Comparative Effectiveness and Safety of Low-Dose Oral Anticoagulants in Patients With Atrial Fibrillation

Aims: Observational studies of various dose levels of direct oral anticoagulants (DOACs) for patients with atrial fibrillation (AF) found that a high proportion of patients received a dose lower than the target dose tested in randomized controlled trials. There is a need to compare low-dose DOACs with warfarin or other DOACs on effectiveness and safety.Methods: Using administrative data from Quebec province, Canada, we built a cohort of new warfarin or DOAC users discharged from hospital between 2011 and 2017. We determined CHA2DS2-VASc and HAS-BLED scores, and comorbidities for 3-year prior cohort entry. The primary effectiveness endpoint was a composite of ischemic stroke/systemic embolism (SE), and secondary outcomes included a safety composite of major bleeding (MB) events and effectiveness composite (stroke/SE, death) at 1-year follow-up. We contrasted each low-dose DOAC with warfarin or other DOACs as references using inverse probability of treatment weighting to estimate marginal Cox hazard ratios (HRs).Results: The cohort comprised 22,969 patients (mean age: 80–86). We did not find a significant risk reduction for the stroke/SE primary effectiveness endpoint for DOACs vs. warfarin; however, we observed a significantly lower risk for low-dose dabigatran vs. warfarin (HR [95%CI]: 0.59 [0.42–0.81]) for effectiveness composite, mainly due to a lower death rate. The differences in effectiveness and safety composites between low-dose rivaroxaban vs. warfarin were not significant. However, low-dose apixaban had a better safety composite (HR: 0.68 [0.53–0.88]) vs. warfarin. Comparisons of dabigatran vs. apixaban showed a lower risk of stroke/SE (HR: 0.53 [0.30–0.93]) and a 2-fold higher risk of MB. The MB risk was higher for rivaroxaban than for apixaban (HR: 1.58 [1.09–2.29]).Conclusions: The results of this population-based study suggest that low-dose dabigatran has a better effective composite than warfarin. Compared with apixaban, low-dose dabigatran had a better effectiveness composite but a worse safety profile. Low-dose apixaban had a better safety composite than warfarin and other low-dose DOACs. Given that the comparative effectiveness and safety seem to vary from one DOAC to another, pharmacokinetic data for specific populations are now warranted.

Monitoring the Effectiveness and Safety of ARNI vs. Angiotensin Receptor Blocker by Frailty Status

Using Medicare data 2015-2017, we conducted 5 sequential 1-to-1 propensity score-matched analyses of ARNI initiators and angiotensin receptor blockers (ARB) initiators, mimicking the accrual of new data every 6 months. Primary effectiveness endpoint was a composite of heart failure hospitalization or all-cause mortality and primary safety endpoint was a composite of hospitalization or emergency department visits for hypotension, acute kidney injury, hyperkalemia, and angioedema. Among non-frail patients (n=5,014), the rates (per 100 person-years) for ARNI vs ARB were 12.7 and 9.2 (rate difference: 3.4, 95% CI: 0.8 to 6.1), respectively, for the effectiveness endpoint and 5.2 and 3.6 (rate difference: 1.5, 95% CI: -0.1 to 3.2), respectively, for the safety endpoint. Among frail patients (n=2,694), the corresponding rates were 19.8 and 21.6 (rate difference: -1.8, 95% CI: -7.0 to 3.4) for the effectiveness endpoint and 10.9 and 8.0 (rate difference: 2.9, 95% CI: -0.6 to 6.4) for the safety endpoint.

Safety and efficacy results of the Flow Redirection Endoluminal Device (FRED) stent system in the treatment of intracranial aneurysms: US pivotal trial

ObjectiveTo evaluate the safety and effectiveness of the Flow Redirection Endoluminal Device (FRED) flow diverter in support of an application for Food and Drug Administration approval in the USA.Methods145 patients were enrolled in a prospective, single-arm multicenter trial. Patients with aneurysms of unfavorable morphology for traditional endovascular therapies (large, wide-necked, fusiform, etc) were included. The trial was designed to demonstrate non-inferiority in both safety and effectiveness, comparing trial results with performance goals (PGs) established from peer-reviewed published literature. The primary safety endpoint was death or major stroke (National Institutes of Health Stroke Scale score ≥4 points) within 30 days of the procedure, or any major ipsilateral stroke or neurological death within the first year. The primary effectiveness endpoint was complete occlusion of the target aneurysm with ≤50% stenosis of the parent artery at 12 months after treatment, and in which an alternative treatment of the target intracranial aneurysm had not been performed.Results145 patients underwent attempted placement of a FRED device, and one or more devices were placed in all 145 patients. 135/145 (93%) had a single device placed. Core laboratory adjudication deemed 106 (73.1%) of the aneurysms large or giant. A safety endpoint was experienced by 9/145 (6.2%) patients, successfully achieving the safety PG of <15%. The effectiveness PG of >46% aneurysm occlusion was also achieved, with the effectiveness endpoint being met in 80/139 (57.6%)ConclusionAs compared with historically derived performance benchmarks, the FRED flow diverter is both safe and effective for the treatment of appropriately selected intracranial aneurysms.Clinical registration numberNCT01801007

