By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
SYNOPSIS: This retrospective review of the natural history of severe calcific mitral valve stenosis demonstrated such patients have a high mortality partly because of a high comorbidity burden and partly because of valve stenosis. Although often symptomatic, symptoms did not predict mortality.
SOURCE: Böhm M, Kario K, Kandzari DE, et al. Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): A multicentre, randomised, sham-controlled trial. Lancet 2020;395:1444-1451.
After years of nearly unbridled enthusiasm for renal denervation, the 2014 sham-controlled SYMPLICITY HTN-3 trial showed no significant advantage to denervation in medically treated patients with resistant hypertension. The results splashed cold water on the entire renal denervation enterprise. But when a series of subsequent pilot studies showed continued promise for this therapy, investigators designed the SPYRAL pivotal trial to demonstrate conclusively whether catheter-based renal denervation successfully lowers blood pressure.
The SPYRAL authors enrolled patients between age 20 and 80 years with office systolic blood pressure between 150 mmHg and 180 mmHg, and office diastolic pressure of at least 90 mmHg. Patients also could qualify with ambulatory systolic blood pressures between 140 mmHg and 170 mmHg. Since this was intended to be a comparison of denervation and sham procedures in the absence of antihypertensive medications, patients who were on blood pressure medications were required to discontinue them. To address the safety of this approach, patients with a recent history of angina or myocardial infarction were not enrolled. Patients with any history of congestive heart failure, stroke, or atrial fibrillation were excluded.
The authors randomized 80 patients in the initial pilot study. Researchers included an additional 251 patients in the Pivotal study, making a total study population of 331 patients from 44 international sites who were randomized to catheter-based denervation or sham procedure. Although the procedure operators were not blinded to the treatment assignment, they were subsequently not involved in care of the patients until after clinical assessment six months later.
At the prespecified three-month time point, the reduction in systolic blood pressure on 24-hour ambulatory monitoring was an average of 4.0 mmHg greater in the renal denervation arm, and the drop in office systolic blood pressure was 6.6 mmHg greater. Notably, the authors saw small but significant reductions in blood pressure in the sham procedure group, emphasizing the importance of a sham control in this study.
During the trial period, fewer patients in the denervation group met the so-called “escape” criteria (either systolic blood pressure > 180 mmHg, or other safety concerns that prompted initiation of antihypertensive medications). A total of 16 renal denervation patients met these criteria compared with 28 sham patients (P = 0.049). Remarkably, no major procedure- or device-related complications were reported. No major safety events were reported at all in the first month. The authors concluded that catheter-based renal denervation was superior to a sham procedure at lowering blood pressure in patients not on antihypertensive medications.
Does renal denervation accomplish safe blood pressure-lowering in hypertensive patients? These results seem to provide a definitive, positive answer. For the naysayers who wondered whether this procedure was any better than placebo, we now have a clear affirmative response. The same voices will note the treatment effect here was relatively small. It is likely the intervention did not reach full antihypertensive effect because of the imperative to make full assessment off meds at only three months. The results of other studies have suggested the treatment effect of renal denervation continues to increase after three months.
The idea of this proof-of-principle study was not to advocate for treating patients with interventional therapy alone without medications, although some may think to use it this way. With the modest reductions in blood pressure observed here, few patients with hypertension in the range seen in the target population would even experience a significant reduction in medication burden, let alone achieve goal blood pressures with this treatment alone. The authors of an accompanying editorial argued the primary role of this and other studies may be to identify those patients who are most likely to benefit, to improve patient selection, and additionally to identify populations that may benefit (e.g., patients with heart failure or chronic kidney disease) separately from the direct effect on blood pressure.
The device used in the trial, as in the prior SYMPLICITY study, is manufactured by study sponsor Medtronic, a large, international medical device company. The manuscript was written by independent authors. However, it is worth noting the sponsor was involved in the design of the study, data collection, validation of the data analyses, and writing the report.
The SPYRAL HTN-OFF MED study provides convincing evidence for a modest but significant blood pressure-lowering effect of catheter-based renal denervation. The ongoing ON MED study is expected to provide further complementary information in more real-world patients who experience uncontrolled hypertension despite taking antihypertensive medication.