Journal Wrap

The hottest research from various peer-reviewed journals – handpicked weekly by the Editorial Board led by Kim A. Eagle, MD, MACC.

AUGUSTUS: Aspirin Associated With Equally Increased Bleeding, Reduced Ischemic Risk For 30 Days in AFib Patients

Taking aspirin may result in an equal tradeoff between increased bleeding risk and reduced ischemic risk for up to 30 days among atrial fibrillation (AFib) patients with a recent acute coronary syndrome (ACS) and/or PCI taking either apixaban or a vitamin K antagonist (VKA), according to results of a post-hoc analysis of the AUGUSTUS trial presented at ACC.20/WCC and published in Circulation.

In this retrospective study, John H. Alexander, MD, MHS, FACC, et al., developed three composite bleeding outcomes and three composite ischemic outcomes to assess risk-benefit tradeoff of aspirin vs. placebo in addition to either apixaban or VKA at 30 days and at six months.

The initial AUGUSTUS trial demonstrated a placebo resulted in less bleeding vs. aspirin among AFib patients with a recent ACS and/or PCI taking a P2Y12 inhibitor and either apixaban or VKA.


The trial enrolled 4,614 patients, with a median age of 71 years, at high risk for both bleeding and ischemic events. The indication was ACS with PCI for 37% of patients, ACS treated medically in 24% and elective PCI in 39%.

Results showed aspirin increases severe bleeding and decreases ischemic events by about the same amount up to 30 days. At 30 days, the absolute risk for the composite bleeding outcomes ranged from 2.1% for severe bleeding to 7.5% for broad bleeding (fatal, intracranial, ISTH major, bleeding hospitalization, clinically relevant nonmajor) for patients taking aspirin vs. 1.1% for severe bleeding to 4.0% for broad bleeding in those taking the placebo.

The absolute risk of an ischemic composite outcome ranged from 1.7% for severe events to 6.7% for broad events among those taking aspirin vs. 2.6% for severe events to 6.8% for broad events in the placebo group.

The same tradeoff did not continue after 30 days, the study shows. For bleeding outcomes, the absolute risk ranged from 3.7% for severe bleeding to 12.1% for broad bleeding in the aspirin group vs. 2.5% for severe bleeding and 7.2% for broad bleeding in the placebo group. The absolute risk of ischemic outcomes ranged from 3.8% for severe events to 14.3% for broad events among patients taking aspirin vs. 4.0% for severe events to 14.3% for broad events in the placebo group.

According to the researchers, the use of aspirin for up to 30 days, in addition to a P2Y12 inhibitor or oral anticoagulant, results in an equal tradeoff between an increased risk of bleeding and reduced risk of an ischemic event. Beyond 30 days, aspirin leads to an increase in bleeding without a reduction in ischemic events.

The findings can help inform evidence-based decisions regarding antithrombotic therapy for AFib patients who experience an ACS and/or PCI and inform patient-centric shared decision-making, they conclude.

Alexander JH, Wojdyla D, Vora AN, et al. Circulation 2020;March 29:[Epub ahead of print].


COMPASS: Rivaroxaban Reduces CV Events in Patients With, Without Diabetes

The combination of rivaroxaban plus aspirin may provide a similar benefit in reducing cardiovascular events in patients with stable atherosclerosis with and without diabetes, according to results of a substudy of the COMPASS trial presented during ACC.20/WCC and published in Circulation.

Deepak L. Bhatt, MD, MPH, FACC, et al., compared the effects of rivaroxaban (2.5 mg twice daily) plus aspirin 100 mg vs. placebo plus aspirin 100 mg on cardiovascular events in patients with and without diabetes and stable coronary or peripheral artery disease in this prespecified analysis.


The overall COMPASS trial included 10,341 patients with diabetes and 17,054 without diabetes. A total of 9,152 patients were randomly assigned to take rivaroxaban plus aspirin, and 9,126 patients took a placebo plus aspirin. The substudy consisted of 6,922 patients with diabetes at baseline and 11,356 without diabetes at baseline.

The primary efficacy endpoint – a composite of cardiovascular death, myocardial infarction (MI) or stroke – occurred in 8.4% of patients with diabetes taking rivaboxaban vs. 10.7% in the placebo group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.61-0.90; p=0.002). Among patients without diabetes, 5.8% in the rivaroxaban group experienced a primary endpoint event vs. 7.2% in the placebo group (HR, 0.77; 95% CI, 0.64-0.93; p=0.005).