Optimal strategy for antiplatelet therapy after coronary drug-eluting stent implantation in high-risk "TWILIGHT-like" patients with diabetes mellitus

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Chinese College of Cardiovascular Physicians, CS Optimizing Antithrombotic Research Fund (Grant No. BJUHFCSOARF201801-01), the National Key Research and Development Program of China (Grant No. 2018YFC1315602), the Beijing Municipal Health Commission (Grant No. 2020-1-4032), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (Grant No. 2016-I2M-1-009), and the National Natural Science Foundation of China (Grant No. 81870277). Background Patients with diabetes mellitus (DM) are known to be at high-risk for both ischemic and bleeding complications post-percutaneous coronary intervention (PCI). The ischemic benefit versus bleeding risk associated with extended dual antiplatelet therapy (DAPT) in high-risk "TWILIGHT-like" patients with diabetes mellitus after PCI has not been established. Methods All consecutive high-risk patients fulfilling the "TWILIGHT-like" criteria undergoing PCI from January 2013 through December 2013 were identified from prospective Fuwai PCI Registry. High-risk "TWILIGHT-like" patients were defined by at least 1 clinical and 1 angiographic feature based on TWILIGHT trial selection criteria. The present analysis evaluated 3425 diabetics patients with concomitant high-risk angiographic features who were event-free at 1 year after PCI. Median follow-up was 2.4 years. The primary effectiveness endpoint was a composite of death, myocardial infarction, or stroke (termed major adverse cardiac and cerebrovascular events) and primary safety endpoint was clinically relevant bleeding according to Bleeding Academic Research Consortium type 2, 3, or 5. Results On inverse probability of treatment weighting (IPTW) analysis, prolonged-term (&gt;1-year) DAPT with aspirin and clopidogrel decreased the risk of primary effectiveness endpoint compared with shorter (≤1-year) DAPT (1.8% vs. 4.3%; hazard ratio [HR]IPTW: 0.381; 95% confidence interval [CI]: 0.252-0.576; P &lt; 0.001) and reduced cardiovascular death (0.1% vs. 1.8%; HRIPTW: 0.056 [0.016-0.193]). Prolonged DAPT was also associated with a reduced risk of definite/probable stent thrombosis (0.2% vs. 0.7%; HRIPTW: 0.258 [0.083-0.802]), and non-significantly lower rate of myocardial infarction (0.5% vs. 0.8%; HRIPTW: 0.676 [0.275-1.661]). There was no significant difference between groups in clinically relevant bleeding (1.1% vs. 1.1%; HRIPTW: 1.078 [0.519-2.241]; P = 0.840). Similar results were observed in multivariable Cox proportional hazards regression model. Conclusion Among high-risk PCI patients with diabetes mellitus without an adverse event through 1 year, extending DAPT &gt; 1-year significantly reduced the risk of major adverse cardiac and cerebrovascular events without an increase in clinically relevant bleeding, suggesting that such high-risk diabetic patients may be good candidates for long-term DAPT. Abstract Figure.

Primary Outcome Evaluation of a Next Generation Left Atrial Appendage Closure Device: Results from the PINNACLE FLX Trial

