CHICAGO – Nephrectomy, compared with sham surgery, was associated with a statistically significant reduction in blood pressure in the recently completed SPYRAL HTN–ON MED trial, but several factors likely worked together to prevent the trial from meeting its primary endpoint. . . .
Of these differences, probably none was more important than the significantly higher proportion of patients in the sham group who received additional antihypertensive drugs during the study, David E. Kandzari, MD, said at the American Heart Association’s Scientific Meetings.
The SPYRAL HTN–ON MED pivotal study followed the previously completed SPYRAL HTN–ON MED pilot study, which demonstrated a significant antihypertensive effect of antihypertensive agents following radiation therapy. In a recent update of the original study, the effect persisted for 3 years.
In the SPYRAL HTN–ON MED program, patients at the second screening visit were required to have a 24-hour systolic blood pressure of 140 to 170 mm Hg. Patients enrolled in the study were randomized to renal replacement therapy or sham control while maintaining antihypertensive therapy at baseline.
The previous pilot study involved 80 patients. The pivotal expansion study added an additional 257 patients for a total of 337 patients. The primary efficacy endpoint was based on a Bayesian analysis of change over 24 hours. systolic inflammation after 6 months in those in the experimental group compared to those on medication alone. Participants from both the flight and key tests were included.
The predefined definition of success for the renal nerve was a 97.5% threshold for superiority probability based on this Bayesian analysis. However, the Bayesian analysis was distorted by differences between experimental and expansion cohorts, complicating the superiority calculation. Therefore, the analysis yielded only a 51% probability of superiority, which is well below the predefined threshold.
Despite the observed difference in blood pressure control in favor of nephropathy, several factors were identified that likely contributed to missing the primary endpoint. One stood out.
“The significant difference in drug prescriptions was disproportionately in favor of the sham group,” said Kandzari, director of the Piedmont Heart Institute, Atlanta. He said that this discrepancy, which was a violation of the protocol mandate, led to a “bias towards the null” for the primary outcome.
The failure to meet the primary outcome was particularly disappointing following a favorable primary study and the SPYRAL HTN–OFF MED pivotal study, both of which were positive.
In the original study, which did not have drug imbalances, there was a decrease of 7.3 mm Hg (P = .004) for 24 hours. ABPM was observed after 6 months. The relative reduction in office-based systolic BP reduction from renal denervation compared with sham was 6.6 mm Hg (P = .03) and 4.0 mm Hg (P = .03) for the plane and expansion groups, respectively.
Based on the win rate derived from a hierarchical analysis of ABMP and drug burden reduction, the 1.50 advantage (P = .005) for the renal neuron arm in the recently completed SPYRAL HTN–ON MED study was also convincing.
At the start of the study, the median number of drugs was 1.9 in both the renal and sham arms. At the end of 6 months, the median number of medications was unchanged in the experimental group, but increased to 2.1 (P = .01) in the sham group. Similarly, there was little change in drug burden from the beginning to the end of the study in the denervation group (2.8 vs. 3.0), but a statistically significant change in the sham group (2.9 vs. 3.5; P = .04).
Furthermore, the net percentage change of patients receiving drugs that contributed to BP reduction during the study did not differ between the experimental and control groups of the experimental group, but was more than 10 times greater among the control group in the expansion group (1.9% vs. 21.8%; P <.0001).
Medication changes during the SPYRAL HTN–ON MED study were even greater in some specific subgroups. Among black participants, for example, 14.2% of those randomized to renal replacement therapy and 54.6% of those randomized to the sham group increased their antihypertensive therapy during the study.
The COVID-19 outbreak is suspected to play another role in the negative results, according to Kandzari. After a short enrollment pause, the SPYRAL HTN–ON MED study was restarted, with approximately 80% of the expansion cohort data collected during this period. When compared, differences in office and 24-hour ABPM were observed for participants who were and were not evaluated during COVID.
“Significant differences in 24-hour ABPM patterns before and during COVID may reflect changes in patient behavior and lifestyle,” Kandzari said.
The data from this study differ from essentially all other studies in the SPYRAL HTN program as well as several other sham-controlled studies with renal function, according to Kandzari.
AHA-invited speaker Ajay J. Kirtane, MD, director of the Cardiac Catheterization Laboratory at Columbia University in New York, largely agreed that several variables seemed to conspire against a positive outcome in this trial, but he addressed the imbalance antihypertensive drugs.
“Any trial that tries to show a difference between the renal nerves and sham surgery has to make sure that the antihypertensive drugs are the same in the two arms. They can’t be different,” he said.
As an active investigator in the field of nephropathy, Kirtane believes the evidence supports benefits of nephropathy, but he believes data is still needed to determine which patients are candidates.
“Nephrectomy is not a replacement for previously known treatments, but it will be an adjunct,” he predicted. The overwhelming evidence supports a clinically meaningful reduction in BP with this approach, “but we need to decide who to consider [for this therapy] and having realistic expectations about the level of benefit.”
Kandzari reported financial relationships with Abbott Vascular, Ablative Solutions, Biotronik, Boston Scientific, CSI, Medtronic Cardiovascular, OrbusNeich, and Teleflex. Kirtane reported financial relationships with Abbott Vascular, Abiomed, Boston Scientific, Cardiovascular Systems, Cathworks, Chiesi, Medtronic, Opens, Philipps, Regeneron, ReCor Medical, Siemens, Spectranetics, and Zoll.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.