Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial.

BACKGROUND: Catheter-based renal denervation has significantly reduced blood pressure in previous studies. Following a positive pilot trial, the SPYRAL HTN-OFF MED (SPYRAL Pivotal) trial was designed to assess the efficacy of renal denervation in the absence of antihypertensive medications. METHODS: In this international, prospective, single-blinded, sham-controlled trial, done at 44 study sites in Australia, Austria, Canada, Germany, Greece, Ireland, Japan, the UK, and the USA, hypertensive patients with office systolic blood pressure of 150 mm Hg to less than 180 mm Hg were randomly assigned 1:1 to either a renal denervation or sham procedure. The primary efficacy endpoint was baseline-adjusted change in 24-h systolic blood pressure and the secondary efficacy endpoint was baseline-adjusted change in office systolic blood pressure from baseline to 3 months after the procedure. We used a Bayesian design with an informative prior, so the primary analysis combines evidence from the pilot and Pivotal trials. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT02439749. FINDINGS: From June 25, 2015, to Oct 15, 2019, 331 patients were randomly assigned to either renal denervation (n=166) or a sham procedure (n=165). The primary and secondary efficacy endpoints were met, with posterior probability of superiority more than 0·999 for both. The treatment difference between the two groups for 24-h systolic blood pressure was -3·9 mm Hg (Bayesian 95% credible interval -6·2 to -1·6) and for office systolic blood pressure the difference was -6·5 mm Hg (-9·6 to -3·5). No major device-related or procedural-related safety events occurred up to 3 months. INTERPRETATION: SPYRAL Pivotal showed the superiority of catheter-based renal denervation compared with a sham procedure to safely lower blood pressure in the absence of antihypertensive medications. FUNDING: Medtronic.

Ambulatory heart rate reduction after catheter-based renal denervation in hypertensive patients not receiving anti-hypertensive medications: data from SPYRAL HTN-OFF MED, a randomized, sham-controlled, proof-of-concept trial.

AIMS: The randomized sham-controlled SPYRAL HTN-OFF MED trial demonstrated that renal denervation (RDN) using a multi-electrode catheter lowers ambulatory blood pressure (BP) in non-medicated hypertensive patients. The current report describes the effects of RDN on heart rate (HR) in this population. METHODS AND RESULTS: Patients were enrolled with an office systolic BP (SBP) of ≥150 mmHg and <180 mmHg, office diastolic BP (DBP) of ≥90 mmHg, and a mean ambulatory SBP of ≥140 mmHg and <170 mmHg. Patients were drug naïve or removed from their anti-hypertensive medications. Eighty patients were randomized 1:1 to RDN or sham procedure. This post hoc analysis examines the effect at 3 months of RDN on HR and of high baseline 24-h HR on BP and HR changes. There was a significant reduction in 24-h HR at 3 months for the RDN group (-2.5 b.p.m.) compared with sham (-0.2 b.p.m.), P = 0.003 (analysis of covariance). Mean baseline-adjusted treatment differences were significantly different between groups at 3 months for average morning HR (-4.4 b.p.m., P = 0.046) and minimum morning HR (-3.0 b.p.m., P = 0.026). RDN patients with baseline 24-h HR above the median (73.5 b.p.m.) had significant reductions in average ambulatory SBP (-10.7 mmHg difference, P = 0.001) and DBP (-7.5 mmHg, P < 0.001), whereas BP changes in RDN patients with below-median HRs were not significant. CONCLUSION: Average and minimum morning HR were significantly reduced at 3 months for RDN compared with sham patients. A baseline 24-h HR above the median predicted greater BP reductions and may allow physicians to select patients likely to respond to the procedure.

Safety and Efficacy of Renal Denervation in Patients Taking Antihypertensive Medications.

BACKGROUND: Renal denervation (RDN) reduces blood pressure (BP) in patients with uncontrolled hypertension in the absence of antihypertensive medications. OBJECTIVES: This trial assessed the safety and efficacy of RDN in the presence of antihypertensive medications. METHODS: SPYRAL HTN-ON MED is a prospective, randomized, sham-controlled, patient- and assessor-blinded trial enrolling patients from 56 clinical centers worldwide. Patients were prescribed 1 to 3 antihypertensive medications. Patients were randomized to radiofrequency RDN or sham control procedure. The primary efficacy endpoint was the baseline-adjusted change in mean 24-hour ambulatory systolic BP at 6 months between groups using a Bayesian trial design and analysis. RESULTS: The treatment difference in the mean 24-hour ambulatory systolic BP from baseline to 6 months between the RDN group (n = 206; -6.5 ± 10.7 mm Hg) and sham control group (n = 131; -4.5 ± 10.3 mm Hg) was -1.9 mm Hg (95% CI: -4.4 to 0.5 mm Hg; P = 0.12). There was no significant difference between groups in the primary efficacy analysis with a posterior probability of superiority of 0.51 (Bayesian treatment difference: -0.03 mm Hg [95% CI: -2.82 to 2.77 mm Hg]). However, there were changes and increases in medication intensity among sham control patients. RDN was associated with a reduction in office systolic BP compared with sham control at 6 months (adjusted treatment difference: -4.9 mm Hg; P = 0.0015). Night-time BP reductions and win ratio analysis also favored RDN. There was 1 adverse safety event among 253 assessed patients. CONCLUSIONS: There was no significant difference between groups in the primary analysis. However, multiple secondary endpoint analyses favored RDN over sham control. (SPYRAL HTN-ON MED Study [Global Clinical Study of Renal Denervation With the Symplicity Spyral Multi-electrode Renal Denervation System in Patients With Uncontrolled Hypertension in the Absence of Antihypertensive Medications]; NCT02439775).

