New-Onset Atrial Fibrillation After PCI or CABG for Left Main Disease: The EXCEL Trial

Background: There is limited information on the incidence and prognostic impact of new-onset atrial fibrillation (NOAF) following percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for left main coronary artery disease (LMCAD). Objectives: This study sought to determine the incidence of NOAF following PCI and CABG for LMCAD and its effect on 3-year cardiovascular outcomes. Methods: In the EXCEL (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial, 1,905 patients with LMCAD and low or intermediate SYNTAX scores were randomized to PCI with everolimus-eluting stents versus CABG. Outcomes were analyzed according to the development of NOAF during the initial hospitalization following revascularization. Results: Among 1,812 patients without atrial fibrillation on presentation, NOAF developed at a mean of 2.7 ± 2.5 days after revascularization in 162 patients (8.9%), including 161 of 893 (18.0%) CABG-treated patients and 1 of 919 (0.1%) PCI-treated patients (p < 0.0001). Older age, greater body mass index, and reduced left ventricular ejection fraction were independent predictors of NOAF in patients undergoing CABG. Patients with versus without NOAF had a significantly longer duration of hospitalization, were more likely to be discharged on anticoagulant therapy, and had an increased 30-day rate of Thrombolysis In Myocardial Infarction major or minor bleeding (14.2% vs. 5.5%; p < 0.0001). By multivariable analysis, NOAF after CABG was an independent predictor of 3-year stroke (6.6% vs. 2.4%; adjusted hazard ratio [HR]: 4.19; 95% confidence interval [CI]: 1.74 to 10.11; p = 0.001), death (11.4% vs. 4.3%; adjusted HR: 3.02; 95% CI: 1.60 to 5.70; p = 0.0006), and the primary composite endpoint of death, MI, or stroke (22.6% vs. 12.8%; adjusted HR: 2.13; 95% CI: 1.39 to 3.25; p = 0.0004). Conclusions: In patients with LMCAD undergoing revascularization in the EXCEL trial, NOAF was common after CABG but extremely rare after PCI. The development of NOAF was strongly associated with subsequent death and stroke in CABG-treated patients. Further studies are warranted to determine whether prophylactic strategies to prevent or treat atrial fibrillation may improve prognosis in patients with LMCAD who are undergoing CABG. (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularizatio

[Accepted Manuscript] Left Main Revascularization With PCI or CABG in Patients With Chronic Kidney Disease: EXCEL Trial.

The optimal revascularization strategy for patients with left main coronary artery disease (LMCAD) and chronic kidney disease (CKD) remains unclear. This study investigated the comparative effectiveness of percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) surgery in patients with LMCAD and low or intermediate anatomical complexity according to baseline renal function from the multicenter randomized EXCEL (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial. CKD was defined as an estimated glomerular filtration rate &lt;60 ml/min/1.73 m2 using the CKD Epidemiology Collaboration equation. Acute renal failure (ARF) was defined as a serum creatinine increase ≥5.0 mg/dl from baseline or a new requirement for dialysis. The primary composite endpoint was the composite of death, myocardial infarction (MI), or stroke at 3-year follow-up. CKD was present in 361 of 1,869 randomized patients (19.3%) in whom baseline estimated glomerular filtration rate was available. Patients with CKD had higher 3-year rates of the primary endpoint compared with those without CKD (20.8% vs. 13.5%; hazard ratio [HR]: 1.60; 95% confidence interval [CI]: 1.22 to 2.09; p = 0.0005). ARF within 30 days occurred more commonly in patients with compared with those without CKD (5.0% vs. 0.8%; p &lt; 0.0001), and was strongly associated with the 3-year risk of death, stroke, or MI (50.7% vs. 14.4%; HR: 4.59; 95% CI: 2.73 to 7.73; p &lt; 0.0001). ARF occurred less commonly after revascularization with PCI compared with CABG both in patients with CKD (2.3% vs. 7.7%; HR: 0.28; 95% CI: 0.09 to 0.87) and in those without CKD (0.3% vs. 1.3%; HR: 0.20; 95% CI: 0.04 to 0.90; pinteraction = 0.71). There were no significant differences in the rates of the primary composite endpoint after PCI and CABG in patients with CKD (23.4% vs. 18.1%; HR: 1.25; 95% CI: 0.79 to 1.98) and without CKD (13.4% vs. 13.5%; HR: 0.97; 95% CI: 0.73 to 1.27; pinteraction = 0.38). Patients with CKD undergoing revascularization for LMCAD in the EXCEL trial had increased rates of ARF and reduced event-free survival. ARF occurred less frequently after PCI compared with CABG. There were no significant differences between PCI and CABG in terms of death, stroke, or MI at 3 years in patients with and without CKD. (EXCEL Clinical Trial [EXCEL]; NCT01205776)

