Difficulties in Antithrombotic Choices in Prevention of Stroke Recurrence: Combination Antiplatelet and Anticoagulant Therapies

The neurologist evaluating a patient with possible transient ischemic attack (TIA) or ischemic stroke in the office setting must address several issues related to antithrombotic management. For patients for whom a cerebrovascular event is first considered in the office setting, the questions are which antithrombotic therapies to initiate and whether to use a combination of drugs. Most of the patients evaluated in the office will have first been seen in the hospital. In these instances, the question becomes whether, and for how long, to continue a dual antithrombotic regimen based on whether the hospital therapeutic plan appropriately addressed all diagnostic concerns. The critical decision points in either instance are whether to use antiplatelet agents or anticoagulants and whether to use them as monotherapy or in combination (see Figure 1 for treatment flow diagram).

Dual Antiplatelet Therapy

Antiplatelet monotherapy, traditionally using aspirin, has been the mainstay in the medical management of noncardioembolic stroke. Three clinical trials—Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT),² Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE),¹ and The Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and ASA (Acetylsalicylic Acid) for Prevention of Stroke and Death (THALES)³—support the use of PY12 inhibitors (clopidogrel or ticagrelor) along with low-dose aspirin for TIA or acute ischemic stroke. CHANCE was a Chinese multicenter randomized study that suggested a benefit for clopidogrel with a loading dose of 300 mg followed by 75 mg/day for 21 days with antiplatelet monotherapy thereafter.1 Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduced the risk of stroke (hazard ratio [HR] .68, 95% CI .57–.81) but did not increase the risk of major hemorrhage compared with monotherapy. POINT was a similar trial, based primarily in North America, in which participants received a clopidogrel loading dose of 600 mg within 24 hours of symptom onset followed by clopidogrel 75 mg/day plus aspirin (at a dose of 50 to 325 mg/day) vs aspirin monotherapy for 90 days.² Subsequent analyses of POINT suggested that the maximal benefit, as with CHANCE, occurred with a DAPT duration of 3 weeks as compared with aspirin monotherapy.² Current American Heart Association (AHA) guidelines therefore recommend that individuals presenting within 24 hours with minor acute ischemic stroke (National Institutes of Health Stroke Scale score ≤3) or high-risk TIA (ABCD2 score ≥4) not attributable to causes requiring anticoagulation or other specific antithrombotic regimens (ie, atrial fibrillation [AF], intracranial stenosis) should receive DAPT for a limited duration followed by antiplatelet monotherapy for secondary stroke prevention, with 21 days of DAPT being the time duration with greatest benefit and least risk of bleeding and no additional benefit for DAPT observed beyond 90 days.⁴ Other medical comorbidities, such as coronary artery disease or peripheral vascular disease, may warrant DAPT for a longer duration for reasons other than cerebrovascular disease.

Clopidogrel and aspirin is the most widely used DAPT combination but efficacy concerns exist for both drugs. Limitations of aspirin include medication noncompliance, polymorphisms of the cyclo-oxygenase-1 (COX-1) gene, reduced absorption due to inadequate dose or as a result of the intake of proton pump inhibitors, advanced age, and body weight specifications.⁵ A meta-analysis involving 8723 people with ischemic stroke or TIA while on aspirin monotherapy at the time of the index ischemic event explored outcomes when people were either switched to a different antiplatelet agent, such as clopidogrel or ticagrelor, or continued on aspirin monotherapy. The analysis showed that switching or adding a second antiplatelet agent was associated with reduced risk of recurrent stroke.⁶ This confirms the rationale for changing to a PY12 inhibitor for people who experienced an event on aspirin.

Clopidogrel is a prodrug metabolized hepatically into its active form that then binds and inactivates P2Y12 platelet receptors, thus inhibiting platelet aggregation. Advanced age, diabetes, and kidney dysfunction are factors that can limit clopidogrel use. Furthermore, the bioavailability of clopidogrel is influenced by genetic polymorphisms in certain populations, with an approximate carrier incidence of the CYP2C19 loss-of-function allele in 25% to 35% of the White population, 35% to 45% of the Black population, and more than 50% to 70% of the Asian population. A meta-analysis showed that among individuals with stroke or TIA treated with clopidogrel, carriers of CYP2C19 loss-of-function alleles had increased risk of recurrent stroke and composite vascular events in comparison with noncarriers.⁷ Genetic testing might be indicated to guide the use of clopidogrel, classifying individuals as normal, intermediate, or poor metabolizers of CYP2C19. Guidelines suggest that for CYP2C19 intermediate and poor metabolizers, there is a moderate recommendation to avoid clopidogrel if possible and consider an alternative P2Y12 inhibitor.⁸ However, genetic testing is not always readily available when therapy is initiated.

