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Anticoagulation and Antiplatelet Therapy for Atrial Fibrillation and Stable Coronary Disease: Meta-Analysis of Randomized Trials

Author/s: 
Sina Rashedi, Mohammad Keykhaei, Alyssa Sato, Philippe Gabriel Steg

Background: The optimal long-term antithrombotic strategy in patients with atrial fibrillation (AF) and stable coronary artery disease (CAD) remains uncertain. Individual randomized controlled trials (RCTs) had variations in their reported results and were not powered for effectiveness outcomes.

Objectives: This study aimed to pool the results of RCTs comparing the effectiveness and safety of oral anticoagulation (OAC) monotherapy vs OAC plus single antiplatelet therapy (SAPT) in patients with AF and stable CAD.

Methods: We systematically searched PubMed, Embase, and ClinicalTrials.gov until September 09, 2024. The primary effectiveness outcome was a composite of myocardial infarction, ischemic stroke, systemic embolism, or death. The primary safety outcome was major bleeding. We obtained unpublished results from principal investigators of the included RCTs, as needed, to calculate pooled HRs and 95% CIs and to perform prespecified subgroup analyses.

Results: Among 690 screened records, 4 RCTs with 4,092 randomized patients were included (2 using edoxaban, 1 using rivaroxaban, and 1 using any oral anticoagulant; mean age 73.9 years, 20.1% women). The median follow-up durations ranged from 12 to 30 months (overall estimated weighted mean follow-up of 21.9 months). There were no statistically significant differences between OAC monotherapy vs OAC plus SAPT in the primary effectiveness outcome (7.3% vs 8.2%; HR: 0.90; 95% CI: 0.72-1.12), myocardial infarction (1.0% vs 0.7%; HR: 1.51; 95% CI: 0.75-3.04), ischemic stroke (1.9% vs 2.1%; HR: 0.89; 95% CI: 0.57-1.37), all-cause death (4.2% vs 5.3%; HR: 0.94; 95% CI: 0.49-1.80), or cardiovascular death (2.4% vs 3.0%; HR: 0.79; 95% CI: 0.54-1.15). OAC monotherapy was associated with a lower risk of major bleeding than OAC plus SAPT (3.3% vs 5.7%; HR: 0.59; 95% CI: 0.44-0.79). Subgroup analyses did not show significant interactions for effectiveness but suggested that the magnitude of bleeding reduction may be greater among men (Pinteraction = 0.03) and among patients with diabetes mellitus (Pinteraction = 0.04).

Conclusions: In patients with AF and stable CAD, OAC monotherapy, compared with OAC plus SAPT, was not associated with a statistically significant increased risk of ischemic events but resulted in a significantly reduced risk of bleeding.

Keywords 
anticoagulants atrial fibrillation coronary artery disease ischemia platelet aggregation inhibitors

Perioperative Management of Patients Taking Direct Oral Anticoagulants

Author/s: 
James D Douketis, Alex C Spyropoulos

Importance: Direct oral anticoagulants (DOACs), comprising apixaban, rivaroxaban, edoxaban, and dabigatran, are commonly used medications to treat patients with atrial fibrillation and venous thromboembolism. Decisions about how to manage DOACs in patients undergoing a surgical or nonsurgical procedure are important to decrease the risks of bleeding and thromboembolism.

Observations: For elective surgical or nonsurgical procedures, a standardized approach to perioperative DOAC management involves classifying the risk of procedure-related bleeding as minimal (eg, minor dental or skin procedures), low to moderate (eg, cholecystectomy, inguinal hernia repair), or high risk (eg, major cancer or joint replacement procedures). For patients undergoing minimal bleeding risk procedures, DOACs may be continued, or if there is concern about excessive bleeding, DOACs may be discontinued on the day of the procedure. Patients undergoing a low to moderate bleeding risk procedure should typically discontinue DOACs 1 day before the operation and restart DOACs 1 day after. Patients undergoing a high bleeding risk procedure should stop DOACs 2 days prior to the operation and restart DOACs 2 days after. With this perioperative DOAC management strategy, rates of thromboembolism (0.2%-0.4%) and major bleeding (1%-2%) are low and delays or cancellations of surgical and nonsurgical procedures are infrequent. Patients taking DOACs who need emergent (<6 hours after presentation) or urgent surgical procedures (6-24 hours after presentation) experience bleeding rates up to 23% and thromboembolism as high as 11%. Laboratory testing to measure preoperative DOAC levels may be useful to determine whether patients should receive a DOAC reversal agent (eg, prothrombin complex concentrates, idarucizumab, or andexanet-α) prior to an emergent or urgent procedure.

