Stroke constitutes a phenotype of cardiovascular disease. International recommendations implement antiplatelet therapy with aspirin and/or clopidogrel for ischaemic stroke patients.
1
Both drugs inhibit pathways of platelet activation. However, there are patients on aspirin or clopidogrel who do not respond appropriately to these drugs. This phenomenon is described as “aspirin/clopidogrel resistance,” with prevalence in the range of 5–65% and 4–30% for each agent respectively, depending on cutoff values chosen, and population tested.- Piepoli M.F.
- Hoes A.W.
- Agewall S.
- Albus C.
- Brotons C.
- Catapano A.L.
- et al.
2016 European guidelines on cardiovascular disease prevention in clinical practice: the sixth joint task force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR).
Atherosclerosis. 2016; 252 (Authors/Task Force Members): 207-274
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, 3
Insufficient response to antiplatelet treatment has been recognised in coronary artery disease (CAD) treatment. Antiplatelet resistance has been identified as an independent predictor of major cardiovascular events in patients with CAD. Thus, in a collaborative meta-analysis including 3059 patients, the level of on-treatment platelet resistance was associated with long-term cardiovascular events after percutaneous coronary intervention, including death, myocardial infarction, and stent thrombosis.
4
Recently, antiplatelet resistance has been the centre of interest in stroke patients. Oh et al.
5
demonstrated that aspirin resistance is associated with an increased risk of severe stroke and large infarct volume. Other studies have suggested that patients with aspirin resistance are more prone to increased clinical severity stroke during the acute phase, early neurological deterioration and recurrent ischaemic lesions during the follow-up period.6
, 7
, 8
Studies on patients with clopidogrel resistance, have suggested that this phenomenon is associated with early neurological deterioration and recurrent ischaemic episode with poor neurological recovery.9
Antiplatelet resistance evaluation has exhibited lack of standardisation in the different measurement techniques and their threshold used to determine sufficient responses.
10
However, there are currently several platelet function tests (Light transmission aggregometry, VerifyNow, Platelet Function Analyser, thromboelastography. etc.) that are used for the assessment of aspirin/clopidogrel resistance in clinical studies, with the only limitation the need for particular attention when interpreting results.11
Recent trials have assessed the efficacy of new P2Y12 receptor inhibitors such as ticagrelor in prevention and treatment of cardiovascular events and stroke. In a pre-specified exploratory analysis of the SOCRATES trial,
12
ticagrelor was superior to aspirin at preventing stroke, myocardial infarction, or death at 90 days in patients with acute ischaemic stroke or transient ischaemic attack when associated with ipsilateral atherosclerotic stenosis. In the PEGASUS-TIMI 54 trial,- Amarenco P.
- Albers G.W.
- Denison H.
- Easton J.D.
- Evans S.R.
- Held P.
- et al.
SOCRATES Steering Committee and Investigators
Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial.
Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial.
Lancet Neurol. 2017; 16: 301-310
13
it was demonstrated that the addition of ticagrelor to aspirin may significantly reduce the risk of ischaemic stroke without increasing the haemorrhagic ones. Within this context, although these trials were not specifically addressing aspirin or clopidogrel resistance, they may point to the potential role of ticagrelor in patients with aspirin resistance.- Bonaca M.P.
- Goto S.
- Bhatt D.L.
- Steg P.G.
- Storey R.F.
- Cohen M.
- et al.
Prevention of stroke with ticagrelor in patients with prior myocardial infarction: insights from PEGASUS-TIMI 54 (prevention of cardiovascular events in patients with prior heart attack using ticagrelor compared to placebo on a background of aspirin-thrombolysis in myocardial infarction 54).
Circulation. 2016; 134: 861-871
Increasing evidence suggests that antiplatelet resistance in patients with cardiovascular disease and particularly in ischaemic stroke patients is common and correlates with the risk of future vascular events.
2
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, 4
, 5
, 6
, 7
, 8
, 9
Additionally, a recent overview of the literature demonstrated that patients displaying antiplatelet resistance are at higher risk of thromboembolic events during and after carotid revascularisation.14
The use of newer, more potent P2Y12 receptor inhibitors, may reduce the incidence of high platelet reactivity, but at the expense of increased bleeding risk.14
Evaluation of ischaemic stroke patients regarding antiplatelet resistance with exclusive laboratory tests might be of clinical importance. This may lead to a more individualised risk assessment because of aspirin and/or clopidogrel resistance. This may also allow the selective use of antiplatelet treatment, while further research is needed to assess the applicability of other newer antiplatelets.
Conflict of Interest
None.
References
- 2016 European guidelines on cardiovascular disease prevention in clinical practice: the sixth joint task force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR).Atherosclerosis. 2016; 252 (Authors/Task Force Members): 207-274
- Variable platelet response to aspirin and clopidogrel in atherothrombotic disease.Circulation. 2007; 115: 2196-2207
- Resistance to clopidogrel: a review of the evidence.J Am Coll Cardiol. 2005; 45: 1157-1164
- Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data.J Am Coll Cardiol. 2011; 58: 1945-1954
- Aspirin resistance is associated with increased stroke severity and infarct volume.Neurology. 2016; 86: 1808-1817
- Association of aspirin resistance with increased stroke severity and infarct size.JAMA Neurol. 2013; 70: 208-213
- Clinical implications of changes in individual platelet reactivity to aspirin over time in acute ischemic stroke.Stroke. 2015; 46: 2534-2540
- Aspirin resistance in the acute stages of acute ischemic stroke is associated with the development of new ischemic lesions.PLoS One. 2015; 10: e0120743
- Clopidogrel resistance increases rate of recurrent stroke and other vascular events in Chinese population.J Stroke Cerebrovasc Dis. 2016; 25: 1222-1228
- Antiplatelet resistance in stroke.Expert Rev Neurother. 2011; 11: 251-263
- Comparison of current platelet functional tests for the assessment of aspirin and clopidogrel response. A review of the literature.Thromb Haemost. 2016; 116: 638-650
- Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial.Lancet Neurol. 2017; 16: 301-310
- Prevention of stroke with ticagrelor in patients with prior myocardial infarction: insights from PEGASUS-TIMI 54 (prevention of cardiovascular events in patients with prior heart attack using ticagrelor compared to placebo on a background of aspirin-thrombolysis in myocardial infarction 54).Circulation. 2016; 134: 861-871
- The role of perioperative antiplatelet therapy and platelet reactivity testing in carotid revascularization: overview of the evidence.J Cardiovasc Surg (Torino). 2015; 56: 165-175
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Published online: May 18, 2017
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