Long-Term Treatment with the Combination of Rivaroxaban and Aspirin in Patients with Chronic Coronary or Peripheral Artery Disease: Outcomes During the Open Label Extension of the COMPASS trial.

AIMS: To describe outcomes of patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) randomized trial who were treated with the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily during long-term open-label extension (LTOLE). METHODS AND RESULTS: Of the 27 395 patients enrolled in COMPASS, 12 964 (mean age at baseline 67.2 years) from 455 sites in 32 countries were enrolled in LTOLE and treated with the combination of rivaroxaban and aspirin for a median of 374 additional days (range 1-1191 days). During LTOLE, the incident events per 100 patient years were as follows: for the primary outcome [cardiovascular death, stroke, or myocardial infarction (MI)] 2.35 [95% confidence interval (CI) 2.11-2.61], mortality 1.87 (1.65-2.10), stroke 0.62 (0.50-0.76), and MI 1.02 (0.86-1.19), with CIs that overlapped those seen during the randomized treatment phase with the combination of rivaroxaban and aspirin. The incidence rates for major and minor bleeding were 1.01 (0.86-1.19) and 2.49 (2.24-2.75), compared with 1.67 (1.48-1.87) and 5.11 (95% CI 4.77-5.47), respectively, during the randomized treatment phase with the combination. CONCLUSION: In patients with chronic CAD and/or PAD, extended combination treatment for a median of 1 year and a maximum of 3 years was associated with incidence rates for efficacy and bleeding that were similar to or lower than those seen during the randomized treatment phase, without any new safety signals.

Rivaroxaban for Prevention of Covert Brain Infarcts and Cognitive Decline: The COMPASS MRI Substudy.

BACKGROUND AND PURPOSE: Covert brain infarcts are associated with cognitive decline. It is not known whether therapies that prevent symptomatic stroke prevent covert infarcts. COMPASS compared rivaroxaban with and without aspirin with aspirin for the prevention of stroke, myocardial infarction, and vascular death in participants with stable vascular disease and was terminated early because of benefits of rivaroxaban 2.5 mg twice daily plus aspirin over aspirin. We obtained serial magnetic resonance imagings and cognitive tests in a consenting subgroup of COMPASS patients to examine treatment effects on infarcts, cerebral microbleeds, and white matter hyperintensities. METHODS: Baseline and follow-up magnetic resonance imagings were completed in 1445 participants with a mean (SD) interval of 2.0 (0.7) years. Whole-brain T1, T2 fluid-attenuated inversion recovery, T2* sequences were centrally interpreted by blinded, trained readers. Participants had serial measurements of cognition and function. The primary end point was the proportion of participants with incident covert infarcts. Secondary end points were the composite of clinical stroke and covert brain infarcts, cerebral microbleeds, and white matter hyperintensities. RESULTS: At baseline, 493 (34.1%) participants had infarcts. Incident covert infarcts occurred in 55 (3.8%) participants. In the overall trial rivaroxaban plus aspirin reduced ischemic stroke by 49% (0.7% versus 1.4%; hazard ratio [95% CI], 0.51 [0.38-0.68]). In the magnetic resonance imaging substudy the effects of rivaroxaban+aspirin versus aspirin were: covert infarcts: 2.7% versus 3.5% (odds ratio [95% CI], 0.77 [0.37-1.60]); Covert infarcts or ischemic stroke: 2.9% versus 5.3% (odds ratio [95% CI], 0.53 [0.27-1.03]). Incident microbleeds occurred in 6.6% of participants and 65.7% of participants had an increase in white matter hyperintensities volume with no effect of treatment for either end point. There was no effect on cognitive tests. CONCLUSIONS: Covert infarcts were not significantly reduced by treatment with rivaroxaban and aspirin but estimates for the combination of ischemic stroke and covert infarcts were consistent with the effect on ischemic stroke in the overall trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.

Rationale, design, and baseline participant characteristics in the MRI and cognitive substudy of the cardiovascular outcomes for people using anticoagulation strategies trial.