Ticagrelor and prasugrel are alternative P2Y12 inhibitors that are not affected by CYP2C19 genetic variants. Prasugrel is contraindicated for use in people with a history of TIA or stroke, however.⁴ In the THALES study, ticagrelor (180 mg loading dose followed by 90 mg twice daily) plus aspirin (300 to 325 mg loading does followed by 75 to 100 mg daily) for 30 days was shown to be slightly superior to aspirin alone in preventing recurrent stroke (recurrent stroke rate, 5% vs 6.3%; P=.004) but was also associated with significantly increased risk of severe bleeding (.5% vs .1%; P=.001).³ A meta-analysis showed that the combination of aspirin plus ticagrelor, although effective for reducing the risk for stroke recurrence and composite efficacy outcomes, is associated with a higher risk of bleeding.⁹ The CHANCE-2 trial exclusively enrolled participants with reduced CYP2C19 function on genetic testing and compared the effects of ticagrelor plus aspirin with standard-dose clopidogrel (75 mg/day) plus aspirin over 90 days.10 Compared with clopidogrel, people with reduced CYP2C19 function treated with ticagrelor experienced significantly lower rates of stroke (7.6% vs 6.0%, respectively; hazard ratio [HR] .77, 95% CI .64–.94; P=.008) and major vascular events (9.2% vs 7.2%, respectively; HR .77, 95% CI .65–.92). Ticagrelor was associated with higher rates of mild bleeding (HR 2.41, 95% CI 1.81–3.20).¹⁰ In addition, ticagrelor is dosed twice daily, which may influence adherence.

Dipyridamole has been studied as an antiplatelet agent for secondary stroke risk reduction when used in combination with aspirin.¹¹ A meta-analysis comparing aspirin plus dipyridamole with aspirin monotherapy for secondary stroke prevention showed that aspirin plus extended-release dipyridamole (ERDP) was superior to aspirin alone in preventing ischemic strokes (relative risk [RR] .76, 95% CI .65–.89).¹² The risk reduction was greater and statistically significant for studies using primarily ERDP as compared with immediate-release dipyridamole. In the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study,¹³ however, comparing aspirin plus ERDP vs clopidogrel, both groups were found to have similar rates of stoke recurrence and risk of major hemorrhagic event without either therapy demonstrating therapeutic superiority as compared with the other treatment arm.¹³ ERDP plus aspirin is of limited use in clinical practice due to twice-daily dosing and adverse effects including headaches and gastrointestinal symptoms leading to high rates of nonadherence and drug discontinuation. As such, this regimen should be considered third-line therapy.

Cilostazol has been studied, particularly in Japan, as an antiplatelet agent for stroke risk reduction. The Second Cilostazol Stroke Prevention Study (CSPS-2),^14,16 a noninferiority study that compared the efficacy and safety of cilostazol vs aspirin for the secondary prevention of stroke, found that stroke recurrence was reduced in the cilostazol group (HR .74, 95% CI .56–.98).¹⁴ Several adverse reactions, including headache and palpitations, led to higher rates of treatment termination in the cilostazol group. These findings were reproduced in a meta-analysis of 6 randomized controlled trials that found cilostazol to be associated with significantly lower rates of strokes (RR .67, 95% CI .55–.82) and bleeding events (RR .53, 95% CI .37–.74) as compared with aspirin.¹⁵ The role of cilostazol as an agent in DAPT for noncardioembolic secondary stroke risk prevention was also studied and showed that combination of cilostazol and clopidogrel significantly reduced the recurrence of ischemic stroke (HR .447, 95% CI .258–.774) without increasing the bleeding risk (HR .730, 95% CI .206–2.588).¹⁶ Another study reviewing the role of cilostazol in DAPT in people with stroke with intracranial stenosis found that combination of cilostazol with either clopidogrel or aspirin was superior to monotherapy with aspirin or clopidogrel for prevention of recurrent stroke without increasing the risk of bleeding.¹⁷ Despite these data, it is important to consider that all these studies involved the Asian population, which limits its generalizability. Cilostazol is not recommended by the AHA as part of an alternate DAPT regimen and cilostazol may be contraindicated in patients with heart failure.

DAPT may be appropriate in longer-term treatment of symptomatic intracranial stenosis. AHA guidelines, based on the Stenting vs Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMPRISS) study,4 recommend that intermediate-term treatment with the combination of aspirin and clopidogrel (within 30 days of the index event) for up to 90 days plus aggressive risk factor management should be considered in people with symptomatic severe intracranial stenosis (70% to 99%).⁴ This recommendation, however, is not based on a randomized comparison of DAPT vs monotherapy but rather a comparison of DAPT vs intracranial stenting over 90 days. Alternate therapies that can be considered include ticagrelor 90 mg twice daily plus aspirin for up to 30 days (started within 24 hours of the event) in people with symptomatic intracranial atherosclerotic stenosis >30% and, although the evidence is not strong, cilostazol plus aspirin or clopidogrel for 50% to 99% stenosis of a major intracranial artery.

Anticoagulant Plus Antiplatelet Therapy

The role of anticoagulation in stroke prevention in people with atrial flutter or AF is well-established. Other indications for anticoagulation in people who experience stroke are numerous, with examples being cancer-related hypercoagulability, treatment of concomitant deep vein thromboses or pulmonary embolism, and treatment of individuals with various genetic and acquired abnormalities of the coagulation and platelet aggregation pathways. The current recommended treatment for these conditions is beyond the scope of this review. Here, we discuss the use of combination antiplatelet and anticoagulation therapy. When using the term “anticoagulation,” we collectively refer to a multitude of oral agents with varying mechanisms of action, primarily vitamin K antagonists such as warfarin or direct oral anticoagulants (DOACs) such as apixaban, rivaroxaban, edoxaban, and dabigatran.