Effect of renal denervation in attenuating the stress of morning surge in blood pressure: post-hoc analysis from the SPYRAL HTN-ON MED trial

Background: Catheter-based renal denervation (RDN) reduces blood pressure (BP) throughout the 24-h period, as reported in several randomized sham-controlled trials. Reduction of BP in the early morning hours is especially important due to increased cardiovascular risks during that time. Objective: In this report, we examine the impact of RDN on systolic BP (SBP) and diastolic BP (DBP) during the critical morning surge period in a post-hoc analysis of patients in the SPYRAL HTN-ON MED trial. Methods and results: Ambulatory BP measurements were collected at baseline and 6 months for treatment and control patient groups over 24-h periods. Average morning BP surge is the difference between average morning BP and average nighttime BP, and the morning surge slope reflects the rate of change of BP from nighttime to morning. Mean morning DBP surge slopes were significantly lower for RDN vs. control groups at 6 months (1.1 vs. 3.6 mmHg/h; p = 0.029). In the RDN group, morning DBP surge slopes were significantly lower at 6 months compared to baseline (1.1 vs. 4.1 mmHg/h; p = 0.006). Similar patterns were observed for mean morning SBP surge slope but did not reach statistical significance. Conclusions: This decrease in the morning DBP surge slope, an index of the sympathetically-mediated morning BP surge, thus indicates a drop in late morning BP relative to early morning/nocturnal BP in the RDN group. Thus, RDN appears effective in attenuating the slope of morning surge in DBP that might indicate possible benefits in a high-risk hypertensive population. Clinical trial registration: https://www.clinicaltrials.gov (NCT02439775), registered May 12, 2015. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature

Confounding factors in renal denervation trials: Revisiting old and identifying new challenges in trial design of device therapies for hypertension

Recent randomized sham-controlled trials have demonstrated significant blood pressure reductions following renal denervation (RDN) in patients with hypertension, both in the presence and absence of antihypertensive therapy. These new data encouraged us to revisit previously published insights into potential clinical trial confounding factors that informed the design and conduct of forthcoming trials. Initially identified confounders related to procedural technique, medication variability, and selected patient subgroups have been addressed in contemporary trial design. Regarding procedural method and technology, blood pressure reductions may be improved by ensuring circumferential lesion creation in the distal renal arteries and branch vessels. Safety of the RDN procedure has been demonstrated in multiple independent meta-analyses including thousands of treated patients with low reported rates of renal vessel complications and maintenance of renal function. However, a newer generation of RDN trials has also introduced insights related to medication adherence, patient selection, and the definition of treatment response. Evolving evidence indicates that RDN therapy may be considered in higher risk populations of uncontrolled hypertension regardless of ethnicity and in patients expressing a strong preference for a nondrug therapy option. Despite advances in procedural technique and clinical trial conduct, inconsistent antihypertensive-drug adherence behavior remains perhaps the most critical clinical trial design issue for device-based hypertension therapies. As the balance in clinical equipoise increasingly favors RDN, justification of sham-controlled trial designs will be revisited, and novel study designs may be required to evaluate the safety and efficacy of novel devices and procedures intended to address the escalating prevalence of poorly controlled hypertension. © 2020 International Anesthesia Research Society

Renal Denervation for Treating Hypertension: Current Scientific and Clinical Evidence

