Lung Institute at Imperial College London. “Actually, what this therapy may tell us is that they may have a common source, or at least that the effects of these diseases may be magnified by an increase in stress hormones.”
As early as the 1930s, physicians recognized that surgical renal denervation could reduce what was termed malignant hypertension (J Clin Invest 1935;14:22-26). But the invasive procedure had long-term complications. Several decades later, the development of antihypertensive agents offered physicians an option for treating patients. But up to 30 percent of patients diagnosed with high blood pressure may fail to respond to three or more antihypertension drugs, says Markus Schlaich, MD, an investigator in Symplicity HTN-1, a clinical trial that assessed the safety and efficacy of renal denervation in patients with treatment-resistant hypertension.
“Treatment-resistant hypertension is something you encounter quite frequently in general practice,” says Schlaich, who also is head of the Neurovascular Hypertension & Kidney Disease Laboratory at Baker IDI Heart and Diabetes Institute in Melbourne, Australia.
Compare the costs
A model designed to assess the cost-effectiveness of renal denervation in resistant hypertensive patients estimated (2010 U.S. dollars):
Source: J Am Coll Cardiol 2012;60(14):1271-1277.
Catheter-based renal denervation is a less invasive approach, but it is still in its infancy. In a proof-of-concept study, Schlaich and colleagues enrolled 50 treatment-resistant hypertensive patients from five centers in Europe and Australia between 2007 and 2008 with a one-year follow-up (Lancet 2009;373:1275-1281). The primary endpoints included office blood pressure and safety data. Ardian, maker of the device in the trial, sponsored the study. Medtronic acquired Ardian in 2010 and now sponsors the Symplicity trial.
Treated patients had a mean baseline office-based blood pressure of 177/101 mm Hg and were taking a mean of 4.7 antihypertensive medications. Office-based blood pressures dropped steadily over the year, from minus 14/minus 10 mm Hg at one month to minus 27/minus 17 mm Hg at 12 months. Five of the 50 patients who were not eligible for renal denervation had a mean increase in blood pressure. Researchers reported one intraprocedural renal artery dissection as the sole renovascular complication.
While the treatment appeared to be effective, its durability still was in doubt. As seen with kidney transplantation, the renal sympathetic efferent nerves may be able to regrow and possibly nullify or override the benefits of renal denervation. Two-year and three-year follow-up results suggest that fear may be unfounded, though.
At two years, the Symplicity HTN-1 researchers found that the benefits persisted over time with no significant adverse events (Hypertension 2011;57:911-917). The study included a larger group of patients—153—at centers from Australia, Europe and the U.S. Three-year results, presented by Schlaich at TCT.12, showed favorable trends in response rates and blood pressure reductions. The rate of patients with a reduction of 10 mm Hg or more in systolic blood pressure was 69 percent at one month and 94 percent at three years. Blood pressure reductions continued over time, from a mean of minus 19 mm Hg at one month to minus 31 mm Hg at three years.
“Having a sustained blood pressure reduction around 30 mm, which doesn’t change between two and three years, seems to indicate that there is long-term benefit of this procedure,” Schlaich says. He adds that quieting the sympathetic nervous system with renal denervation may have beneficial effects on arterial remodeling on target organ damage. “This takes time to occur. We believe that this is part of the reason why we see a delayed response in some patients.”
Schlaich and colleagues have since launched Symplicity HTN-2, a prospective clinical trial that randomized treatment-resistant patients between June 9, 2009, and Jan. 15, 2010, with a baseline systolic blood pressure of 160 mm Hg or more to either renal denervation with their previous therapy or to a control group that maintained its therapy (Lancet 2010;376:1903-1909). At six months, office-based blood pressure measurements in the renal denervation group (52 patients) dropped by 32/12 mm Hg but remained the same in the control group (54 patients). Symplicity HTN-3, a single-blind randomized controlled trial, is now underway in the U.S. to evaluate renal denervation’s safety and efficacy, the results of which the company hopes to use in its U.S. regulatory filing.