Background: Left atrial appendage (LAA) occlusion provides an alternative to oral anticoagulation (OAC) for thromboembolic risk reduction in patients with non-valvular atrial fibrillation (NVAF). Since regulatory approval in 2015, the WATCHMAN device has been the only LAA closure device available for clinical use in the United States. The PINNACLE FLX study evaluated the safety and effectiveness of the next-generation WATCHMAN FLX LAA closure device in patients with NVAF in whom OAC is indicated, but who have an appropriate rationale to seek a non-pharmaceutical alternative. Methods: This was a prospective, non-randomized, multi-center FDA study. The primary safety endpoint was the occurrence of one of the following events within 7 days post-procedure or by hospital discharge, whichever was later: death, ischemic stroke, systemic embolism, or device- or procedure-related events requiring cardiac surgery. The primary effectiveness endpoint was the incidence of effective LAA closure (peri-device flow ≤5mm), as assessed by the echocardiography core laboratory at 12-month follow-up. Results: A total of 400 patients were enrolled. The mean age was 73.8{plus minus}8.6 years and the mean CHA2DS2-VASc score was 4.2{plus minus}1.5. The incidence of the primary safety endpoint was 0.5% with a one-sided 95% upper confidence interval (CI) of 1.6%, meeting the performance goal (PG) of 4.2% (P<0.0001). The incidence of the primary effectiveness endpoint was 100%, with a onesided 95% lower CI of 99.1%, again meeting the PG of 97.0% (P<0.0001). Device-related thrombus was reported in 7 patients, no patients experienced pericardial effusion requiring open cardiac surgery, and there were no device embolizations. Conclusions: LAA closure with this next generation LAA closure device was associated with a low incidence of adverse events and a high incidence of anatomic closure. Clinical Trial Registration: URL https://clinicaltrials.gov Unique Identifier NCT02702271

Optimal Strategy for Antiplatelet Therapy After Coronary Drug-Eluting Stent Implantation in High-Risk “TWILIGHT-like” Patients With Diabetes Mellitus

Background: Patients with diabetes mellitus (DM) are known to be at high-risk for both ischemic and bleeding complications post-percutaneous coronary intervention (PCI). The ischemic benefit vs. bleeding risk associated with extended dual antiplatelet therapy (DAPT) in high-risk “TWILIGHT-like” patients with diabetes mellitus after PCI has not been established.Methods: All consecutive high-risk patients fulfilling the “TWILIGHT-like” criteria undergoing PCI from January 2013 through December 2013 were identified from the prospective Fuwai PCI Registry. High-risk “TWILIGHT-like” patients were defined by at least one clinical and one angiographic feature based on the TWILIGHT trial selection criteria. The present analysis evaluated 3,425 diabetic patients with concomitant high-risk angiographic features who were event-free at 1 year after PCI. Median follow-up was 2.4 years. The primary effectiveness endpoint was a composite of death, myocardial infarction, or stroke (termed major adverse cardiac and cerebrovascular events), and primary safety endpoint was clinically relevant bleeding according to the Bleeding Academic Research Consortium types 2, 3, or 5.Results: On inverse probability of treatment weighting (IPTW) analysis, prolonged-term (&gt;1-year) DAPT with aspirin and clopidogrel decreased the risk of primary effectiveness endpoint compared with shorter ( ≤ 1-year) DAPT [1.8 vs. 4.3%; hazard ratio (HR)IPTW: 0.381; 95% confidence interval (CI): 0.252–0.576; P &lt; 0.001] and reduced cardiovascular death [0.1% vs. 1.8%; HRIPTW: 0.056 (0.016–0.193)]. Prolonged DAPT was also associated with a reduced risk of definite/probable stent thrombosis [0.2 vs. 0.7%; HRIPTW: 0.258 (0.083–0.802)] and non-significantly lower rate of myocardial infarction [0.5 vs. 0.8%; HRIPTW: 0.676 (0.275–1.661)]. There was no significant difference between groups in clinically relevant bleeding [1.1 vs. 1.1%; HRIPTW: 1.078 (0.519–2.241); P = 0.840). Similar results were observed in multivariable Cox proportional hazards regression model.Conclusion: Among high-risk PCI patients with diabetes mellitus without an adverse event through 1 year, extending DAPT &gt;1-year significantly reduced the risk of major adverse cardiac and cerebrovascular events without an increase in clinically relevant bleeding, suggesting that such high-risk diabetic patients may be good candidates for long-term DAPT.

Three-Year Results of the IN.PACT SFA Japan Trial Comparing Drug-Coated Balloons With Percutaneous Transluminal Angioplasty

Purpose: To evaluate the 3-year safety and effectiveness of the MDT-2113 (IN.PACT Admiral) drug-coated balloon (DCB) vs percutaneous transluminal angioplasty (PTA) in a Japanese population with femoropopliteal occlusive disease. Materials and Methods: The multicenter, prospective, IN.PACT SFA Japan randomized controlled trial ( ClinicalTrials.gov identifier NCT01947478) was an independently adjudicated study evaluating Japanese participants randomized 2:1 to DCB (n=68) or PTA (n=32). The effectiveness endpoint was primary patency through 36 months, defined as freedom from clinically-driven target lesion revascularization (CD-TLR) and freedom from restenosis (by duplex ultrasound). The effectiveness endpoint was evaluated using the Kaplan-Meier method; estimates are presented with the 95% confidence intervals (CIs). The safety composite endpoint was freedom from device- and procedure-related death through 30 days and freedom from major target limb amputation and clinically-driven target vessel revascularization through 36 months. Results: Primary patency by Kaplan-Meier estimate was higher in the DCB group (68.9%, 95% CI 57.5% to 80.2%) vs the PTA group (46.9%, 95% CI 29.6% to 64.2%) at 36 months (log-rank p=0.001). The CD-TLR rates were 14.9% (10/67) for the DCB group and 20.7% (6/29) for PTA (p=0.554). The safety composite endpoint occurred in 83.6% (56/67) of DCB participants and 75.9% (22/29) of PTA participants (p=0.402). All-cause death was similar between groups at 36 months [DCB 6.0% (4/67) vs PTA 6.9% (2/29), p>0.999), with no device- or procedure-related deaths in either group. Conclusion: The final report of the IN.PACT SFA Japan trial showed that the IN.PACT Admiral DCB is safe and had durable outcomes through 3 years in Japanese participants with femoropopliteal occlusive disease.