Conclusions and relevance: When patients who are taking a DOAC require an elective surgical or nonsurgical procedure, standardized management protocols can be applied that do not require testing DOAC levels or heparin bridging. When patients taking a DOAC require an emergent, urgent, or semiurgent surgical procedure, anticoagulant reversal agents may be appropriate when DOAC levels are elevated or not available.

Keywords 
Perioperative oral anticoagulants

Perioperative Management of Antithrombotic Therapy

Author/s: 
Maureen D Lyons, Bailey Pope, Jason Alexander

Guideline title Perioperative Management of Antithrombotic Therapy: An American College of Chest Physicians Clinical Practice Guideline

Release date November 2022

Developer and funding source American College of Chest Physicians

Target population Patients taking oral anticoagulation or antiplatelet therapy who are undergoing an elective surgery or procedure

Selected recommendations

For patients requiring aspirin therapy who are undergoing an elective noncardiac surgery, continuing aspirin through the surgery is suggested (conditional recommendation; moderate certainty of evidence [COE]).

For patients with atrial fibrillation taking vitamin K antagonists (VKAs) who are undergoing an elective surgery or procedure with low to moderate risk of thromboembolism, temporary use of therapeutic heparin doses during interruption of VKA (heparin bridging) is not recommended (strong recommendation; moderate COE).

For patients with a mechanical heart valve with low to moderate risk of thromboembolism who require VKA interruption for an elective surgery or procedure, heparin bridging is not suggested (conditional recommendation; very low COE).

For patients receiving a direct oral anticoagulant (DOAC) who will be undergoing an elective surgery or procedure, discontinuing DOAC therapy is suggested with the timing dependent on the specific DOAC and the bleeding risk of the procedure (conditional recommendation; very low COE).

Keywords 
anticoagulants Antithrombotic Therapy Perioperative

Transient ischemic attack and minor stroke: diagnosis, risk stratification and management

Author/s: 
Perry, J. J., Yadav, K., Syed, S., Shamy, M.

Patients with suspected cerebral ischemia should be urgently assessed to distinguish between transient ischemic attack (TIA), minor stroke or mimics such as migraine, seizure, vertigo or syncope.

The Canadian TIA Score can be used to determine risk for early subsequent stroke in patients with a suspected TIA or minor stroke.

All patients with TIA or minor stroke should undergo urgent electrocardiography and computed tomography of the head.

Clinicians should order early vascular imaging for patients at moderate or high risk of subsequent stroke; urgent revascularization should be considered if there is more than 50% arterial stenosis congruent with symptom presentation.

Clinicians should prescribe dual antiplatelet drugs for high-risk patients, single antiplatelet agents for low-risk patients or direct oral anticoagulants for patients with atrial fibrillation.

All patients with TIA or minor stroke should be counselled about modifiable lifestyle factors (including smoking cessation), be treated with statins and take steps toward optimizing blood pressure, including treatment with antihypertensive drugs, if necessary.

Keywords 
atrial fibrillation Brain Ischemia Cerebral Infarction Migraine Disorders electrocardiography

International normalized ratio and activated partial thromboplastin time testing

Author/s: 
Chornenki, N. L. J., Fralick, M., Sholzberg, M.

International normalized ratio (INR) and activated partial thromboplastin time (aPTT) have limited clinical utility
The INR and aPTT should be used only for specific clinical indications (see Appendix 1, available at www.cmaj.ca/lookup/doi/10.1503/cmaj.220629/tab-related-content).1

Bleeding history is the most important predictor of an inherited bleeding disorder
The INR and aPTT have poor sensitivity (1.0%–2.1%) for bleeding disorders. 1 Clinicians considering an inherited bleeding disorder should first use a Bleeding Assessment Tool (BAT).2 A negative BAT score has a sensitivity approaching 100% to rule out von Willebrand disease (the most common inherited bleeding disorder).2 A positive BAT score should prompt referral to a hematologist for consideration of specialized coagulation testing.1