The FDA has yet to approve any renal denervation system for treating resistant hypertension in the U.S., and use of the therapy is investigational only. But Symplicity received CE Mark in Europe and has been approved for commercial use in Australia and parts of Asia and Africa. And Medtronic is not alone. ReCor Medical, a developer of an ultrasound renal denervation therapy, announced its CE Mark in February 2012. St. Jude Medical soon followed suit, with a multielectrode ablation technology called the EnligHTN renal denervation system, which received CE Mark in May 2012.
Covidien acquired Maya Medical in April 2012, soon after the start-up received CE Mark for its OneShot renal denervation system. In November 2012, Boston Scientific announced its acquisition of Vessix Vascular, whose radiofrequency balloon catheter system also has CE Mark and is approved in Australia.
Interventional cardiologists and interventional radiologists predominantly have performed the renal denervation procedures on hypertensive patients in the trials, Schlaich says. But occasionally electrophysiologists have contributed, too. Among the pioneering electrophysiologists was Evgeny Pokushalov, MD, PhD, deputy director at the State Research Institute of Circulation Pathology in Novosibirsk, Russia.
When Pokushalov’s facility signed a collaborative research agreement with Valley Health System’s Valley Heart & Vascular lnstitute in Ridgewood, N.J., the cross-pollination of backgrounds and skills led to a novel notion: using renal denervation to treat AF. “We are all skilled at accessing vascular systems,” points out Jonathan S. Steinberg, MD, director of the Arrhythmia Institute at Valley Health System. “We [electrophysiologists] are more experienced and skilled at performing ablation, but technically, any one of these specialties can be involved in its clinical application.”
Both hypertension and AF are prevalent and often coexist. Also, hypertension is associated with changes in the heart’s structure and physiology that may develop into AF. Hypothesizing that renal denervation would prove beneficial for some patients with both AF and hypertension, the international team designed a prospective, randomized trial using patients with a history of symptomatic drug-refractory paroxysmal or persistent AF and drug-resistant hypertension (J Am Coll Cardiol 2012;60:1163-1170). The study compared patients treated with pulmonary vein isolation (PVI) and renal artery denervation (13 patients) with those who received only PVI (14 patients).
All patients were followed for one year. Neither the patients nor their physicians who performed follow-up care were informed about which patients received which procedure. At the one-year follow-up, 69 percent of the PVI plus renal artery denervation group remained AF-free and had mean reductions in systolic and diastolic blood pressure of 25 mm Hg and 10 mm Hg, respectively, compared with baseline. In contrast, 29 percent of the PVI only group was AF-free and the group showed no significant changes in systolic or diastolic blood pressure.
“To our great satisfaction, our small study showed very positive results,” Steinberg says.
In an accompanying editorial, Ralph J. Verdino, MD, wrote that the results raised more question than they answered, including whether renal denervation should be a standalone treatment for AF and whether electrophysiologists currently may be targeting the wrong organ. “For a population that has poorly controlled hypertension in addition to their atrial fibrillation, it is a reasonable treatment strategy, based on what they showed,” says Verdino, of the Hospital of the University of Pennsylvania in Philadelphia. “It also improved their hypertension; maybe by just treating hypertension we will get better at treating atrial fibrillation.”
Steinberg and his colleagues are in discussions with sponsors in the U.S. and Europe to conduct randomized clinical trials on a variety of arrhythmias. Their initial findings need to be backed with more evidence from large-scale efficacy and safety trials. They also need more clarity on the appropriate patient populations, disease states and outcomes before the procedure will be accepted in clinical practice. If the evidence continues to be favorable, Steinberg says, “then I see it being tested in a variety of environments involving atrial fibrillation: standalone, prior failed ablation and in combination with ablation techniques in patients with more advanced atrial fibrillation.”
‘A crazy concept’
In theory, renal denervation could be applied to not only resistant hypertension but also difficult-to-treat hypertension, controlled hypertension and—if indicated for another cardiovascular disease—even in those with normal blood pressure. “Importantly, we want to know its effects on blood pressure in both hypertensive and non-hypertensive patients,” Steinberg says. History supports those concerns. Among the debilitating side effects of surgical renal denervation was postural hypotension; treated patients would get severely dizzy when trying to rise from a reclining position.
