Evolving Approaches to Antithrombotics in Stroke Prevention and Treatment

Vijayakumar Javalkar, MD, MCh; Okkes Kuybu, MD; Abdallah Amireh, MD; Roger E. Kelley, MD


South Med J. 2020;113(11):585-592. 

In This Article



Stroke prevention with oral anticoagulation in the setting of AF is recommended in higher-risk patients with thromboembolic disease with an elevated CHA2DS2VASc score of ≥2 in men or ≥3 in women.[10] In recent years, four NOACs (Table 3) have been approved for stroke prevention in NAVF based on their superiority or noninferiority in efficacy, as well as safety, compared with warfarin in randomized controlled trials (RCTs).[11] No dose monitoring is required and fewer drug–drug and drug–food interactions are observed with NOACs. They also tend to be better tolerated in older adults.[12]

There are no head-to-head RCTs comparing the efficacy of one NOAC to another. A retrospective observational study of patients with NAVF treated with apixaban, dabigatran, rivaroxaban, or warfarin was conducted with pooled data from the Centers for Medicare & Medicaid Services and four US commercial claims databases.[13] In this nonrandomized study, apixaban was associated with a lower rate of stroke/systemic embolism (SSE) and major bleeding when compared with dabigatran (SSE hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.56–0.84; major bleed HR 0.77, 95% CI 0.68–0.87) and rivaroxaban (SSE HR 0.80, 95% CI 0.71–0.91; major bleed HR 0.55, 95% CI 0.51–0.59). Dabigatran was associated with a lower rate of major bleeding (HR 0.70, 95% CI 0.63–0.77) compared with rivaroxaban, with similar rates of SSE (HR 1.15, 95% CI 0.96–1.37). These results should be interpreted with caution because the comparisons were intended for hypothesis generation only.

AF in Acute Coronary Syndrome (ACS) With or Without Percutaneous Coronary Intervention (PCI)

Approximately 5% to 7% of patients who undergo PCI have AF.[14] The optimal strategy is not clear because one must balance the risk of stent thrombosis with embolic stroke risk and bleeding complications. Combination therapy is reported to be associated with a higher bleeding risk, with rates up to 2.2% within the first month and 4% to 12% within the first year of treatment.[15]

The AUGUSTUS (Aspirin Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention) trial[16] looked at ischemic events versus bleeding in patients with AF and recent ACS with or without PCI. This study showed that an antithrombotic regimen that included a P2Y12 inhibitor plus apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations. Furthermore, this was without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both.

The PIONEER AF-PCI trial (A Study Exploring Two Strategies of Rivaroxaban [JNJ39039039; BAY-59–7939] and One of Oral Vitamin K Antagonist in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention)[15] compared three antithrombotic regimens in patients with AF undergoing PCI with stents. This study reported that the administration of either 15 mg/day rivaroxaban plus a P2Y12 inhibitor for 12 months or 2.5 mg/day rivaroxaban twice daily, plus dual antiplatelet therapy (DAPT), for 1, 6, or 12 months, was associated with a lower rate of clinically significant bleeding than was therapy with a vitamin K antagonist plus DAPT for 1, 6, or 12 months. There was no significant increase in the risk of ischemic events, including stroke, or stent thrombosis.

AF Treatment in Patients With Cerebral Microbleeds (CMBs)

The presence of CMBs on brain magnetic resonance imaging scan raises concerns about a possibly enhanced bleeding risk with anticoagulant therapy in AF. CMBs have been associated with a greater relative risk of both ischemic and hemorrhagic strokes.[17] In a subgroup analysis of five RCTs, the estimated absolute risk reduction of all of the anticoagulants for ischemic stroke exceeded the absolute estimated rates of hemorrhagic stroke across all of the subtypes of CMB.[18] The analysis supports that the benefit of anticoagulant therapy in AF patients persists in patients with CMBs; however, further stratification of risk with CMBs is in order.[19]

AF and Valvular Heart Disease

Dabigatran was compared with warfarin in patients with mechanical heart valves.[20] There were increased thromboembolic events and bleeding complications with dabigatran that resulted in early trial termination. In the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial of dabigatran versus warfarin in patients with AF, with a subsequent analysis[21] of patients with valvular heart disease, the thromboembolic event rates were lower for dabigatran at a dose of 150 mg twice per day, compared with warfarin, with similar rates seen between warfarin and dabigatran dosing of 110 mg twice per day. Both the American Heart Association and the American College of Cardiology,[22] as well as their European counterparts[23] advise against the use of NOACs in patients with AF and prosthetic heart valves, especially mechanical, significant mitral stenosis, or valvular heart disease that requires intervention, however.