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.

Abstract and Introduction

Abstract

The optimization of antithrombotic therapy for acute stroke treatment and secondary prevention is an evolving process based on an increasing array of studies that provide an evidence-based approach. Options have increased dramatically with the release of the non–vitamin K oral anticoagulants and with the results of recent randomized clinical trials designed to assess potential benefits versus risks for patients in an individualized fashion. Recent studies have provided important information to guide choice and dosing of antiplatelet agents as well as the length of treatment. Anticoagulant use is particularly pertinent for stroke prevention in patients at higher risk of atrial fibrillation and may have a place in certain other stroke mechanisms. One important focus of study is the potential benefit of combined antiplatelet and anticoagulant therapy. Options for our patients, when the initial choice of therapy does not demonstrate benefit or is not well tolerated, clearly, are valuable. For example, short-term dual antiplatelet therapy for minor stroke and transient ischemic attack is being adopted, but with the recognition that longer-term combined therapy is not worth the increased risk of bleeding. Alternative antiplatelet choices, such as cilostazol and possibly ticagrelor, may be of benefit for refractory patients and this could affect the decision-making process. This review represents an effort to incorporate the information from more recent stroke prevention and treatment studies with information gleaned from prior studies.

Introduction

Antithrombotic therapy typically is subcategorized to antiplatelet therapy and anticoagulant therapy. Antiplatelet agents include aspirin, clopidogrel, dipyridamole, ticagrelor, prasugrel, and cilostazol. Aspirin, as a monotherapy for the prevention of recurrent nonembolic stroke, is well established. In selected cases, aspirin for primary prevention of stroke is justified, as summarized in Table 1.^[1,2] There have been a number of studies addressing secondary ischemic stroke prevention with the antiplatelet agents aspirin, dipyridamole, and clopidogrel either alone or in combination. The results have been somewhat contradictory, based upon clinical trials and meta-analyses. Table 2 ^[2–4] attempts to summarize the pertinent information provided by these previous studies. Anticoagulants include warfarin and non–vitamin K oral anticoagulants (NOACs) for prevention of stroke in higher risk patients with nonvalvular atrial fibrillation (NVAF). In previous trials, warfarin showed no benefit over aspirin in secondary stroke prevention for patients with nonembolic stroke, those with at least 50% symptomatic intracranial atherosclerosis, or those with significantly reduced cardiac ejection fraction.^[5–7]

Following atherosclerotic plaque rupture, platelets play an important role in the formation of occlusive thrombus by platelet activation and aggregation.^[8] The relative contribution of various platelet activation pathways (ie, adenosine diphosphate platelet, thromboxane A2 platelet, thrombin platelet, coagulation, and phosphodiesterase activity) to the development of thrombus formation in the individual patient is unknown.^[9]

More recent studies, guided by information provided from earlier studies, have provided important information regarding preferable antiplatelet dosing and length of treatment. The choice of an antithrombotic agent for stroke treatment and prevention should be based on a mechanistic approach toward the ischemic threat. For example, anticoagulant therapy tends to be most applicable for a cardiogenic source of cerebral embolus, hypercoagulable condition, or cerebral venous sinus thrombosis. Small- or large-vessel thrombotic risk is more effectively managed with antiplatelet therapy; however, a combination of therapies may be in order in certain conditions. This review focuses on how to effectively navigate an evidence-based approach to optimize stroke preventive care for our patients.

We conducted a cumulative review by researching the available English-language studies. The literature review was performed using PubMed. Randomized trials and their subgroup analyses, relevant society guidelines, and meta-analyses were included. When faced with the lack of availability of controlled comparisons, we included relevant descriptive studies. The studies reviewed were published from 1996 to 2019. The mechanism of action of the antiplatelet agents and NOACs, as well as suggested dosing, are summarized in Table 3.