International normalized ratio and aPTT testing are not indicated before low-risk surgery or interventional radiology
Abnormal INR or aPTT results are not associated with an increased bleeding risk in the setting of low-risk procedures.3,4 An abnormal result with no bleeding history or anticoagulant use should be repeated to rule out artifact or sample handling error. Investigation is generally not indicated for an aPTT of less than 4 seconds above the upper limit of normal.2

An abnormal INR or aPTT in a patient who is bleeding suggests a potential medical emergency
Actionable causes of bleeding such as anticoagulant use, severe liver disease or acquired hemophilia may be indicated by the elevated INR or aPTT, respectively.5

Clinical history and drug pharmacokinetics are more important than INR or aPTT results in guiding clinical decision-making in patients taking direct oral anticoagulants (DOACs)
Direct oral anticoagulants variably and inconsistently affect INR and aPTT results. If a patient is bleeding, decisions on the use of a reversing blood product or drug should be based on the last reported drug dose, renal function and pharmacokinetics. In some centres, DOAC-calibrated assays are available to evaluate the presence of clinically relevant drug activity.6

Keywords 
Bleeding disorder direct oral anticoagulants activated partial thromboplastin International normalized ratio Specimen handling

Adverse Events Associated With the Addition of Aspirin to Direct Oral Anticoagulant Therapy Without a Clear Indication

Author/s: 
Schaefer, J. K., Errickson, J., Li, Y., Kong, X., Alexandris-Souphis, T., Ali, M. A., Decamillo, D., Haymart, B., Kaatz, S., Kline-Rogers, E., Kozlowski, J. H., Krol, G. D., Shankar, S, R., Sood, S. L., Froehlich, J. B., Barnes, G. D.

Importance: It is unclear how many patients treated with a direct oral anticoagulant (DOAC) are using concomitant acetylsalicylic acid (ASA, or aspirin) and how this affects clinical outcomes.

Objective: To evaluate the frequency and outcomes of prescription of concomitant ASA and DOAC therapy for patients with atrial fibrillation (AF) or venous thromboembolic disease (VTE).

Design, setting, and participants: This registry-based cohort study took place at 4 anticoagulation clinics in Michigan from January 2015 to December 2019. Eligible participants were adults undergoing treatment with a DOAC for AF or VTE, without a recent myocardial infarction (MI) or history of heart valve replacement, with at least 3 months of follow-up.

Exposures: Use of ASA concomitant with DOAC therapy.

Main outcomes and measures: Rates of bleeding (any, nonmajor, major), rates of thrombosis (stroke, VTE, MI), emergency department visits, hospitalizations, and death.

Results: Of the study cohort of 3280 patients (1673 [51.0%] men; mean [SD] age 68.2 [13.3] years), 1107 (33.8%) patients without a clear indication for ASA were being treated with DOACs and ASA. Two propensity score-matched cohorts, each with 1047 patients, were analyzed (DOAC plus ASA and DOAC only). Patients were followed up for a mean (SD) of 20.9 (19.0) months. Patients taking DOAC and ASA experienced more bleeding events compared with DOAC monotherapy (26.0 bleeds vs 31.6 bleeds per 100 patient years, P = .01). Specifically, patients undergoing combination therapy had significantly higher rates of nonmajor bleeding (26.1 bleeds vs 21.7 bleeds per 100 patient years, P = .02) compared with DOAC monotherapy. Major bleeding rates were similar between the 2 cohorts. Thrombotic event rates were also similar between the cohorts (2.5 events vs 2.3 events per 100 patient years for patients treated with DOAC and ASA compared with DOAC monotherapy, P = .80). Patients were more often hospitalized while undergoing combination therapy (9.1 vs 6.5 admissions per 100 patient years, P = .02).

Conclusion and relevance: Nearly one-third of patients with AF and/or VTE who were treated with a DOAC received ASA without a clear indication. Compared with DOAC monotherapy, concurrent DOAC and ASA use was associated with increased bleeding and hospitalizations but similar observed thrombosis rate. Future research should identify and deprescribe ASA for patients when the risk exceeds the anticipated benefit.

