“We need to be very careful not to kill a promising technology with incorrect patient selection,” Pierre-François Plouin, Paris, France, warned delegates at the EuroPCR Great Debate 2012 on renal denervation. In the debate, Plouin and four other experts in interventional cardiology, interventional radiology and nephrology agreed that identifying the right group of patients is key for the future of the technique. The group also discussed patient compliance to medical therapy, clinical data associated with the procedure and the balance between risk and benefit.
Millions of people worldwide are impacted from complications of prolonged, uncontrolled high blood pressure. Renal denervation is indicated for patients with resistant hypertension, which is defined as office blood pressure higher than 140/90mmHg despite treatment with at least three antihypertensive drug classes including a diuretic.
Plouin, internist, professor of Cardiovascular Medicine, European Hospital Georges Pompidou, Paris, stated that the main issue to assess resistant hypertension is compliance and added that the first step is to investigate the quality of the treatment.
“Patients with resistant hypertension use many drugs for hypertension and for comorbidities. To use many drugs is associated with having many side effects. And having many side effects might be associated with poor compliance. Ask the patient about his drug intake the day of the consultation, the day before and the week before. Ask him about the degree of content about each of the drugs. Sometimes patients omit the intake of some of the drugs and this needs to be investigated. Ask also about side effects,” he said.
William Wijns, Cardiovascular Centre, OLVZ Aalst, Belgium, EuroPCR course director, who was the chairman of the debate, asked whether the method by which blood pressure was measured mattered.
“It is not so simple to check blood pressure. The usual way is to use this old fashioned system, the sphygmomanometer. This technique has many limitations including variability of measurements, calibration issues, and inappropriate cuff choice for very obese patients. Another limitation is the white coat effect caused by the stress and anxiety of being in the office,” said Jean Renkin interventional cardiologist, assistant professor of Cardiology, Catheterisation Laboratory, UCL St Luc University Hospital Brussels, Belgium.
Plouin noted that ambulatory blood pressure measurement (ABPM) is a more reliable and effective technique to confirm resistant hypertension. With ABPM, the patient’s blood pressure is monitored for 24 hours. He added, “Using ABPM, the reference value for daytime blood pressure is 135/85mmHg which is a different cut-off than that with the office blood pressure.”
Thomas Zeller, head, Department of Angiology at Universitats-Herzzentrum Freiburg-Bad Krozingen, Germany, agreed and told delegates that, his team “does not discuss any indication of renal denervation therapy without performing an ABPM examination to rule out white coat hypertension and other reasons for increased hypertension that might give a false positive answer qualifying these patients as having resistant hypertension.”
“ABPM gives us some extra information – whether the patient is a dipper (patients with lower blood pressure at night time) or a non-dipper (an indication of higher cardiovascular risk) if he has a hyperactivation of his sympathetic nerve system,” Zeller said.
The panel agreed that an antihypertensive drug algorithm needs to be followed to consider a patient untreatable via medical therapy.
“In our centre it takes between three and six months before finally deciding that the patient is a good candidate for renal denervation. We also receive many patients from outside, already screened by other specialists, nephrologists, cardiologists, internists, being referred to us for renal denervation. Then we re-start the screening and after this filtering process only 30% of these patients are really candidates for renal denervation, according to the current criteria,” Renkin said.
“We are talking about a high-risk patient population. They are coming to your office and you do not know how to handle them. They are at high cardiovascular risk; they are heavily medicated and poorly controlled,” said Felix Mahfoud, interventional cardiologist, University Hospital Homburg/Saar, Germany. He said that 450 patients have been treated with renal denervation there.
Mahfoud told delegates that, so far, the results are positive. “SYMPLICITY HTN-1 shows us that the blood pressure reduction is sustained over three years, so it gives us information and evidence that over this longer follow-up there has been no evidence of functional re-growth of the renal nerves.”
The panel also highlighted that there are different degrees of response to renal denervation.
“The SYMPLICITY HTN-2 trial shows us that there are three groups of patients. About 10% are non-responders; 39% are excellent responders, with blood pressure going below 140mmHg; and in between there are 50% of patients with some response, with at least 10mmHg drop, but at the moment we do not know what the clinical relevance of this drop is,” Renkin said.
Predictors of success
Wijns asked if any of the interventionists had identified predictors of who might respond to treatment.
Mahfoud said, “We define response to treatment as systolic blood pressure reduction above 10mmHg six months after treatment. So far we have identified two multivariable stable predictors: systolic blood pressure at baseline – the higher the blood pressure at baseline the greater is the reduction – and patients with type 2 diabetes. Diabetic patients seem to be the ones who benefit especially from the procedure. And these patients are also characterised by an increased sympathetic tone.”
In terms of safety, Zeller noted that the procedure “seems to be safe”.
“We only have two trials (SYMPLICITY HTN-1 and SYMPLICITY HTN-2), with 259 patients, and acute and six-month safety data. In the acute phase, there were five complications – two renal artery dissections and three access complications. This is not unusual as this is a high-risk population. Six-month data do not show any big concerns. It also seems to be a safe procedure with regard to the integrity of the renal artery,” he said.
William McKane, clinical director of Sheffield Kidney Institute, Sheffield, UK, was more cautious. “The SIMPLICITY study excluded patients who had an eGFR [estimated glomerular filtration rate] of less than 45. So we cannot say much about renal safety in moderate to more advanced chronic kidney disease patients. I am not convinced that the renal artery surveillance was quite as robust as it might have been. I do not want to be sucked into the trap of believing that the evolution of a renal artery stenosis after this therapy will be along the time course of an atherosclerotic plaque, two to three years,” he said. “It is more likely to be a slower time course. Radiotherapy-induced stenosis in both the carotid and renal artery can take up to 10 years to evolve. And finally, about the statement that there was no significant change in renal function at one year, it is quite a small study. There was a decline in GFR, probably three to six times what you would expect to be the rate of GFR decline in the general population.”
Zeller explained that in the SYMPLICITY HTN-1 and HTN-2 trials two cases of stenosis induced by the procedure had been seen. “There was a progression from moderate to severe stenosis in two cases, but the disease was present prior to commencement of renal denervation treatment.”
Zeller concluded: “For me it is crystal clear that we have to be very careful in expanding the use of this interventional approach. We have to limit our attention to those patients where we have evidence that this therapy is worth performing, and that is in cases of resistant hypertension.”
Deepak Bhatt, Harvard Medical School, Boston, USA, principal investigator SYMPLICITY HTN-3, which is enrolling patients in the USA, told Cardiovascular News: “Renal denervation is an interventional technique and careful patient selection is key. Physicians performing the procedure should have expertise in renal angiography and renal intervention. The renal artery anatomy can be tricky, especially in tortuous, atherosclerotic aortas, and careful guide catheter and wire skills are necessary.”
The EuroPCRâ€ˆGreat Debate was sponsored by Medtronic.