Prospective long-term follow-up of silicone-polyurethane-insulated implantable cardioverter-defibrillator leads.

BACKGROUND: St Jude Medical (now Abbott) Optim-insulated implantable cardioverter-defibrillator (ICD) leads were expected to overcome problems with insulation abrasion and externalized conductors in earlier models. Long-term follow-up is essential to the evaluation of lead performance. OBJECTIVE: To determine, in a prospective cohort of Optim-insulated ICD leads, the rates of all-cause mechanical failure and its subtypes (conductor fracture, insulation abrasion, externalized conductors, and other mechanical failures) and electrical dysfunction adjudicated as nonmechanical failure. METHODS: Abbott established 3 prospective registries, enrolling 11,155 leads among 10,872 patients beginning in 2006. There was standardized baseline documentation, 6-monthly follow-up, adverse events reporting, and documentation of lead revision or inactivation, study withdrawal, and death or transplant. The Population Health Institute (McMaster University) reviewed database functions, adjudicated all potential mechanical lead failures, and conducted independent data analyses. RESULTS: During a median follow-up of 4.6 years, there were 171 mechanical failures (1.53%, 95.4% freedom from failure by 12 years). There were no significant differences in survival among Durata DF4 and DF1 and Riata ST Optim leads. The year-to-year rate of failure of leads increased over time. There were 69 electrical dysfunctions (0.62%, 98.8% freedom from failure by 12 years) adjudicated as nonmechanical failure. CONCLUSION: During follow-up as long as 12 years (median 4.6 years), Optim-insulated leads had low rates of mechanical failure and electrical dysfunction. Independent analyses provide reliable data on the long-term outcomes essential to analyzing ICD lead performance.

Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source.

BACKGROUND: Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin. METHODS: We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding. RESULTS: A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001). CONCLUSIONS: Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).

Characterization of Patients with Embolic Strokes of Undetermined Source in the NAVIGATE ESUS Randomized Trial.

BACKGROUND: The New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) trial is a randomized phase-III trial comparing rivaroxaban versus aspirin in patients with recent ESUS. AIMS: We aimed to describe the baseline characteristics of this large ESUS cohort to explore relationships among key subgroups. METHODS: We enrolled 7213 patients at 459 sites in 31 countries. Prespecified subgroups for primary safety and efficacy analyses included age, sex, race, global region, stroke or transient ischemic attack prior to qualifying event, time to randomization, hypertension, and diabetes mellitus. RESULTS: Mean age was 66.9 ± 9.8 years; 24% were under 60 years. Older patients had more hypertension, coronary disease, and cancer. Strokes in older subjects were more frequently cortical and accompanied by radiographic evidence of prior infarction. Women comprised 38% of participants and were older than men. Patients from East Asia were oldest whereas those from Latin America were youngest. Patients in the Americas more frequently were on aspirin prior to the qualifying stroke. Acute cortical infarction was more common in the United States, Canada, and Western Europe, whereas prior radiographic infarctions were most common in East Asia. Approximately forty-five percent of subjects were enrolled within 30 days of the qualifying stroke, with earliest enrollments in Asia and Eastern Europe. CONCLUSIONS: NAVIGATE-ESUS is the largest randomized trial comparing antithrombotic strategies for secondary stroke prevention in patients with ESUS. The study population encompasses a broad array of patients across multiple continents and these subgroups provide ample opportunities for future research.

Dabigatran etexilate and reduction in serum apolipoprotein B.

OBJECTIVE: Carboxylesterases, which convert dabigatran etexilate to its active form, dabigatran, have also been shown to influence lipoprotein metabolism, although any pleotropic effects of the drug based on this possible mechanism has not been evaluated. We examined the effects of dabigatran etexilate on serum lipoprotein markers in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study. METHODS: 2513 participants from the RE-LY randomised control trial with baseline and 3-month apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1) measurements were included. We prospectively compared the effects of dabigatran 110 mg twice daily, dabigatran 150 mg twice daily and warfarin on changes in ApoB and ApoA1 concentrations using a mixed model analysis. RESULTS: From baseline to 3 months, a significant reduction in ApoB concentration was observed with low-dose dabigatran (-0.057 (95% CI -0.069 to -0.044) g/L, p<0.001) and high-dose dabigatran (-0.065 (95% CI -0.078 to -0.053) g/L, p<0.001) but not warfarin (-0.006 g/L (95% CI -0.018 to 0.007) g/L, p=0.40). Compared with warfarin, ApoB reduction was significantly greater with both doses of dabigatran (p<0.001 for both groups). Reductions in ApoA1 concentrations did not statistically differ with either dose of dabigatran when compared with warfarin. CONCLUSIONS: Dabigatran is associated with a significant (∼7%) reduction in ApoB concentration, suggesting a novel effect of this drug on lipoprotein metabolism. Further studies are needed to determine the mechanism of this observed effect, and its impact on clinical outcomes.

Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: Design of the NAVIGATE ESUS randomized trial.

BACKGROUND: Embolic strokes of undetermined source comprise up to 20% of ischemic strokes. The stroke recurrence rate is substantial with aspirin, widely used for secondary prevention. The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source international trial will compare the efficacy and safety of rivaroxaban, an oral factor Xa inhibitor, versus aspirin for secondary prevention in patients with recent embolic strokes of undetermined source. MAIN HYPOTHESIS: In patients with recent embolic strokes of undetermined source, rivaroxaban 15 mg once daily will reduce the risk of recurrent stroke (both ischemic and hemorrhagic) and systemic embolism (primary efficacy outcome) compared with aspirin 100 mg once daily. DESIGN: Double-blind, randomized trial in patients with embolic strokes of undetermined source, defined as nonlacunar cryptogenic ischemic stroke, enrolled between seven days and six months from the qualifying stroke. The planned sample size of 7000 participants will be recruited from approximately 480 sites in 31 countries between 2014 and 2017 and followed for a mean of about two years until at least 450 primary efficacy outcome events have occurred. The primary safety outcome is major bleeding. Two substudies assess (1) the relative effect of treatments on MRI-determined covert brain infarcts and (2) the biological underpinnings of embolic strokes of undetermined source using genomic and biomarker approaches. SUMMARY: The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source trial is evaluating the benefits and risks of rivaroxaban for secondary stroke prevention in embolic strokes of undetermined source patients. Main results are anticipated in 2018.

Prospective long-term evaluation of Optim-insulated (Riata ST Optim and Durata) implantable cardioverter-defibrillator leads.

BACKGROUND: St Jude Medical Optim-insulated implantable cardioverter-defibrillator leads were designed to impart lubricity, strength, and abrasion resistance while maintaining flexibility and biostability. No long-term prospective follow-up data have been published. OBJECTIVE: The objective of this study was to determine the rates of all-cause mechanical failure and its subtypes (conductor fracture, insulation abrasion, externalized conductors, and other mechanical failures) in a prospective cohort of Optim-insulated implantable cardioverter-defibrillator leads. METHODS: St Jude Medical established 3 prospective registries and enrolled 11,016 leads implanted in 10,835 patients beginning in 2006. There was standardized baseline documentation, 6-monthly follow-up, adverse events reports (verified by expert staff using detailed algorithms), and documentation of lead revisions or inactivation, study withdrawal, and death. The Population Health Research Institute (McMaster University) was engaged to review database functions, adjudicate all potential mechanical lead failures, and conduct independent analyses of the data. RESULTS: During a median follow-up of 3.2 years, there were 51 mechanical failures (0.46%), with 99.0% survival free of this outcome by 5 years of follow-up. Freedom from conductor fracture was identified in 99.4% and from all-cause abrasion in 99.8% of the leads, and there were no reports of externalized conductors. There were no significant differences in survival among Durata DF4, Durata DF1, and Riata ST Optim leads. CONCLUSION: Over a mean follow-up of 3.2 years, Optim-insulated leads have low rates of all-cause mechanical failure and no observed externalized conductors. Independent analyses of these registries are designed to provide reliable long-term follow-up information and are ongoing.

Causes of death and influencing factors in patients with atrial fibrillation: a competing-risk analysis from the randomized evaluation of long-term anticoagulant therapy study.