There remains an ongoing debate about anticoagulation in presumptive embolic stroke of unknown source (ESUS).¹⁸ Potential embolic causes include subclinical AF, atrial cardiopathy, occult myocardial infarction (with or without reduction in ejection fraction or apical akinesis), cancer-related hypercoagulability, atherosclerotic rupture and embolism, or other arterial vascular pathologies (dissection, infection, or inflammation).

New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS)²⁰ and Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate versus Acetylsalicylic Acid in Patients with Embolic Stroke of Undetermined Source (RESPECT-ESUS)¹⁹ both assessed anticoagulation for stroke prevention, in comparison with aspirin, in cases of unproven cardioembolic stroke. NAVIGATE-ESUS was discontinued early due to futility but RESPECT-ESUS was followed through to completion. In both studies, anticoagulation resulted in an increased incidence of bleeding without apparent reduction in stroke risk. Subgroup analysis suggested that for individuals at higher risk for AF, there might be a benefit to anticoagulation.

Shoamanesh et al.²¹ further analyzed the NAVIGATE-ESUS data for any correlation between presence of cerebral microbleeds and outcomes and found little correlation between rivaroxaban alone and increased bleeding risk in people with cerebral microbleeds. Martí-Fàbregas and colleagues²² presented data from 12,669 people with TIA or ischemic stroke and demonstrated that antiplatelet or anticoagulant therapy alone in people with cerebral siderosis or cerebral microbleeds was associated with decreased recurrent stroke risk and no increase in hemorrhagic risk. Combination therapy, however, was associated with increased bleeding in this population. People with cortical superficial siderosis (CSS) who were treated with both antiplatelet and anticoagulant drugs had a higher incidence of intracranial hemorrhage (incidence ratio [IR] 107.5 vs 4.9 per 1000 patient-years; adjusted HR 13.26, 95% CI 2.90–60.63; P=.001) and any stroke (IR 198.8 vs 34.7 per 1000 patient-years; adjusted HR 5.03, 95% CI 2.03–12.44; P<.001) compared with the group without CSS.22 Therefore, obtaining an MRI to rule out the possibility of microbleeds or CSS prior to initiating anticoagulant plus antiplatelet therapy may be warranted.

An additional risk factor for ESUS is the presence of a patent foramen ovale (PFO). There are limited data on the role of specific anticoagulation therapies, or combination therapy vs closure, as most of the PFO closure studies compared closure with antiplatelet monotherapy. In one meta-analysis, performed in 2021, there appeared to be no difference in outcomes for individuals receiving either aspirin or anticoagulation.¹⁸ There are insufficient trial data to address this specific issue.

One subcategory of ESUS includes people with atrial cardiopathy and its role in thrombus generation in the absence of AF. The Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke (ARCADIA) trial²³ is investigating whether apixaban is superior to aspirin for the prevention of stroke in patients with cryptogenic stroke and atrial cardiopathy. The results of this trial may demonstrate benefit of anticoagulation in biomarkers suggestive of subclinical AF or intracardiac pathology leading to thrombus generation that may benefit from anticoagulation even when AF is not detected.²³

Anticoagulation alone is preferred in individuals with stroke and AF with concomitant atherosclerotic cerebrovascular disease, although some researchers had argued for DOACs plus aspirin in this subgroup. The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial²⁴ supports the concept of lower-dose DOAC anticoagulation in combination with aspirin, at least in noncardioembolic stroke. People with stable cardiovascular disease, including those with carotid artery disease, were assigned to one of three groups: lower dose rivaroxaban 2.5 mg twice daily in combination with aspirin 100 mg daily, rivaroxaban 5 mg twice daily (the dose used in AF), and aspirin 100 mg daily. The trial was stopped early when the combination therapy demonstrated better efficacy in reducing stroke. Anticoagulation monotherapy caused further bleeding risk without additional cardiovascular benefit.²⁴

Despite the presumed necessity of triple therapy—anticoagulation and DAPT for certain groups (ie, individuals with AF requiring a cardiac stent or peripheral artery stent)—triple therapy was associated with a significant increase in bleeding events when the additional antiplatelet agent was extended beyond 30 days.²⁵ Thus, triple therapy should be avoided in individuals who have had a stroke and should not be used beyond 30 days in most people with cardiovascular disease.

Summary

With few exceptions, dual antithrombotic therapies should be used for only a few weeks. For the office-based neurologist, the long-term decision remains to determine which monotherapy is best suited for an individual patient based on careful delineation and confirmation of the underlying stroke mechanism. Anticoagulation should be reserved for defined and established embolic or hypercoagulable stroke etiologies with antiplatelet monotherapy as the default long-term treatment paradigm.