Renal denervation: will the Phoenix rise from the ashes?

On Monday, 28 August 28 2017 at 11 am, in the late breaking clinical trial session of the European Society of Cardiology (ESC) in Barcelona, the results of the SPYRAL HTN-OFF MED trial were reported and simultaneously published in the Lancet. Not surprisingly, the findings elicited a high level of interest because they stood in sharp contrast to those of SYMPLICITY HTN-3, a sham-controlled renal artery denervation (RDN) trial, which was sponsored by the same company (Medtronic) and published 3 years ago. As one may remember, this 535 patient blinded trial did not show a significant reduction of systolic blood pressure in patients with resistant hypertension 6 months after RDN as compared with a sham control. Irrational exuberance came to a grinding halt, ‘ugly facts refuted beautiful hypotheses’. We were invited to comment on these disappointing results and concluded our Editorial with ‘the SYMPLICITY studies merely document the natural history of resistant hypertension in clinical trials, and the time has come to turn the page on renal denervation for hypertension but by all means, let us not close the book’. Fortunately, the sponsor was committed to keep the book open and embarked on the SPYRAL HTN-OFF MED and ON MED studies. These studies were designed to address the potentially confounding factors identified in SYMPLICITY HTN-3 such as procedural variability, inconsistent patient drug adherence, and inclusion of patients less likely to benefit. Of note, the positive results reported at the ESC meeting were based on a pre-specified interim analysis on the first 80 randomized patients at the 3-month follow-up in the OFF MED study. The hypothesis of the SPYRAL HTN-OFF MED study was to confirm that RDN lowers blood pressure in untreated hypertension. Obviously, the most reliable method to control for the confounding effects of antihypertensive medications is to exclude them entirely. However, since in this preliminary report the sample size is small, the results have to be interpreted with great caution and by all means should not be extrapolated to patients who would not have fulfilled the rather strict inclusion criteria of SPYRAL HTN trials. What then are the major differences between SYMPLICITY HTN-3 and SPYRAL HTN-OFF MED trial? (Table 1). Based on the blood pressure inclusion criteria, patients with isolated systolic hypertension were virtually excluded in SPYRAL HTN. Also, since patients had to be taken off their antihypertensive drugs, they did not have resistant or accelerated hypertension. In fact, many patients were drug naı̈ve and wished to participate in the study in the hope that drug therapy could be avoided altogether. Not surprisingly, therefore, the study population of SPYRAL HTN-OFF MED was substantially younger than in SYMPLICITY HTN-3 and had much less severe hypertensive cardiovascular disease, presumably with less target organ damage. Sympathetic overactivity has been documented to occur in the early phases of hypertension as well as in the advanced stages with hypertensive heart disease. The present working hypothesis pertaining to the underlying mechanisms of RDN is that the procedure interrupts sympathetic fibres and reduces norepinephrine levels. One should also consider that irreversible changes may have occurred in a vascular tree that has been exposed to the ravages of hypertension for years and decades. Attesting to this are the findings of REGARDS; normotensive patients (systolic blood pressure <120 mmHg) on triple antihypertensive therapy exhibit a higher risk of stroke than those with stage 1 hypertension (systolic blood pressure 140–159 mmHg) on no medication. A young population with little or no target organ disease as in SPYRAL HTN-OFF MED should therefore be particularly susceptible to benefit from RDN. Conceivably when applied early, RDN may allow us to postpone pharmacological treatment for hypertension or at least to mitigate it. Of note, the achieved decrease in BP in SPYRAL HTN-OFF MED has to be seen in proper context. When compared to antihypertensive efficacy of standard drug classes as measured by 24-hour ambulatory BP monitoring the decrease of 5.5/4.8 mmHg seems to be rather paltry (Figure 1). Importantly, safety data of the procedure have been satisfactory; subsequent renal artery stenosis has been reported, but overall renal function has been found to be stable after 12 months. However the benefits of RDN, if any, have so far only been defined by the not infallible surrogate endpoint of blood pressure. Only a prospective randomized trial looking at the