HF patients often have normal or low blood pressure. At the same time, these patients also typically have a chronically elevated renal sympathetic nervous system that may exacerbate cardiac deterioration and renal dysfunction (Eur Heart J 2005;26:906-913). As positive results on the effectiveness of renal denervation for controlling treatment-resistant hypertension rolled in, Davies and colleagues postulated that the treatment also might benefit patients with chronic HF, unless it lowered blood pressure deleteriously in patients who already have low blood pressure.
“It is a crazy concept, in a way,” Davies admits. “You have a treatment for lowering blood pressure and you take someone who already has low blood pressure and give him the treatment.”
To evaluate the safety of renal denervation in HF patients, they designed a first-in-man study (Int J Cardiol online Sept. 29, 2012). The study enrolled seven clinically stable patients in 2011 with chronic symptomatic systolic HF who were on maximal tolerated therapy for the condition. The mean blood pressure at referral was 112/65 mm Hg. Each patient underwent renal denervation followed by a five-day inpatient observation, weekly follow-up for four weeks and then monthly follow-up for six months.
Davies and colleagues reported no procedural or post-procedural complications, no readmissions and no hypotensive episodes. However, they found a nonsignificant trend toward lower blood pressure at six months. Renal function remained stable, and loop diuretic therapy was reduced or stopped in four of the seven patients. They noted a trend in reductions in beta-blocker dosages and angiotensin II receptor blockers as well. All seven patients described improvements in symptoms and had increased distance in a six-minute walk test.
Davies emphasizes that it was a small, single-center study. But, “there is a trend growing where it looks potentially that it is safe to do this technique in people with chronic stable heart failure.” For instance, Czech researchers reported similar benefits using renal denervation in patients with advanced HF at the 2012 European Society of Cardiology Congress, and Medtronic has launched a Symplicity-Heart Failure trial.
Davies and colleagues are now recruiting patients for REACH (Renal Artery Denervation in Heart Failure), a prospective double-blind randomized trial to study the safety and efficacy of renal denervation in approximately 100 HF patients over one year.
“When the nervous system becomes chronically overactive—stress, stress, stress—for long periods of time,” it may play havoc with the heart, Davies says. “By reducing that stress level, we may have a knock at reducing atrial fibrillation, blood pressure and improving heart failure symptoms. While these small studies are encouraging, they need to be repeated in other groups and in larger trials to confirm that they are consistent.”
Steinberg concurs. “Our study is positive, but I’ve been in clinical trials for 25 years and small sample sizes are fraught with error,” he cautions.
Symplicity safety data have allayed some worries that the procedure might cause harm, including renal artery stenosis and impairment of renal function. Researchers reported no catheter or generator malfunctions and four complications, including one renal artery dissection during catheter delivery and three access-site complications. All patients were managed with no further complication. At 18 months, they reported progress of one pre-existing stenosis unrelated to the treatment and one new moderate stenosis that was not hemodynamically relevant and needed no treatment. There were no new reports of vascular complications or late adverse events at 36 months.
But the HTN-1 study excluded patients who had renovascular abnormalities, type 1 diabetes mellitus or estimated glomerular filtration rates of less than 45 mL/min/1.73m2. “All of these patients had good renal function,” Schlaich says. “There is limited data that it seems to be safe in patients with some form of renal impairment, but at this time we would recommend that it should be used in patients with normal renal function [in countries where it is an approved therapy].”
Results in practice may differ from those in clinical trials as well. Cardiologists at the CardioVascular Center in Frankfurt, Germany, reported one case of renal artery stenosis after renal denervation and encouraged physicians to participate in registries to monitor such incidences (J Am Coll Cardiol online Oct. 24, 2012). “[G]iven the small number of individuals with surveillance imaging follow-up after RDN [renal denervation] reported thus far and the frequently clinically silent nature of RAS [renal artery stenosis], it is conceivable that we have not yet learned the true incidence and magnitude of this complication,” they wrote.