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Table 1. Aspirin therapy for primary prevention of stroke ^1,2
	Level of evidence
Not considered beneficial for the prevention of first stroke in low-risk individuals	Class III; Level of Evidence A
The use of aspirin for cardiovascular or cerebrovascular prophylaxis is reasonable for people at sufficiently high ischemic risk. The 10-y risk identified is >10% for the benefits to outweigh the risks associated with treatment.	Class IIa; Level of Evidence A
Aspirin at 81 mg/d or 100 mg every other day may be of potential value for primary stroke prevention in women with diabetes mellitus and whose risk is sufficiently high, factoring in risks versus the benefits of treatment.	Class IIa; Level of Evidence B
Aspirin is not useful in primary stroke prevention in diabetic patients in the absence of other high-risk comorbid factors.	Class III; Level of Evidence A
As a result of a lack of relevant clinical trials, antiplatelet regimens other than aspirin, as well as cilostazol, are not recommended for the prevention of a first stroke.	Class III; Level of Evidence C

Table 2. Comparison of aspirin, aspirin plus dipyridamole, and clopidogrel
RCT/meta-analysis	Antiplatelet studied	Primary endpoint	Results
CAPRIE³	Clopidogrel 75 mg vs aspirin 325 mg/d	Ischemic stroke, MI, or vascular death.	Annual endpoint risk was 5.32% with clopidogrel vs 5.83% with aspirin (P = 0.043). The RR reduction was 8.7% in favor of clopidogrel In the ischemic stroke subgroup, the RR reduction was 7.3% (not significant) There were no major differences in terms of safety with similar rates of hemorrhage
Meta-analysis²	Aspirin vs aspirin plus dipyridamole	Recurrent stroke	Extended-release dipyridamole showed a statistically significant difference in favour of the combination for stroke alone with RR 0.76 and for the composite outcome with RR 0.82
PRoFESS⁴	Clopidogrel vs ASA-ERDP	Recurrent stroke	Recurrent stroke of any type, clopidogrel (8.8%) vs ASA-ERDP (9%), (HR 1.01, 95% CI 0.92–1.11) More hemorrhagic events in the ASA-ERDP group (HR 1.15, 95% CI 1–1.32)

ASA-ERDP, Aspirin plus Extended Release Dipyridamole; CAPRIE, Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events; CI, confidence interval; HR, hazard ratio; MI, myocardial infarction; PRoFESS, Prevention Regimen for Effectively Avoiding Second Strokes; RCT, randomized controlled trial; RR, relative risk.

Table 3. Antithrombotic agents, mechanism of action, and dosing
	Mechanism of action	Suggested dosing
Antiplatelets
Aspirin	Inhibits platelet cyclooxygenase and the synthesis of prostaglandin and thromboxane A2; inhibits platelet aggregation	Initial acute stroke dose 160–325 mg Long-term dose 81–325 mg
Clopidogrel	Inhibitor of ADP-induced pathway for platelet aggregation Activemetabolite irreversibly binds to the P2Y12 class of ADP receptors on platelets	300–600 mg loading dose when indicated, followed by 75 mg/d
Dipyridamole	Inhibition of adenosine uptake into platelets, erythrocytes, and endothelial cells, thereby inhibiting platelet reactivity Phosphodiesterase inhibition increasing cAMP in platelets Inhibition of thromboxane A2 formation	Available in 200mg combined with 25 mg aspirin to be given twice daily
Ticagrelor	Drug and its major metabolite reversibly interact with the platelet P2Y12 ADP receptor to prevent signal transduction and platelet activation	Loading dose of 180mg when indicated followed by 90 mg twice daily
Cilostazol	Inhibits phosphodiesterase III, causing cAMP to increase, which in turn inhibits platelet aggregation Causes homogeneous vasodilation	100 mg twice daily Has been effective in stroke prevention when combined with aspirin or clopidogrel
NOAC
Apixaban	Blocks selectively and reversibly the active site of factor Xa without requiring a cofactor for activity; no direct effect on platelet aggregation but indirectly inhibits platelet aggregation induced by thrombin (blood coagulation cascade is dependent on the activation of factor X to factor Xa via the intrinsic and extrinsic pathways)	5 mg twice daily Dose reduced to 2.5 mg/d if 2 of the 3 dose-reducing criteria are met^a
Rivaroxaban	Blocks selectively the active site of factor Xa without requiring a cofactor for activity	20 mg/d for atrial fibrillation Showed efficacy at 2.5mg twice daily plus aspirin in presence of concomitant stable CAD or PAD
Edoxaban	Blocks selectively and reversibly the active site of factor Xa without requiring a cofactor for activity	CrCl >50 mL/min: 60 mg/d CrCl 15–50 mL/min: 30 mg/d
Dabigatran	Prevents thrombus development through direct, competitive inhibition of thrombin (thrombin enables fibrinogen conversion to fibrin during the coagulation cascade)	CrCl >30 mL/min: 150 mg twice daily CrCl 15–30 mL/min: 75 mg twice daily

ADP, adenosine diphosphate; CAD, coronary artery disease; cAMP, cyclic adenosine monophosphate; CrCl, creatinine clearance; NOAC, non-vitamin K oral anticoagulants; PAD, peripheral artery disease
^aApixaban dose is reduced to 2.5 mg twice daily when 2 of the following criteria are met: age ≥80 y, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.

