What, if anything, went wrong in the SYMPLICITY HTN-3 trial will probably remain up for debate, but a post hoc analysis may help to keep subsequent trials on the right path.
Results from the randomized, sham-controlled SYMPLICITY HTN-3 trial presented at the 2014 American College of Cardiology conference showed renal denervation using the Medtronic’s device was safe, but the study failed to meet its efficacy endpoint. The findings contrasted with other studies on renal denervation that reported greater reductions in systolic blood pressure in treatment-resistant patients who received ablation treatments. The discordant results raised questions about the study design, operator experience and other possible influences.
SYMPLICITY HTN-3 researcher David Kandzari, MD, of Piedmont Heart Institute in Atlanta, and colleagues conducted post hoc analyses using propensity score matching to identify possible confounding factors. The study findings were published recently in the European Heart Journal.
Between two screening visits, 94 percent of patients were on stable doses of antihypertensive medications and 78 percent were on maximum tolerated doses of at least three drugs for at least six weeks. After randomization, 39 percent of patients had a change in dose or medication class between randomization and the six-month endpoint.
“These changes typically represented both alterations in dose and class of prescribed medications, a finding that challenges the premise that patients were actually receiving maximally tolerated doses at enrolment,” they wrote. They also questioned whether a two-week screening period to ensure medications were adequately stabilized was sufficient and wondered if close supervision as mandated in the trial may have improved medication adherence.
As a whole, African-American patients in the sham group experienced a large decrease in systolic blood pressure compared with non-African-American counterparts. Changes in adherence or medication, with a higher proportion of African-Americans receiving vasodilator therapy, may be a factor, they observed.
They identified several areas of need, including a method to verify procedural success and better understanding of the sympathetic nervous system’s physiology. According to their analysis, the difference in systolic blood pressure increased between groups with an increase in the number of ablations. Other trials reported more ablations per patient than in SYMPLICITY HTN-3. About three-quarter of patients in HTN-3 did not receive four-quadrant ablations.
They emphasized that their analysis was based on a negative trial with limited patient cohorts, making the findings exploratory and hypothesis-generating only.