BACKGROUND: Atrial fibrillation is associated with increased mortality, but the specific causes of death and their predictors have not been described among patients on effective anticoagulant therapy. METHODS AND RESULTS: The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial randomized 18 113 patients (age, 71.5 ± 9 years; male, 64%; CHADS2 score, 2.1 ± 1) to receive dabigatran or warfarin. Median follow-up was 2 years, and complete follow-up was achieved in 99.9% of patients. All deaths were categorized by the investigators using prespecified definitions followed by central adjudication. Overall, 1371 deaths occurred (annual mortality rate, 3.84%; 95% confidence interval [CI], 3.64-4.05). Cardiac deaths (sudden cardiac death and progressive heart failure) accounted for 37.4% of all deaths, whereas stroke- and hemorrhage-related deaths represented 9.8% of the total mortality. An examination of the causes of death according to dabigatran or warfarin showed that dabigatran significantly reduced vascular (embolism and hemorrhage-related) mortality (relative risk, 0.63; 95% CI, 0.45-0.88; P=0.007), whereas other causes of death were similar between treatments, including cardiac mortality (relative risk, 0.96; 95% CI, 0.80-1.15; P=0.638). The two strongest independent predictors of cardiac death in this population were heart failure (hazard ratio, 3.02; 95% CI, 2.45-3.73; P<0.0001), and prior myocardial infarction (hazard ratio, 2.05; 95% CI, 1.61-2.62; P<0.0001). CONCLUSIONS: The majority of deaths are not related to stroke in a contemporary anticoagulated atrial fibrillation population. These results emphasize the need to identify interventions beyond effective anticoagulation to further reduce mortality in atrial fibrillation. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.

Relevance of electrical remodeling in human atrial fibrillation: results of the Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial mechanisms of atrial fibrillation study.

BACKGROUND: In animal models of atrial fibrillation (AF), changes in atrial electrophysiological properties are associated with the development of AF. Their relevance to human AF is unclear. METHODS AND RESULTS: The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial enrolled 2580 patients receiving a dual-chamber pacemaker, who were older than the age of 65 and had a history of hypertension, but no history of AF. Serial noninvasive electrophysiological testing was performed over 2 years in a subgroup of 485 patients. There were no differences in the clinical characteristics between patients with and those without device-detected atrial tachyarrhythmias during the first year. Patients with atrial tachyarrhythmias had longer paced (153±29 versus 145±28 ms; P=0.046) and sensed (128±46 versus 118±25 ms; P=0.06) P-wave durations and were more likely to have AF induced during electrophysiological testing (23.5% versus 13.6%; P=0.03). They had similar corrected sinus node recovery times at 90 bpm (388±554 versus 376 ± 466 ms; P=0.86), atrial effective refractory periods at 90 bpm (250±32 versus 248±36 ms; P=0.70), and rate-adaptive shortening of the atrial effective refractory periods (14±13 versus 12±14 ms; P=0.11). There were no significant differences in the change in electrophysiological properties over 2 years between patients with and those without atrial tachyarrhythmias. CONCLUSIONS: Prolonged P-wave duration, but not differences in atrial effective refractory periods, was associated with the development of atrial tachyarrhythmias in pacemaker patients.

Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial.

BACKGROUND: Dabigatran reduces ischemic stroke in comparison with warfarin; however, given the lack of antidote, there is concern that it might increase bleeding when surgery or invasive procedures are required. METHODS AND RESULTS: The current analysis was undertaken to compare the periprocedural bleeding risk of patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial treated with dabigatran and warfarin. Bleeding rates were evaluated from 7 days before until 30 days after invasive procedures, considering only the first procedure for each patient. A total of 4591 patients underwent at least 1 invasive procedure: 24.7% of patients received dabigatran 110 mg, 25.4% received dabigatran 150 mg, and 25.9% received warfarin, P=0.34. Procedures included: pacemaker/defibrillator insertion (10.3%), dental procedures (10.0%), diagnostic procedures (10.0%), cataract removal (9.3%), colonoscopy (8.6%), and joint replacement (6.2%). Among patients assigned to either dabigatran dose, the last dose of study drug was given 49 (35-85) hours before the procedure on comparison with 114 (87-144) hours in patients receiving warfarin, P<0.001. There was no significant difference in the rates of periprocedural major bleeding between patients receiving dabigatran 110 mg (3.8%) or dabigatran 150 mg (5.1%) or warfarin (4.6%); dabigatran 110 mg versus warfarin: relative risk, 0.83; 95% CI, 0.59 to 1.17; P=0.28; dabigatran 150 mg versus warfarin: relative risk, 1.09; 95% CI, 0.80 to 1.49; P=0.58. Among patients having urgent surgery, major bleeding occurred in 17.8% with dabigatran 110 mg, 17.7% with dabigatran 150 mg, and 21.6% with warfarin: dabigatran 110 mg; relative risk, 0.82; 95% CI, 0.48 to 1.41; P=0.47; dabigatran 150 mg: relative risk, 0.82; 95% CI, 0.50 to 1.35; P=0.44. CONCLUSIONS: Dabigatran and warfarin were associated with similar rates of periprocedural bleeding, including patients having urgent surgery. Dabigatran facilitated a shorter interruption of oral anticoagulation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.