The industrialization of ablation: a highly standardized and reproducible workflow for radiofrequency ablation of atrial fibrillation

Background or Purpose The purpose of this analysis was to report on efficacy of a standardized workflow for atrial fibrillation (AF) ablation using technology advances such as 3D imaging and contact force sensing in a real-world setting. Methods Consecutive AF ablations from 2014 to 2015 at a high-volume site in Belgium were included. The workflow consisted of a pre-specified procedure sequence including 3D modeling followed by radiofrequency encircling of the pulmonary veins (25 W posterior wall, 35 W anterior wall) with a THERMOCOOL SMARTTOUCH® Catheter guided by CARTO VISITAG™ Module (2.5 mm/5 s stability, 50% > 7 g) and ablation index (targets: 550 anterior wall, 400 posterior wall). Efficiency endpoints were procedure time, fluoroscopy time, and radiation dose. The primary effectiveness endpoint was freedom from atrial arrhythmia recurrence. Results A total of 605 paroxysmal AF (PAF) and 182 persistent AF (PsAF) patients were followed for 436 ± 199 days. Mean procedure times were short (PAF: 96.1 ± 26.2 min; PsAF: 109.2 ± 35.6 min) with most procedures (90.6% PAF; 81.3% PsAF) completed in ≤ 120 min. Minimal fluoroscopy was utilized (PAF: 6.1 ± 3.8 min, 5.9 ± 3.4 Gy*cm2; PsAF: 6.9 ± 4.7 min, 7.4 ± 4.9 Gy*cm2). Freedom from atrial arrhythmia recurrence was higher for PAF than PsAF patients (OR: 2.0, 95% CI: 1.4–2.9, p = 0.0003), but adjusted mean rates were high in both groups (81.0% vs. 67.9%). Rates were adjusted for prior ablation and age (at 65 years). Conclusion AF ablation using a standardized workflow resulted in low procedure times and variability, with minimal fluoroscopy exposure. Long-term freedom from atrial arrhythmia recurrence was high in both PAF and PsAF populations.

Prospective study on embolization of intracranial aneurysms with the pipeline device: the PREMIER study 1 year results

BackgroundPreliminary clinical studies on the safety and efficacy of the pipeline embolization device (PED) for the treatment of small/medium aneurysms have demonstrated high occlusion rates with low complications.ObjectiveTo evaluate the safety and effectiveness of the PED for treatment of wide necked small and medium intracranial aneurysms.MethodsPREMIER is a prospective, multicenter, single arm trial. Patients were treated with the PED for unruptured wide necked aneurysms, measuring ≤12 mm along the internal carotid artery or vertebral artery, between July 2014 and November 2015. At 1 year post-procedure, the primary effectiveness endpoint was complete occlusion (Raymond grade 1) without major parent vessel stenosis (≤50%) or retreatment, and the primary safety endpoint was major stroke in the territory supplied by the treated artery or neurologic death.ResultsA total of 141 patients were treated with PEDs (mean age 54.6±11.3 years, 87.9% (124/141) women). Mean aneurysm size was 5.0±1.92 mm, and 84.4% (119/141) measured <7 mm. PED placement was successful in 99.3% (140/141) of patients. Mean number of PEDs implanted per patient was 1.1±0.26; a single PED was used in 92.9% (131/141) of patients. At 1 year, 97.9% (138/141) of patients underwent follow-up angiography with 76.8% (106/138) of patients having met the study’s primary effectiveness endpoint. The combined major morbidity and mortality rate was 2.1% (3/140).ConclusionsTreatment of wide necked small/medium aneurysms with the PED results in high rates of complete occlusion without significant parent vessel stenosis and low rates of permanent neurologic complications.Trial registrationNCT02186561.