• Radiofrequency RDN Patients Saw More Stable Blood Pressure and Fewer Cardiovascular Events: 3-Year GSR-DEFINE Results

    Blood pressure reduction measures such as TTR must be accepted as surrogate for otherwise ‘almost impossible’ to prove heart outcomes, investigator says

    Patients who received radiofrequency renal denervation (RF RDN) spent a greater amount of time within target blood pressure range afterward than before the procedure and had fewer cardiovascular events, including stroke, myocardial infarction and cardiovascular death, in the 3-year Global SYMPLICITY Registry DEFINE (GSR-DEFINE).

    The findings were reported Tuesday in a late breaking session at EuroPCR 2022 in Paris by GSR-DEFINE executive committee member and investigator Felix Mahfoud, MD, from Saarland University Hospital, Germany.

    The GSR is the largest and longest followed study of real-world patients with uncontrolled hypertension treated with RDN documenting the long-term safety and effectiveness of Medtronic’s Symplicity RDN system, which includes the Symplicity Flex and Symplicity Spyral.

    However, the clinical impact of long-term blood pressure control following RF RDN – specifically related to hypertension – “needs further evaluation,” said Mahfoud.

    To gauge clinical outcomes, the current study – funded by Medtronic – utilized time in target therapeutic blood pressure range (TTR) as an independent predictor of cardiovascular events.

    It was the second study reported in the Tuesday morning session using TTR as an outcome measure for Symplicity devices (after a 3-year follow-up of the PYRAL HTN-ON MED trial), but the first to use TTR to predict outcomes.

    Study results

    The GSR is a prospective, open-label, single-arm, multi-center, all-comer observational study that has enrolled 3,077 patients to date, out of a planned 5,000 consecutive patients with uncontrolled hypertension, treated with Symplicity Flex (2,231 patients) or Spyral (846 patients).

    TTR was estimated through successive systolic blood pressure measurements from baseline through 6-month, 1-year, 2-year and 3-year follow-ups, and the time a patient spent under target systolic blood pressure was calculated using maximum value of office systolic blood pressure (OSBP) ≤140 mmHg or 24-hour ambulatory systolic blood pressure (ASBP) ≤130 mmHg.

    At baseline, the patients had a mean age of 60 years, 42.2% were female, 37.9% were type 2 diabetic, 36.5% had hypercholesterolemia, 20.8% chronic kidney disease, 12.3% atrial fibrillation, 46.8% had a history of cardiac disease, and 10.2% were current smokers.

    The mean OSBP among the entire cohort was 166 mmHg, and the 24-hour systolic blood pressure was 154 mmHg.

    The patients were on a mean 4.9 antihypertensive medications at baseline, dropping to 4.85 at 6 months and 4.79 at 3 years (P = 0.007).

    At 3 years, 1,568 of the Flex group and 328 of the Spyral group had been followed-up.

    Crucially, the study showed significant reductions in both office and 24-hour systolic blood pressure over 3 years in “this largest registry of over 3,000 RDN patients,” Mahfoud noted in a press conference the same day.

    The decrease in blood pressure was progressive over each time check, he added, with office blood pressure down by 13.2% at 6 months, 14% at 1 year, 15.3% at 2 years, and finally 16.7% at 3 years (P < 0.001 vs. baseline). The same time checks for 24-hour ABPM were down 7.3%, 8.2%, 8.9% and 9%, respectively (P < 0.001 vs. baseline).

    It meant that TTR increased over 3 years, from 28.2% at 3 months, to 30.6% at 6 months, 32.8% at 1 year, to 33.9% at 2 years and finally 34.9% at 3 years. The number of days spent in therapeutic range (determined by multiplying TTR by the number of days in the time period) saw a similar trend over the same checkpoints, at 25 days, 55 days, 118 days, 244 days, 377 days and at the final 3-year follow-up.

    Mahfoud also highlighted the distribution of office blood pressure throughout the study – which he marked “interesting” as “physicians are using this technology to get patients to blood pressure control.”

    “Only 13% [13.5%] of the patients had an office systolic blood pressure of below 140 [mmHg] at baseline, and that significantly increased – in fact tripled – throughout three years of follow-up, reaching almost 39% [38.4%] at 3 years” (P < 0.001 vs. baseline), he said.

    Safety events at 3 years among all 1,896 of the followed-up GSR patients included major adverse cardiac events (MACE) in 9.3%, end-stage renal disease in 1.9%, creatinine elevation by >50% in 1.3% and new renal artery stenosis >70% in 0.3%.

    Associated cardiovascular event reduction

    Patient TTR from baseline to 6 months was used to inform a logistic regression model to predict how TTR affects MACE rates between 6 and 36 months.

    “Higher TTR is associated with less cardiovascular events,” said Mahfoud. “You can see a significant and almost proportional reduction in MACE rates … and the same did hold true for cardiovascular death, myocardial infarction and, particularly, the most devastating complication of hypertension, stroke.”

    For those with no time spent in TTR from baseline to 6 months, 10.3% (n=766) experienced a MACE, compared to 6.2% (530) for those who spent zero to 50% of their time in TTR, and 2.9% (512) for those with more than 50% of time in TTR.

    The same results for cardiovascular death were 4%, 3.5% and 1.5%, respectively; for myocardial infarction they were 2%, 1.5% and 0.8% ,respectively; and for stroke, the results were 5.4%, 2.4% and 0.1%, respectively.

    A 10% decrease in TTR from baseline to 6 months was associated with a 16% decrease in MACE from 6 to 36 months, Mahfoud added (odds ratio: 0.84; 95% confidence interval: 0.79 – 0.90; P < 0.001).

    “I truly believe that this is an attractive adjunct treatment option for patients with uncontrolled blood pressure,” Mahfoud concluded.

    BP reduction an ‘accepted surrogate’ for improved outcomes

    TTR, meanwhile, is a “promising approach” to assess whether RF RDN may translate into improved heart outcomes, said Mahfoud – a question long-sought in the medical community.

    He said that calculations conducted by the researchers on a required sample size to show that renal denervation – “or any other device-based treatment” – lowers heart outcomes suggest “almost impossible” patient numbers would be required.

    The researchers expected a MACE rate of 3.5% based on the recent STEP study published in The New England Journal of Medicine. “If you show a reduction of 10 mm of mercury, that would translate into 13% cardiovascular risk reduction – that would require 20,000 patients.”

    Such a study will “very likely never be happening,” he said, stressing: “I think we need to use new surrogates” such as TTR.

    “I think sooner or later, we’ll have to accept … that pure blood pressure reduction itself is an accepted surrogate for improved outcomes,” he added, noting that regulatory agencies such as the U.S. Food and Drug Administration already acknowledge the issue.

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