The researchers note a consistent, similar relative risk reduction associated with rivaroxaban plus aspirin for patients both with and without diabetes. Due to higher baseline risk, the absolute risk reduction appeared larger in patients with diabetes vs. without diabetes, but both subgroups derived similar benefits (2.3% vs. 1.4% for the primary endpoint at three years).

The primary safety endpoint was a modification of the International Society on Thrombosis and Haemostasis (ISTH) criteria for major bleeding. For patients with diabetes, major bleeding increased from 3.4% to 4.5% at three years (HR, 1.69; 95% CI, 1.33-2.15; p=0.0006) vs. 3.2% to 4.4% for those without diabetes (HR, 1.69; 95% CI, 1.33-2.15; p<0.0001). However, there was no increase in fatal or intracranial bleeding.

The researchers conclude that a low dose of rivaroxaban plus aspirin was associated with a reduction in major cardiovascular events in patients with stable atherosclerosis both with and without diabetes. They note the net clinical benefit for irreversible outcomes appeared numerically greater in patients with diabetes.

Bhatt DL, Eikelboom JW, Connolly SJ, et al. Circulation 2020;March 28:[Epub ahead of print].


PRONOMOS: Rivaroxaban Better Than Enoxaparin in Preventing VTE After Nonmajor Orthopedic Surgery

Rivaroxaban was more effective than enoxaparin for preventing venous thromboembolism (VTE) events without increasing bleeding risk in patients immobilized after nonmajor lower limb orthopedic surgery, according to the Late-Breaking Clinical Trial PRONOMOS presented during ACC.20/WCC and published in the New England Journal of Medicine.

This international, double-blind, randomized controlled trial is the first to compare oral rivaroxaban against subcutaneous enoxaparin in this moderate-risk population. The noninferiority trial planned to test for superiority if rivaroxaban was shown to be noninferior to enoxaparin.

The trial was terminated early in April 2018, because of slower than expected recruitment, which led to reaching expiration dates of the study drugs and the cost to replace them was prohibitively high. The data were blinded at the time of the trial termination.


Researchers studied 3,604 patients from 10 countries who were deemed to be at moderate VTE risk post surgery by the investigator. They were randomized to rivaroxaban 10 mg (1,809 patients) or enoxaparin 4,000 IU (1,795 patients). Their median age was 41 years and two-thirds were men. Overall, patients had a median of 28 days of reduced mobility.

The primary efficacy outcome of major VTE – the composite of symptomatic distal or proximal deep vein thrombosis (DVT), pulmonary embolism, or VTE-related death during the treatment period or asymptomatic proximal DVT at the end of treatment – occurred in four of 1,661 patients (0.2%) in the rivaroxaban group and 18 of 1,640 patients (1.1%) in the enoxaparin group (risk ratio with multiple imputation, 0.25; 95% confidence interval 0.09-0.75; p<0.001 for noninferiority; p=0.01 for superiority).

Bleeding rates did not differ between the rivaroxaban and enoxaparin groups (1.1% and 1.0%, respectively, for major plus nonmajor clinically relevant bleeding; 0.6% and 0.7%, respectively, for major bleeding).

"In Europe, all the guidelines agree that some level of thromboprophylaxis should be given, but overall there is no agreement on what should be done for the patient population who remains at moderate risk for clots because of being immobilized during their recovery," said Nadia Rosencher, MD, a study author.

"This study represents a major step forward in our treatment of patients after many orthopedic procedures because it proves that we can more effectively prevent thrombosis with a once-daily oral medication versus a daily injection with the same safety."

Samama CM, Laporte S, Rosencher N, et al. N Engl J Med 2020; March 29:[Epub ahead of print].


Caravaggio Trial: Apixaban Noninferior to Dalteparin in Treatment of Cancer-Associated VTE

Oral apixaban is noninferior to subcutaneous dalteparin for the treatment of cancer-associated recurrent venous thromboembolism (VTE), according to the results of the international Caravaggio trial, presented during ACC.20/WCC and published in the New England Journal of Medicine.

Giancarlo Agnelli, MD, et al., sought to assess in this open-label trial with blinded adjudication whether oral apixaban would be noninferior to subcutaneous dalteparin for the prevention of recurrent VTE in patients with cancer without increasing the risk of major bleeding.

Recent guidelines recommend the consideration of other oral anticoagulants for the treatment of VTE in patients with cancer, but the benefits are limited due to the increased risk of bleeding associated with their use.


Participants who had symptomatic or incidental acute proximal deep vein thrombosis or pulmonary embolism were randomly assigned to receive oral apixaban (10 mg twice daily for first seven days, followed by 5 mg twice daily) or subcutaneous dalteparin (200 IU/kg of body weight once daily for the first month, followed by 150 IU/kg once daily).