Nor is it clear how many patients with treatment-resistant hypertension would be eligible for renal denervation. Of the 50 patients enrolled in the proof-of-concept Symplicity study, five were excluded for anatomical reasons, mostly due to dual renal artery systems. In addition, 30 of the 190 patients in Symplicity HTN-2 were found to have incompatible renal artery anatomy and 36 failed to meet blood pressure inclusion criteria. Physicians at the Vascular Medicine and Hypertension Unit at the Georges Pompidou Hospital in Paris (five of whom were Symplicity HTN-2 investigators) applied the Symplicity HTN-2 eligibility criteria to a cohort of their patients in 2011 and concluded that only 1.5 percent of patients with resistant hypertension met the standards (J Am Coll Cardiol online Oct. 25, 2012).
Additionally, even at 36 months, a small fraction of treated Symplicity HTN-1 patients remained non-responders. Schlaich also notes that it is unclear how repeat ablations might be done if the durability of renal denervation therapy fails to persist in the long term. “Theoretically, you could repeat [the procedure], but there are lots of questions,” he says. “Do you treat in the same area or try to target other areas? We do not have any data to tell us about the safety or success of a repeat procedure.”
The end game is less about achieving optimal blood pressure than it is about reducing risk, Davies points out. Although trends are positive at three years, even if blood pressures begin to revert to previous levels after three years, renal denervation will have fulfilled its promise by potentially averting stroke and other adverse outcomes. “Ultimately, if you take someone who has uncontrolled blood pressure and you manage to control it, three years of good control hugely drops their risk of having a cardiovascular event,” he says.
Intracranial stenting: A cautionary tale
Physicians approach device-based therapies for difficult-to-treat diseases with cautious enthusiasm, and for good reason. What appear as soaring successes in preliminary studies may sputter and nosedive in larger randomized clinical trials.
Atherosclerotic intracranial arterial stenosis falls under that category. Intracranial atherosclerotic disease is considered a major cause of stroke, and stroke patients with severe stenosis treated with medical therapy face a 22 percent risk of recurrence or death the first year after a stroke (N Engl J Med 2005; 352:1305-1316). The possibility of a percutaneous approach offered a welcome alternative for high-risk patients when the FDA approved the use of the Wingspan stent system (then Boston Scientific, now Stryker) as a Humanitarian Use Device for patients with treatment-resistant intracranial atherosclerotic disease with stenosis of 50 percent or greater.
Results from small studies using a combination of angioplasty and stenting suggested the strategy was a viable option for patients with severe stenosis, but in-stent restenosis rates of up to 35 percent cast doubt on its durability (Stroke 2007;38:881-887).
The SAMMPRIS trial (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) was launched in 2008 to compare medical management alone with medical management plus percutaneous transluminal angioplasty and stenting (PTAS) in patients who had a recent transient ischemic attack (TIA) or stroke attributed to severe intracranial arterial stenosis. Enrollment in the randomized controlled trial was stopped early when results showed a higher than expected risk of stroke or death in the PTAS group (30-day rate of 14.7 percent) and a lower than expected benefit (5.8 percent) in the medical management group (N Engl J Med 2011; 365:993-1003).
Soon after the results were published, the advocacy group Citizens First petitioned the FDA to withdraw approval of the Wingspan system. After a meeting of expert advisers and review of SAMMPRIS and other data, the FDA narrowed its indication on Aug. 8, 2012, saying that “Wingspan may present unacceptable risks, such as stroke or death, to many patients previously considered appropriate for treatment with Wingspan.”
That is not the end of the story, though, says SAMMPRIS principal investigator Marc I. Chimowitz, MB, ChB, of the Medical University of South Carolina Stroke Program in Charleston, S.C. While they halted enrollment, they continued follow up of study participants and expect to publish long-term results this year. Some panelists at the FDA advisory meeting argued that Wingspan offered benefit to a subset of patients, for instance, and final results may provide some clarity. Stryker also is conducting a post-market surveillance study, as ordered by the FDA.
Anecdotally, the initial findings likely have affected clinical practice. “Physicians recognize when a trial is stopped early for safety reasons that is a wake-up call to change the way they practice,” Chimowitz says.
But neurologists and neurointerventionists still face the challenge of effectively treating high-risk patients who presently have limited options. “There certainly will be patients who will require alternative therapies, and we have to figure out who those patients are, what those therapies are and test them in a clinical trial,” he says. Whether the answer lies in device-based endovascular therapy using angioplasty alone, angioplasty with stenting or a new strategy remains to be seen.