Subclinical atrial fibrillation and the risk of stroke.

BACKGROUND: One quarter of strokes are of unknown cause, and subclinical atrial fibrillation may be a common etiologic factor. Pacemakers can detect subclinical episodes of rapid atrial rate, which correlate with electrocardiographically documented atrial fibrillation. We evaluated whether subclinical episodes of rapid atrial rate detected by implanted devices were associated with an increased risk of ischemic stroke in patients who did not have other evidence of atrial fibrillation. METHODS: We enrolled 2580 patients, 65 years of age or older, with hypertension and no history of atrial fibrillation, in whom a pacemaker or defibrillator had recently been implanted. We monitored the patients for 3 months to detect subclinical atrial tachyarrhythmias (episodes of atrial rate >190 beats per minute for more than 6 minutes) and followed them for a mean of 2.5 years for the primary outcome of ischemic stroke or systemic embolism. Patients with pacemakers were randomly assigned to receive or not to receive continuous atrial overdrive pacing. RESULTS: By 3 months, subclinical atrial tachyarrhythmias detected by implanted devices had occurred in 261 patients (10.1%). Subclinical atrial tachyarrhythmias were associated with an increased risk of clinical atrial fibrillation (hazard ratio, 5.56; 95% confidence interval [CI], 3.78 to 8.17; P<0.001) and of ischemic stroke or systemic embolism (hazard ratio, 2.49; 95% CI, 1.28 to 4.85; P=0.007). Of 51 patients who had a primary outcome event, 11 had had subclinical atrial tachyarrhythmias detected by 3 months, and none had had clinical atrial fibrillation by 3 months. The population attributable risk of stroke or systemic embolism associated with subclinical atrial tachyarrhythmias was 13%. Subclinical atrial tachyarrhythmias remained predictive of the primary outcome after adjustment for predictors of stroke (hazard ratio, 2.50; 95% CI, 1.28 to 4.89; P=0.008). Continuous atrial overdrive pacing did not prevent atrial fibrillation. CONCLUSIONS: Subclinical atrial tachyarrhythmias, without clinical atrial fibrillation, occurred frequently in patients with pacemakers and were associated with a significantly increased risk of ischemic stroke or systemic embolism. (Funded by St. Jude Medical; ASSERT ClinicalTrials.gov number, NCT00256152.).

Dabigatran versus warfarin in patients with atrial fibrillation.

BACKGROUND: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. METHODS: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. RESULTS: Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). CONCLUSIONS: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.)

Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran.

Vitamin K antagonists (VKAs) are effective for stroke prevention in patients with atrial fibrillation (AF) but are difficult to use. Dabigatran etexilate is a prodrug that is rapidly converted to the active direct thrombin inhibitor dabigatran. It is administered in a fixed dose without laboratory monitoring and is being compared with warfarin (international normalized ratio 2-3) in the RE-LY trial. Two doses of dabigatran (110 and 150 mg BID) are being evaluated. RE-LY is a phase 3, prospective, randomized, open-label multinational (44 countries) trial of patients with nonvalvular AF and at least 1 risk factor for stroke. Recruitment concluded with a total of 18,113 patients. Patients who were VKA-naive and experienced are included in balanced proportions. The primary outcome is stroke (including hemorrhagic) or systemic embolism. Safety outcomes are bleeding, liver function abnormalities, and other adverse events. Adjudication of end points is blinded to drug assignment. The trial is expected to accrue a minimum of 450 events with a minimum 1-year of follow-up. RE-LY is the largest AF stroke prevention trial yet undertaken. It is unique because it includes equal numbers of VKA-experienced and naive patients and evaluates 2 different dosages of dabigatran, which may allow tailoring of dosing to individual patient needs. The worldwide site distribution and broad range of stroke risk further increase the general applicability of the trial. Results are expected in 2009.