Treatment lasted six months. The primary outcome was objectively confirmed recurrent VTE and major bleeding was the principal safety outcome.

The results of the study showed that recurrent VTE occurred in 32 of the 576 patients (5.6%) in the apixaban group and in 46 of 579 patients (7.9%) in the dalteparin group (hazard ratio, 0.63; 95% confidence interval [CI], 0.37-1.07; p<0.001 for noninferiority). Major bleeding occurred in 22 patients (3.8%) in the apixaban group and in 23 patients (4.0%) of the dalteparin group (hazard ratio, 0.82; 95% CI, 0.40-1.69; p=0.60).

In an accompanying editorial comment, Agnes Y. Y. Lee, MD, notes "the evidence from the [Caravaggio and prior] trials makes a compelling case for adding apixaban as another anticoagulant option for the treatment of [VTE] in patients with cancer. But given the heterogeneity of available trials, it is inappropriate to conclude that one direct oral anticoagulant is better than another without a head-to-head comparison."

When choosing which anticoagulant to use, "[clinicians] need to rely on a detailed clinical history, ascertaining the cancer type, status, and the treatment, along with bleeding risk, concomitant medications, and the patient's experiences and values," said Lee.

Agnelli G, Becattini C, Meyer G, et al. N Engl J Med 2020; March 29:[Epub ahead of print].


POPular-TAVI: OAC Alone Post TAVR For AFib?

Oral anticoagulation (OAC) alone after TAVR for patients with atrial fibrillation (AFib) was associated with a lower rate of bleeding, compared with OAC plus clopidogrel, and it was noninferior for major adverse ischemic events, according to results from the open-label POPular-TAVI trial presented during ACC.20/WCC and published in the New England Journal of Medicine.

Researchers enrolled 313 patients with AFib undergoing TAVR at 17 sites in four European countries. Half were assigned to OAC alone and half to OAC plus clopidogrel for three months after TAVR.

At 12 months, the co-primary outcome of all bleeding (Valve Academic Research Consortium-2 [VARC-2]) occurred in 21.7% of the OAC alone group vs. 34.6% of the OAC plus clopidogrel group (p=0.01). Among those treated with a vitamin K antagonist, the relative risk for all bleeding with OAC alone vs. OAC plus clopidogrel was 0.75 (95% confidence interval [CI], 0.5-1.14). For those treated with a direct oral anticoagulant, the relative risk was 0.28 (95% CI, 0.1-0.75).


The co-primary outcome of nonprocedural bleeding (Bleeding Academic Research Consortium [BARC]), occurred in 21.7% of the OAC alone group vs. 34.0% of the OAC plus clopidogrel group (p=0.02).

There was no increased risk of clotting-related complications in the OAC alone group, meeting the trial's prespecified secondary endpoint for noninferiority. A composite of cardiovascular death, ischemic stroke and myocardial infarction occurred in 13.4% of the OAC alone group and 17.3% of the OAC plus clopidogrel group (p for superiority not significant). A composite of those outcomes plus nonprocedural bleeding occurred in 31.2% and 45.5%, respectively (p for superiority <0.05).

"This study helps physicians to better understand the risks of adding antiplatelet therapy to oral anticoagulants—namely, that doing so leads to more bleeding without reducing the rate of ischemic events. I think once physicians are aware of this, they will not treat patients undergoing TAVR so aggressively, leading to better outcomes," says Vincent Nijenhuis, MD, the study's lead author." The researchers are assessing antiplatelet management in patients without AFib in a separate cohort of the ongoing POPular TAVI study.

Nijenhuis VJ, Brouwer J, Delewi R, et al. N Engl J Med 2020;March 29:[Epub ahead of print].


Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Pulmonary Hypertension and Venous Thromboembolism, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and ACS, Anticoagulation Management and Atrial Fibrillation, Anticoagulation Management and Venothromboembolism, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Interventions and ACS, Interventions and Vascular Medicine

Keywords: ACC Publications, Cardiology Magazine, Anticoagulants, Enoxaparin, Atrial Fibrillation, Aspirin, Peripheral Arterial Disease, Fibrinolytic Agents, Acute Coronary Syndrome, Odds Ratio, Risk, Numbers Needed To Treat, Double-Blind Method, Confidence Intervals, Retrospective Studies, Dalteparin, Venous Thromboembolism, Platelet Aggregation Inhibitors, Confidence Intervals, Brain Ischemia, Transcatheter Aortic Valve Replacement, Stroke, Pyridones, Pyrazoles, Hemorrhage

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