Initial studies of catheter-based renal denervation (RDN) for uncontrolled HTN using radiofrequency ablation in the main renal arteries showed that RDN was effective in lowering office blood pressure (BP). However, the first randomized sham-controlled trial, SYMPLICITY-HTN-3, did not show significantly lower office or 24-h ambulatory systolic BP compared with sham treatment. Subsequent studies in both animals and humans demonstrated the potential importance of more distal and branch renal artery radiofrequency ablation, and a second-generation multielectrode system became available. Two recent randomized sham-controlled trials in patients not taking antihypertensive drugs (SPYRAL HTN-OFF MED) or continuing to take drugs (SPYRAL HTN-ON MED) performed RDN with the second-generation radiofrequency ablation system using an ablation protocol that included treatment of the distal renal artery as well as the branch renal arteries. These studies showed that RDN significantly reduced office and 24-h ambulatory BP compared with sham treatment. Another recent randomized sham-controlled trial in patients not receiving medications showed that RDN with catheter-based ultrasound (RADIANCE-HTN SOLO) applied in just the main renal arteries significantly lowered daytime ambulatory and office BP compared with sham treatment. These trials have renewed clinical and scientific interest in defining the appropriate role of RDN in hypertension treatment. In addition, other important issues will need to be addressed in the future such as the development of tests to determine the extent of RDN at the time of the procedure and the potential of renal nerve fibers to regain their patency at some later stage following the ablation procedure. © 2019 American College of Cardiology Foundatio

Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial

Background: Renal denervation has been shown to lower blood pressure in the presence of antihypertensive medications; however, long-term safety and efficacy data from randomised trials of renal denervation are lacking. In this pre-specified analysis of the SPYRAL HTN-ON MED study, we compared changes in blood pressure, antihypertensive drug use, and safety up to 36 months in renal denervation versus a sham control group. Methods: This randomised, single-blind, sham-controlled trial enrolled patients from 25 clinical centres in the USA, Germany, Japan, the UK, Australia, Austria, and Greece, with uncontrolled hypertension and office systolic blood pressure between 150 mm Hg and 180 mm Hg and diastolic blood pressure of 90 mm Hg or higher. Eligible patients had to have 24-h ambulatory systolic blood pressure between 140 mm Hg and less than 170 mm Hg, while taking one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned (1:1) to radiofrequency renal denervation or a sham control procedure. Patients and physicians were unmasked after 12-month follow-up and sham control patients could cross over after 12-month follow-up completion. The primary endpoint was the treatment difference in mean 24-h systolic blood pressure at 6 months between the renal denervation group and the sham control group. Statistical analyses were done on the intention-to-treat population. Long-term efficacy was assessed using ambulatory and office blood pressure measurements up to 36 months. Drug surveillance was used to assess medication use. Safety events were assessed up to 36 months. This trial is registered with ClinicalTrials.gov, NCT02439775; prospectively, an additional 260 patients are currently being randomly assigned as part of the SPYRAL HTN-ON MED Expansion trial. Findings: Between July 22, 2015, and June 14, 2017, among 467 enrolled patients, 80 patients fulfilled the qualifying criteria and were randomly assigned to undergo renal denervation (n=38) or a sham control procedure (n=42). Mean ambulatory systolic and diastolic blood pressure were significantly reduced from baseline in the renal denervation group, and were significantly lower than the sham control group at 24 and 36 months, despite a similar treatment intensity of antihypertensive drugs. The medication burden at 36 months was 2·13 medications (SD 1·15) in the renal denervation group and 2·55 medications (2·19) in the sham control group (p=0·26). 24 (77%) of 31 patients in the renal denervation group and 25 (93%) of 27 patients in the sham control group adhered to medication at 36 months. At 36 months, the ambulatory systolic blood pressure reduction was −18·7 mm Hg (SD 12·4) for the renal denervation group (n=30) and −8·6 mm Hg (14·6) for the sham control group (n=32; adjusted treatment difference −10·0 mm Hg, 95% CI −16·6 to −3·3; p=0·0039). Treatment differences between the renal denervation group and sham control group at 36 months were −5·9 mm Hg (95% CI −10·1 to −1·8; p=0·0055) for mean ambulatory diastolic blood pressure, −11·0 mm Hg (−19·8 to −2·1; p=0·016) for morning systolic blood pressure, and −11·8 mm Hg (−19·0 to −4·7; p=0·0017) for night-time systolic blood pressure. There were no short-term or long-term safety issues associated with renal denervation. Interpretation: Radiofrequency renal denervation compared with sham control produced a clinically meaningful and lasting blood pressure reduction up to 36 months of follow-up, independent of concomitant antihypertensive medications and without major safety events. Renal denervation could provide an adjunctive treatment modality in the management of patients with hypertension. Funding: Medtronic. © 2022 Elsevier Lt