Low-Voltage Myocardium-Guided Ablation Trial of Persistent Atrial Fibrillation.

BACKGROUND: Clinically effective ablation approaches for patients with persistent atrial fibrillation (AF) are still being debated. So far, ablation targets and strategies beyond pulmonary vein isolation (PVI) have failed to show systematic outcome improvement in randomized controlled clinical trials. METHODS: We conducted a multicenter, randomized trial to determine whether PVI plus individualized substrate ablation of atrial low-voltage myocardium improves outcome in patients with persistent AF. We randomly assigned 324 patients in a 1:1 ratio to receive PVI alone (163 patients; PVI only) or PVI plus substrate modification (161 patients; PVI+SM). The primary study end point was the first recurrence of an atrial arrhythmia longer than 30 seconds after single ablation, with 3 months blanking, using serial 7-day electrocardiogram recordings over 12 months of observation. Patients were also encouraged to receive implantable cardiac monitors. RESULTS: The primary study end point occurred in 75 PVI-only patients (50%) and in 54 PVI+SM patients (35%) (Kaplan­Meier event rate estimates: hazard ratio=0.62, 95% confidence interval [CI]=0.43 to 0.88, log rank P=0.006). Adverse events occurred in three PVI-only patients (1.8%) and in six PVI+SM patients (3.7%) (difference: −1.9 percentage points, 95% CI=−5.5 to 1.7 percentage points). Implant monitoring was used in 242 patients. Among them, 65 PVI-only patients (55%) versus 47 PVI+SM patients (39%) experienced recurrences (difference: 15 percentage points, 95% CI=3 to 28 percentage points). CONCLUSIONS: In this randomized trial, PVI plus individualized ablation of atrial low-voltage myocardium significantly improved outcomes in patients with persistent AF. (ClinicalTrials.gov number, NCT02732626.)

Incidence of left atrial abnormalities under treatment with dabigatran, rivaroxaban, and vitamin K antagonists.

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran or rivaroxaban are alternatives to vitamin K antagonists (VKAs) for prevention of stroke and systemic embolism in patients with atrial fibrillation (AF) and atrial flutter (AFL). Incidences of risk factors for left atrium (LA) and left atrial appendage (LAA) thrombus formation, such as dense spontaneous echo contrast (SEC), low LAA velocity (LAAV) <20 cm/s under treatment with dabigatran and rivaroxaban in comparison with VKAs are unknown. METHODS: We studied 306 patients with AF (94 %) and AFL (6 %) undergoing transesophageal echocardiography. Patients received VKAs (n = 138), dabigatran (n = 68), or rivaroxaban (n = 100) for at least 3 weeks prior to investigation. Time in therapeutic range was 67 % for VKA. Mean CHADS2 score and CHA2DS2-VASc score were 1.3 and 2.5, respectively. Left atrial abnormality was defined as either dense SEC, low LAAV <20 cm/s, or thrombus. RESULTS: Any LA abnormality occurred in 9, 3, and 5 % of patients receiving VKA, dabigatran, and rivaroxaban, respectively. The most frequent abnormality was LAA thrombus (VKA: 4 %, dabigatran: 0 %, rivaroxaban: 2 %) and low LAAV of less than 20 cm/s (VKA: 4 %, dabigatran: 1 %, rivaroxaban: 1 %), followed by dense SEC (VKA: 2 %, dabigatran: 1 %, rivaroxaban: 2 %). Results of uni- and multivariate analyses revealed a numerically lower but not significantly different frequency of any LA abnormality under dabigatran (OR 0.4, 95 % Cl 0.08 - 1.88, p = 0.25) and rivaroxaban (OR 0.65, 95 % Cl 0.22 - 1.98, p = 0.45) compared to VKA. CONCLUSION: With respect to the incidence of LA abnormalities, dabigatran and rivaroxaban are not inferior to VKA.