BACKGROUND: Covert vascular disease of the brain manifests as infarcts, white matter hyperintensities, and microbleeds on MRI. Their cumulative effect is often a decline in cognition, motor impairment, and psychiatric disorders. Preventive therapies for covert brain ischemia have not been established but represent a huge unmet clinical need. AIMS: The MRI substudy examines the effects of the antithrombotic regimens in COMPASS on incident covert brain infarcts (the primary outcome), white matter hyperintensities, and cognitive and functional status in a sample of consenting COMPASS participants without contraindications to MRI. METHODS: COMPASS is a randomized superiority trial testing rivaroxaban 2.5 mg bid plus acetylsalicylic acid 100 mg and rivaroxaban 5 mg bid against acetylsalicylic acid 100 mg per day for the combined endpoint of MI, stroke, and cardiovascular death in individuals with stable coronary artery disease or peripheral artery disease. T1-weighted, T2-weighted, T2*-weighted, and FLAIR images were obtained close to randomization and near the termination of assigned antithrombotic therapy; biomarker and genetic samples at randomization and one month, and cognitive and functional assessment at randomization, after two years and at the end of study. RESULTS: Between March 2013 and May 2016, 1905 participants were recruited from 86 centers in 16 countries. Of these participants, 1760 underwent baseline MRI scans that were deemed technically adequate for interpretation. The mean age at entry of participants with interpretable MRI was 71 years and 23.5% were women. Coronary artery disease was present in 90.4% and 28.1% had peripheral artery disease. Brain infarcts were present in 34.8%, 29.3% had cerebral microbleeds, and 93.0% had white matter hyperintensities. The median Montreal Cognitive Assessment score was 26 (interquartile range 23-28). CONCLUSIONS: The COMPASS MRI substudy will examine the effect of the antithrombotic interventions on MRI-determined covert brain infarcts and cognition. Demonstration of a therapeutic effect of the antithrombotic regimens on brain infarcts would have implications for prevention of cognitive decline and provide insight into the pathogenesis of vascular cognitive decline.

Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease.

BACKGROUND: We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention. METHODS: In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months. RESULTS: The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=-4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group. CONCLUSIONS: Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424 .).

Radiofrequency catheter ablation of atrial fibrillation guided by spectral mapping of atrial fibrillation nests in sinus rhythm.

BACKGROUND: Two types of myocardia can be observed through the endocardial spectral mapping (SM) in sinus rhythm: the compact type with a smooth spectrum and the fibrillar type with a segmented spectrum (atrial fibrillation nests). During the atrial fibrillation (AF), the compact type has an organized activation and low frequency (passive), whereas the fibrillar type has a rather disorganized activation and high frequency (active/resonant), with both being activated by high-frequency sustained tachycardia--the background tachycardia (BT). OBJECTIVE: To describe the treatment of AF by the ablation of the AF nests and BT. METHODS: 1) Catheter ablation of the AF nests with RF [4/8 mm-60 masculine/30-40 J/30s] guided by SM in sinus rhythm, outside the pulmonary vein; 2) atrial stimulation -300 ppm; 3) Additional ablation of the AF nests if AF is induced; 4) Focal ablation if BT and/or Flutter is induced; 5) Clinical follow-up+ ECG+ Holter. RESULTS: A total of 50+/-18 AF nests/patient were treated. After 11.3+/-8 m, 81 patients (88%) did not present AF (28.3% with antiarrhythmic drugs). After the ablation of the AF nests, AF was not reinduced in 61 patients (71%) and BT was induced and treated in 24 patients (26%). There were two episodes of pericardial bleeding (1 treated clinically and 1 surgically), caused by sheaths that are no longer used CONCLUSION: The SM in sinus rhythm can be used in the ablation of AF nests. During the AF, the AF nests present a reactive-resonant pattern and the compact myocardium is passive, stimulated by the high frequency of the BT. After the ablation of the AF nests and the BT, it was not possible to reinduce the sustained AF. The Ablation of AF nests outside the pulmonary veins showed to be safe and highly effective in the cure and/or clinical control of the AF.