Table 4. Antithrombotic regimens used in major trials and meta-analyses
Trial/meta-analysis	Antithrombotic regimen
Symptomatic intracranial stenosis (SAMMPRIS)⁴⁹	Aspirin 325 mg/d and clopidogrel 75 mg for 90 d, management of the primary risk factors with control of systolic blood pressure <140 mm Hg (<130 mm Hg, if diabetic) and low-density lipoprotein-cholesterol <1.81 mmol/L, management of secondary risk factors (diabetes mellitus, non–high-density lipoprotein-cholesterol, smoking, weight, exercise) with the help of lifestyle-modification programs
Minor stroke/high-risk TIA (pooled analysis of CHANCE and POINT)⁴⁷	The benefit of DAPT (aspirin plus clopidogrel) appeared to be confined to the first 21 d after minor ischemic stroke or high-risk TIA
Aortic Arch Disease with complex features (ARCH and the subgroup analysis of NAVIGATE ESUS)^62–65	Warfarin (INR 2–3) was not superior to aspirin (75–150 mg) plus clopidogrel 75 mg Rivaroxaban 15 mg/d was not superior to aspirin 100 mg/d
Extracranial Cervical Artery or Vertebral Artery Dissection (CADISS)⁵⁴	No difference in stroke recurrence among aspirin-only, clopidogrel-only, dipyridamole-only, or in dual therapy or anticoagulation
Symptomatic Ipsilateral Intracranial/Extracranial Stenosis (SOCRATES)⁵²	Ticagrelor at an initial dose of 180 mg, followed by 90 mg b.i.d. for 90 d was superior to aspirin 300 mg, followed by 100 mg/d
High-risk noncardioembolic stroke⁴⁴ (meet at least 1 of the following 3 criteria: at least 50% stenosis of a major intracranial artery, at least 50% stenosis of an extracranial artery, and ≥2 risk factors derived from the Essen Stroke Risk Score and Fukuoka Stroke Risk Score)	Cilostazol 100 mg b.i.d. plus aspirin (81 or 100 mg/d) or clopidogrel (50 or 75 mg/d) was superior to monotherapy aspirin or clopidogrel
Stable CAD and PVD (COMPASS)⁵³	Rivaroxaban 2.5 mg b.i.d. + aspirin 100 mg daily was superior than aspirin 100 mg daily only or rivaroxaban 5 mg twice daily only
Atrial fibrillation in ACS or after PCI (AUGUSTUS)¹²	Apixaban 5 mg b.i.d. plus Plavix 75 mg
Nonvalvular atrial fibrillation⁷	NOACs
PFO²²	In patients <60 years old, PFO closure + medical antithrombotic (primarily antiplatelet) beneficial reduction in recurrent ischemic stroke when compared with long-term antithrombotic therapy (antiplatelet or anticoagulant) alone

ARCH, Aortic Arch Related Cerebral Hazard; ACS, acute coronary syndrome; AUGUSTUS, Aspirin Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention; CAD, coronary artery disease; CHANCE, Clopidogrel With Aspirin in Acute Minor Stroke or Transient Ischemic Attack; COMPASS, Stroke Outcomes In The Cardiovascular Outcomes For People Using Anticoagulation Strategies Dual Antiplatelet Therapy; INR, international normalized ratio; NAVIGATE-ESUS, The New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. ASA to Prevent Embolism in Embolic Stroke of Undetermined Source; NOAC, non-vitamin K oral anticoagulants; PCI, percutaneous coronary intervention; PFO, patent foramen ovale; POINT, The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke; SAMMPRIS, Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis; SOCRATES, The Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes; TIA, transient ischemic attack.