Challenges and Unmet Needs in Antithrombotic Therapy for Stroke Prevention
Warfarin has long been established as the standard of care for prevention of stroke and thromboembolism in patients with AF. Several studies have evaluated the efficacy of antiplatelet therapy for the prevention of stroke in AF. In a meta-analysis of antithrombotic therapy to prevent stroke in patients with AF, antiplatelet therapy (eight trials, totalling 4,876 participants) reduced stroke by 22 % (CI, 6 to 35 %) compared to control. In contrast, adjusted-dose warfarin (six trials, totalling 2,900 participants) reduced stroke by 64 % (95 % CI, 9 to 74 %). 74 Thus, the low efficacy of aspirin compared with warfarin is a severe limitation.
However, effective warfarin therapy depends on inter- and intra-individual variability in maintaining the international normalised ratio (INR), which is driven by a number of genetic and
environmental factors. 76,105–111 For effective thromboprophylaxis with warfarin, the target intensity of anticoagulation involves a balance between stroke prevention and avoidance of haemorrhage, particularly intracranial haemorrhage. Maintaining the narrow therapeutic range of warfarin requires close and frequent monitoring of the patient’s INR, highlighting the benefit of monitoring in a designated anticoagulation clinic setting rather than community practice, although self-management can be effective in anticoagulation therapy.
The greater the proportion of time spent in the therapeutic range of warfarin the more effective the anticoagulation. By contrast, increased time spent outside the therapeutic range is associated
with an increased risk of mortality, ischaemic stroke or other thromboembolic event, myocardial infarction and major bleeding. Due to the risk of major bleeding, particularly intracranial haemorrhage, warfarin may not be recommended in patients at significant risk of bleeding. 12,28 The risk of major bleeding is greater in elderly patients ≥80 years of age, 90 who make up a large
proportion of patients with AF.
In antithrombotic therapy for stroke prevention in AF, the beneficial effect of antiplatelet therapy on ischaemic stroke appears to decrease with age compared with treatment with warfarin. In a meta-analysis, aspirin was associated with a lower rate of intracranial haemorrhage included in major bleeding event rates and extracranial haemorrhage compared with warfarin. These
findings were not supported in a study comparing warfarin and aspirin treatment in an elderly population (mean age = 81.5 years), which observed similar rates of major bleeding, including intra- or
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extracranial haemorrhage, in the two treatment groups.
Indeed, increasing age has a deleterious effect on the efficacy of aspirin, with little or no reduction in the risk of stroke in patients aged >75 years.
The consequences of inadequate thromboprophylaxis were highlighted in a study examining the effect of pre-admission antithrombotic therapy on stroke severity in 1,938 patients with
acute brain ischemia; 329 out of the 1,938 patients included had AF (17 %). 94 Fewer severe strokes were seen in patients treated with warfarin to INR ≥2.0 (38 %) (p=0.01) compared to patients treated with warfarin to INR <2.0 (59 %), patients treated with antiplatelet therapy (55 %) or patients receiving no treatment (70 %). Moreover, adequate adjusted-dose warfarin therapy was associated with better rates of survival (p=0.004).
Despite the demonstrated efficacy of warfarin for stroke prevention in AF, the perceived limitations of current therapeutic options have resulted in substantial underuse of antithrombotic therapy . This underuse has also been shown to result in increased risk for the combined endpoint of cardiovascular death, thromboembolism, or major bleeding. Underuse of vitamin K
agonists (VKAs) may be due to a number of physician and patient
related factors.
Current Guidelines on Stroke Prevention
Risk factors can be incorporated either formally in a scoring system as has been suggested by the European Society of Cardiology (ESC) or in an informal fashion as recommended in the 2006 American College of Cardiology Foundation/American Heart Association/ESC guidelines. The current ESC guidelines have been framed with an emphasis on a risk factor-based approach and less emphasis on
the use of the artificial low-/moderate-/high-risk strata due to the latter’s poor predictive value. The concept of stroke risk as a continuum has been adopted within the latest ESC guidelines, thus
emphasising the cumulative effect of various risk factors.
In relation to stroke prevention, the ESC recommendations for assessing antithrombotic therapy requirements utilise this risk factor-based approach. The CHADS2 scoring system is
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recommended for an initial rapid assessment of risk in non-valvular AF. For a more comprehensive assessment of risk, the CHA2DS2- VASc scheme, which considers ‘major’ and ‘clinically relevant non- major’ stroke risk factors, should be used. The antithrombotic strategy should be based on CHADS2/CHA2DS2-VASc scores.
The ESC guidelines also suggest the use of a new scoring system to evaluate the risk of bleeding, HAS-BLED (uncontrolled hypertension, abnormal renal/liver function, stroke, bleeding history or
predisposition, labile INR, elderly e.g. >65 years, drugs/alcohol concomitantly) (see Table 5). Each factor scores one point, with a maximum score of nine. A score of three or more suggests high risk
for bleeding. The predictive accuracy for one-year bleeding risk was consistent in different subgroups. This score is simple and provides a potentially practical tool in clinical decision-making. 102 A regular review of those patients with a HAS-BLED score ≥3 upon initiation of antithrombotic therapy is highly recommended.
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