Ablação da fibrilação atrial por cateter com radiofreqüência guiada por mapeamento espectral endocárdico dos "ninhos de FA" em ritmo sinusal / Radiofrequency catheter ablation of atrial fibrillation guided by spectral mapping of atrial fibrillation nests in sinus rhythm

FUNDAMENTO: Através de mapeamento espectral-(ME) endocárdico em ritmo sinusal, observam-se dois tipos de miocárdio atrial: o compacto de espectro liso e o fibrilar de espectro segmentado ("Ninho de FA" [NFA]). Durante a FA o compacto tem ativação organizada e baixa freqüência (passivo) enquanto o fibrilar apresenta ativação bastante desorganizada e alta freqüência (ativo/ressonante) sendo ambos ativados por uma taquicardia protegida de alta freqüência, taquicardia de background (TB). OBJETIVO: Descrever o tratamento da FA pela ablação dos NFA e da TB. MÉTODOS: 1) Ablação por cateter-RF [4/8mm-60°/30-40J/30s] dos NFA guiada por ME em ritmo sinusal, fora das veias pulmonares; 2) Estimulação atrial-300ppm; 3) Ablação adicional de NFA se induzida FA; 4) Ablação focal se induzida TB e/ou Flutter; 5) Seguimento clínico+ECG+Holter. RESULTADOS: Foram tratados 50±18 NFA/paciente. Após 11,3±8m 81p (88 por cento) estavam sem FA (28,3 por cento com antiarrítmico). Após a ablação dos NFA: a FA não foi reinduzida em 61p(71 por cento); TB foi induzida e tratada em 24p(26 por cento). Ocorreram 2 sangramentos pericárdicos (1 tratado clinicamente e 1 cirurgicamente) ocasionados por bainhas não mais utilizadas. CONCLUSÃO: O ME em ritmo sinusal ablaciona os NFA. Durante a FA os NFA apresentam um padrão reativo-ressonante e o miocárdio compacto apresenta-se passivo, estimulados pela alta freqüência da TB. Após a ablação dos NFA e da TB não foi possível reinduzir FA sustentada. A ablação dos NFA fora das VP se mostrou segura e altamente eficiente para a cura e/ou o controle clínico da FA.

BACKGROUND: Two types of myocardia can be observed through the endocardial spectral mapping (SM) in sinus rhythm: the compact type with a smooth spectrum and the fibrillar type with a segmented spectrum (atrial fibrillation nests). During the atrial fibrillation (AF), the compact type has an organized activation and low frequency (passive), whereas the fibrillar type has a rather disorganized activation and high frequency (active/resonant), with both being activated by high-frequency sustained tachycardia - the background tachycardia (BT). OBJECTIVE: To describe the treatment of AF by the ablation of the AF nests and BT. METHODS: 1) Catheter ablation of the AF nests with RF [4/8mm-60°/30-40J/30s] guided by SM in sinus rhythm, outside the pulmonary vein; 2) atrial stimulation -300ppm; 3) Additional ablation of the AF nests if AF is induced; 4) Focal ablation if BT and/or Flutter is induced; 5)Clinical follow-up+ ECG+ Holter. RESULTS: A total of 50±18 AF nests/patient were treated. After 11.3±8m, 81 patients (88 percent) did not present AF (28.3 percent with antiarrhythmic drugs). After the ablation of the AF nests, AF was not reinduced in 61 patients (71 percent) and BT was induced and treated in 24 patients (26 percent). There were two episodes of pericardial bleeding (1 treated clinically and 1 surgically), caused by sheaths that are no longer used CONCLUSION: The SM in sinus rhythm can be used in the ablation of AF nests. During the AF, the AF nests present a reactive-resonant pattern and the compact myocardium is passive, stimulated by the high frequency of the BT. After the ablation of the AF nests and the BT, it was not possible to reinduce the sustained AF. The Ablation of AF nests outside the pulmonary veins showed to be safe and highly effective in the cure and/or clinical control of the AF.

Cardiovascular effects of local anesthesia with vasoconstrictor during dental extraction in coronary patients.

OBJECTIVE: To evaluate the occurrence of variables detecting myocardial ischemia during or after dental treatment under anesthesia with vasoconstrictor (epinephrine). METHODS: A total of 54 coronary patients undergoing dental extraction under local anesthesia with or without vasoconstrictor were included. They were divided into two groups (by drawing envelopes): group I (27 patients) using anesthetics with vasoconstrictor, and group II (27 cases) without vasoconstrictor. 24-hour Holter monitoring, Doppler-echocardiogram before and after dental intervention, and determination of biochemical markers (CK-MB mass, CK-MB activity, and troponin T) before and 24 hours after dental extraction were performed in all patients. Heart rate and blood pressure were also measured in the pre, post-anesthesia and post-dental extraction phases. Doppler echocardiography assessed left ventricular segmental contractility and the occasional occurrence of mitral regurgitation. The usual pharmaceutical treatment prescribed by the cardiologist was maintained in all cases. RESULTS: Three patients in group I presented ST-segment depression (1.0 mm) during administration of anesthesia; two other patients in group I had CK-MB mass elevation, and ischemia was not observed in any other case, as assessed by the other methods. No chest pain, arrhythmias, occurrence or worsening of left ventricular segmental hypocontractility or mitral regurgitation were observed in the study. CONCLUSION: Dental extraction performed under anesthesia with 1:100,000 epinephrine does not imply additional ischemic risks, as long as performed with good anesthetic technique and maintenance of the pharmacological treatment prescribed by the cardiologist.