Keywords 
aspirin anticoagulant therapy treatment heart-valve replacement thrombosis

Outcomes Associated With Oral Anticoagulants Plus Antiplatelets in Patients With Newly Diagnosed Atrial Fibrillation

Author/s: 
Fox, KAA, Velentgas, P, Camm, AJ, Bassand, JP, Fitzmaurice, DA, Gersh, BJ, Goldhaber, SZ, Goto, S, Haas, S, Misselwitz, F, Pieper, KS, Turpie, AGG, Verhegut, FWA, Dabrowski, E, Luo, K, Gibbs, L, Kakkar, AK, GARFIELD-AF Investigators

IMPORTANCE:

Patients with nonvalvular atrial fibrillation at risk of stroke should receive oral anticoagulants (OAC). However, approximately 1 in 8 patients in the Global Anticoagulant Registry in the Field (GARFIELD-AF) registry are treated with antiplatelet (AP) drugs in addition to OAC, with or without documented vascular disease or other indications for AP therapy.

OBJECTIVE:

To investigate baseline characteristics and outcomes of patients who were prescribed OAC plus AP therapy vs OAC alone.

DESIGN, SETTING, AND PARTICIPANTS:

Prospective cohort study of the GARFIELD-AF registry, an international, multicenter, observational study of adults aged 18 years and older with recently diagnosed nonvalvular atrial fibrillation and at least 1 risk factor for stroke enrolled between March 2010 and August 2016. Data were extracted for analysis in October 2017 and analyzed from April 2018 to June 2019.

EXPOSURE:

Participants received either OAC plus AP or OAC alone.

MAIN OUTCOMES AND MEASURES:

Clinical outcomes were measured over 3 and 12 months. Outcomes were adjusted for 40 covariates, including baseline conditions and medications.

RESULTS:

A total of 24 436 patients (13 438 [55.0%] male; median [interquartile range] age, 71 [64-78] years) were analyzed. Among eligible patients, those receiving OAC plus AP therapy had a greater prevalence of cardiovascular indications for AP, including acute coronary syndromes (22.0% vs 4.3%), coronary artery disease (39.1% vs 9.8%), and carotid occlusive disease (4.8% vs 2.0%). Over 1 year, patients treated with OAC plus AP had significantly higher incidence rates of stroke (adjusted hazard ratio [aHR], 1.49; 95% CI, 1.01-2.20) and any bleeding event (aHR, 1.41; 95% CI, 1.17-1.70) than those treated with OAC alone. These patients did not show evidence of reduced all-cause mortality (aHR, 1.22; 95% CI, 0.98-1.51). Risk of acute coronary syndrome was not reduced in patients taking OAC plus AP compared with OAC alone (aHR, 1.16; 95% CI, 0.70-1.94). Patients treated with OAC plus AP also had higher rates of all clinical outcomes than those treated with OAC alone over the short term (3 months).

CONCLUSIONS AND RELEVANCE:

This study challenges the practice of coprescribing OAC plus AP unless there is a clear indication for adding AP to OAC therapy in newly diagnosed atrial fibrillation.

Keywords 
anticoagulants atrial fibrillation stroke antiplatelet

Diagnosis of Pulmonary Embolism with d-Dimer Adjusted to Clinical Probability

Author/s: 
Kearon, C, de Wit, K, Parpia, S, Schulman, S, Afilalo, M, Hirsch, A, Spencer, FA, Sharma, S, D'Aragon, F, Deshaies, JF, Le Gal, G, Lazo-Langer, A, Wu, C, Rudd-Scott, L, Bates, SM, Julian, JA, PEGeD Study Investigators

BACKGROUND:

Retrospective analyses suggest that pulmonary embolism is ruled out by a d-dimer level of less than 1000 ng per milliliter in patients with a low clinical pretest probability (C-PTP) and by a d-dimer level of less than 500 ng per milliliter in patients with a moderate C-PTP.

METHODS:

We performed a prospective study in which pulmonary embolism was considered to be ruled out without further testing in outpatients with a low C-PTP and a d-dimer level of less than 1000 ng per milliliter or with a moderate C-PTP and a d-dimer level of less than 500 ng per milliliter. All other patients underwent chest imaging (usually computed tomographic pulmonary angiography). If pulmonary embolism was not diagnosed, patients did not receive anticoagulant therapy. All patients were followed for 3 months to detect venous thromboembolism.