Efeitos cardiovasculares da anestesia local com vasoconstritor durante exodontia em coronariopatas / Cardiovascular effects of local anesthesia with vasoconstrictor during dental extraction in coronary patients

OBJETIVO: Avaliar a ocorrência de variáveis detectoras de isquemia miocárdica, durante ou após o tratamento odontológico, sob anestesia com vasoconstritor (adrenalina). MÉTODOS: Foram incluídos 54 pacientes coronariopatas submetidos a exodontia sob anestesia local com ou sem vasoconstritor, divididos em dois grupos (sorteio por envelope): grupo I, composto por 27 que receberam anestésico com vasoconstritor; e grupo II, composto por 27 que receberam anestésico sem vasoconstritor. Todos os pacientes foram submetidos a monitoração eletrocardiográfica com Holter por 24 horas, a Doppler-ecocardiografia realizada antes e após intervenção odontológica, e a dosagem dos marcadores bioquímicos antes e 24 horas após a exodontia (creatina cinase fração MB [CK-MB] massa, CK-MB atividade e troponina T). A freqüência cardíaca e a pressão arterial nas fases pré-anestesia, pós-anestesia e pós-exodontia também foram aferidas. A Doppler-ecocardiografia teve como objetivo avaliar a contratilidade segmentar do ventrículo esquerdo e a eventual ocorrência de insuficiência mitral. Em todos os casos foi mantido o protocolo farmacológico habitual prescrito pelo cardiologista. RESULTADOS: Três pacientes do grupo I apresentaram depressão do segmento ST (1,0 mm) durante a aplicação da anestesia, dois outros pacientes do mesmo grupo tiveram elevação da CK-MB massa, e em nenhum caso foi verificada presença de isquemia avaliada pelos demais métodos. Não houve registro, neste estudo, de precordialgia, arritmias e ocorrência ou agravamento de hipocontratilidade segmentar do ventrículo esquerdo ou insuficiência mitral. CONCLUSÃO: A exodontia praticada sob uso de anestesia com adrenalina 1:100.000 não implica riscos isquêmicos adicionais quando realizada com boa técnica anestésica e manutenção do tratamento farmacológico prescrito pelo cardiologista.

OBJECTIVE: To evaluate the occurrence of variables detecting myocardial ischemia during or after dental treatment under anesthesia with vasoconstrictor (epinephrine). METHODS: A total of 54 coronary patients undergoing dental extraction under local anesthesia with or without vasoconstrictor were included. They were divided into two groups (by drawing envelopes): group I (27 patients) using anesthetics with vasoconstrictor, and group II (27 cases) without vasoconstrictor. 24-hour Holter monitoring, Doppler-echocardiogram before and after dental intervention, and determination of biochemical markers (CK-MB mass, CK-MB activity, and troponin T) before and 24 hours after dental extraction were performed in all patients. Heart rate and blood pressure were also measured in the pre, post-anesthesia and post-dental extraction phases. Doppler echocardiography assessed left ventricular segmental contractility and the occasional occurrence of mitral regurgitation. The usual pharmaceutical treatment prescribed by the cardiologist was maintained in all cases. RESULTS: Three patients in group I presented ST-segment depression (1.0 mm) during administration of anesthesia; two other patients in group I had CK-MB mass elevation, and ischemia was not observed in any other case, as assessed by the other methods. No chest pain, arrhythmias, occurrence or worsening of left ventricular segmental hypocontractility or mitral regurgitation were observed in the study. CONCLUSION: Dental extraction performed under anesthesia with 1:100,000 epinephrine does not imply additional ischemic risks, as long as performed with good anesthetic technique and maintenance of the pharmacological treatment prescribed by the cardiologist.