RESULTS:

A total of 2017 patients were enrolled and evaluated, of whom 7.4% had pulmonary embolism on initial diagnostic testing. Of the 1325 patients who had a low C-PTP (1285 patients) or moderate C-PTP (40 patients) and a negative d-dimer test (i.e., <1000 or <500 ng per milliliter, respectively), none had venous thromboembolism during follow-up (95% confidence interval [CI], 0.00 to 0.29%). These included 315 patients who had a low C-PTP and a d-dimer level of 500 to 999 ng per milliliter (95% CI, 0.00 to 1.20%). Of all 1863 patients who did not receive a diagnosis of pulmonary embolism initially and did not receive anticoagulant therapy, 1 patient (0.05%; 95% CI, 0.01 to 0.30) had venous thromboembolism. Our diagnostic strategy resulted in the use of chest imaging in 34.3% of patients, whereas a strategy in which pulmonary embolism is considered to be ruled out with a low C-PTP and a d-dimer level of less than 500 ng per milliliter would result in the use of chest imaging in 51.9% (difference, -17.6 percentage points; 95% CI, -19.2 to -15.9).

CONCLUSIONS:

A combination of a low C-PTP and a d-dimer level of less than 1000 ng per milliliter identified a group of patients at low risk for pulmonary embolism during follow-up. (Funded by the Canadian Institutes of Health Research and others; PEGeD ClinicalTrials.gov number, NCT02483442.).

Keywords 
pulmonary embolism PE d-dimer CT computed tomography

Rivaroxaban Versus Vitamin K Antagonist in Antiphospholipid Syndrome: A Randomized Noninferiority Trial

Author/s: 
Ordi-Ros, J, Sáez-Comet, L., Pérez-Conesa, M., Vidal, X., Riera-Mestre, A., Castro-Salomó, A., Cuquet-Pedragosa, J., Ortiz-Santamaria, V., Mauri-Plana, M., Solé, C., Cortés-Hernández, J.

BACKGROUND:

The potential role of new oral anticoagulants in antiphospholipid antibody syndrome (APS) remains uncertain.

OBJECTIVE:

To determine whether rivaroxaban is noninferior to dose-adjusted vitamin K antagonists (VKAs) for thrombotic APS.

DESIGN:

3-year, open-label, randomized noninferiority trial. (EU Clinical Trials Register: EUDRA [European Union Drug Regulatory Authorities] code 2010-019764-36).

SETTING:

6 university hospitals in Spain.

PARTICIPANTS:

190 adults (aged 18 to 75 years) with thrombotic APS.

INTERVENTION:

Rivaroxaban (20 mg/d or 15 mg/d, according to renal function) versus dose-adjusted VKAs (target international normalized ratio, 2.0 to 3.0, or 3.1 to 4.0 in patients with a history of recurrent thrombosis).

MEASUREMENTS:

The primary efficacy outcome was the proportion of patients with new thrombotic events; the primary safety outcome was major bleeding. The prespecified noninferiority margin for risk ratio (RR) was 1.40. Secondary outcomes included time to thrombosis, type of thrombosis, changes in biomarker levels, cardiovascular death, and nonmajor bleeding.

RESULTS:

After 3 years of follow-up, recurrent thrombosis occurred in 11 patients (11.6%) in the rivaroxaban group and 6 (6.3%) in the VKA group (RR in the rivaroxaban group, 1.83 [95% CI, 0.71 to 4.76]). Stroke occurred more commonly in patients receiving rivaroxaban (9 events) than in those receiving VKAs (0 events) (corrected RR, 19.00 [CI, 1.12 to 321.9]). Major bleeding occurred in 6 patients (6.3%) in the rivaroxaban group and 7 (7.4%) in the VKA group (RR, 0.86 [CI, 0.30 to 2.46]). Post hoc analysis suggested an increased risk for recurrent thrombosis in rivaroxaban-treated patients with previous arterial thrombosis, livedo racemosa, or APS-related cardiac valvular disease.

LIMITATION:

Anticoagulation intensity was not measured in the rivaroxaban group.

CONCLUSION:

Rivaroxaban did not show noninferiority to dose-adjusted VKAs for thrombotic APS and, in fact, showed a non-statistically significant near doubling of the risk for recurrent thrombosis.

PRIMARY FUNDING SOURCE:

Bayer Hispania.

Keywords 
rivaroxaban thrombosis wafarin
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