A Combination of Aspirin and Clopidogrel Predict More Favorable Dynamics of Platelet Reactivity versus Clopidogrel Alone in the Acute Phase of Minor Stroke

Background: The combined use of clopidogrel and aspirin is recommended for the short-term (21 days) therapy of minor stroke or transient ischemic attack. Previous studies have demonstrated its efficacy and superiority over treatment with a single antiplatelet agent. However, there is insufficient support for the advantages of such therapy based on platelet function testing. We aimed to compare the effect of the concomitant use of clopidogrel and aspirin versus clopidogrel alone on the dynamics of platelet reactivity over time to determine the appropriate antiplatelet treatment strategy for minor strokes. Methods: We enrolled 74 ischemic stroke subjects, including 38 minor strokes. Platelet reactivity was assessed by impedance aggregometry (Multiplate Analyzer) 48 and 96 h after a first 75 mg dose of clopidogrel, using the acetylsalicylic acid platelet inhibition (ASPI) test and the adenosine diphosphate (ADP) test. Dual antiplatelet therapy was strictly reserved only to minor strokes, as the other strokes received clopidogrel alone in the secondary prevention. The dynamics of platelet reactivity refer to the difference between two assessments, and a decrease in values over time was considered favorable. Results: The incidence of clopidogrel non-responsiveness was 64.8%, and this was similar in the group of minor strokes and the group of more disabling strokes. We indicated diabetes mellitus as an independent predictor of high on-clopidogrel platelet reactivity (Odds ratio OR 5.69 95% Confidence Interval CI 1.13–41.26, p = 0.0386). Among minor strokes treated with dual antiplatelet therapy, in relation to clopidogrel, we reported a trend toward more favorable dynamics of platelet reactivity over time compared to the group using clopidogrel alone (p = 0.0652 vs. p = 0.3384, respectively). We identified five predictors (sex, female; small-vessel disease; no diabetes; no hyperlipidemia; and no alcohol abuse) related to a significant decrease in platelet reactivity over time with respect to clopidogrel. No significant dynamics of platelet reactivity when using aspirin were found. Conclusions: Our findings, based on the favorable dynamics of platelet reactivity over time in relation to clopidogrel, confirm the usefulness of dual antiplatelet therapy in minor strokes and support the continuation of the secondary prevention with clopidogrel alone rather than aspirin, particularly among identified beneficiaries of such a strategy.

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Multifactorial Background for a Low Biological Response to Antiplatelet Agents Used in Stroke Prevention

Medicina ◽

10.3390/medicina57010059 ◽

2021 ◽

Vol 57 (1) ◽

pp. 59

Author(s):

Adam Wiśniewski

Keyword(s):

Ischemic Stroke ◽

Secondary Prevention ◽

Antiplatelet Therapy ◽

Negative Impact ◽

Platelet Reactivity ◽

Antiplatelet Agent ◽

Biological Response ◽

Antiplatelet Agents ◽

Platelet Inhibition ◽

High Risk Group

Effective platelet inhibition is the main goal of the antiplatelet therapy recommended as a standard treatment in the secondary prevention of non-embolic ischemic stroke. Acetylsalicylic acid (aspirin) and clopidogrel are commonly used for this purpose worldwide. A low biological response to antiplatelet agents is a phenomenon that significantly reduces the therapeutic and protective properties of the therapy. The mechanisms leading to high on-treatment platelet reactivity are still unclear and remain multifactorial. The aim of the current review is to establish the background of resistance to antiplatelet agents commonly used in the secondary prevention of ischemic stroke and to explain the possible mechanisms. The most important factors influencing the incidence of a low biological response were demonstrated. The similarities and the differences in resistance to both drugs are emphasized, which may facilitate the selection of the appropriate antiplatelet agent in relation to specific clinical conditions and comorbidities. Despite the lack of indications for the routine assessment of platelet reactivity in stroke subjects, this should be performed in selected patients from the high-risk group. Increasing the detectability of low antiaggregant responders, in light of its negative impact on the prognosis and clinical outcomes, can contribute to a more individualized approach and modification of the antiplatelet therapy to maximize the therapeutic effect in the secondary prevention of stroke.

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Unfavorable Changes of Platelet Reactivity on Clopidogrel Therapy Assessed by Impedance Aggregometry Affect a Larger Volume of Acute Ischemic Lesions in Stroke

Diagnostics ◽

10.3390/diagnostics11030405 ◽

2021 ◽

Vol 11 (3) ◽

pp. 405

Author(s):

Adam Wiśniewski ◽

Joanna Sikora ◽

Aleksandra Karczmarska-Wódzka ◽

Przemysław Sobczak ◽

Adam Lemanowicz ◽

...

Keyword(s):

Platelet Reactivity ◽

Antiplatelet Agent ◽

Vascular Lesions ◽

Ischemic Lesion ◽

Entire Study ◽

Impedance Aggregometry ◽

Ischemic Infarct ◽

Clopidogrel Therapy ◽

The Impact ◽

Over Time

Background: High on-treatment platelet reactivity or its equivalent—resistance to the antiplatelet agent—significantly reduces the efficacy of the therapy, contributing to a negative impact on stroke course. Previous studies demonstrated that aspirin resistance is associated with a larger size of acute ischemic infarct. Due to the increasing use of clopidogrel in the secondary prevention of stroke, we aimed to assess the impact of clopidogrel resistance on the size and extent of ischemic lesions, both acute and chronic. Methods: This prospective, single-center and observational study involved 74 ischemic stroke subjects, treated with 75 mg of clopidogrel. We used impedance aggregometry to determine platelet reactivity 6–12 h after a dose of clopidogrel as a first assessment and 48 h later as the second measurement. A favorable dynamics of platelet reactivity over time was the decrease in the minimum value equal to the median in the entire study. The volume of acute ischemic infarct was estimated within 48 h after onset in diffusion-weighted imaging and fluid-attenuated inversion recovery sequences of magnetic resonance and the severity of chronic vascular lesions by Fazekas scale. Results: Subjects with mild severity of chronic vascular lesions (Fazekas 1) exhibited a significant decrease of platelet reactivity over time (p = 0.035). Dynamics of platelet reactivity over time differed between subjects with large, moderate, mild and insignificant size of acute ischemic lesion (Kruskall-Wallis H = 3.2576; p = 0.048). In multivariate regression models, we reported unfavorable dynamics of platelet reactivity alone and combined with a high initial value of platelet reactivity as independent predictors of higher risk of a significant ischemic infarct volume (OR 7.16 95%CI 1.69–30.31, p = 0.008 and 26.49 95%CI 1.88–372.4, p = 0.015, respectively). Conclusions: We emphasized that unfavorable dynamics of platelet reactivity over time during clopidogrel therapy in acute phase of stroke affect the volume of acute infarct and the severity of chronic vascular lesions.

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Impact of Long-Term Dual Antiplatelet Therapy on Immature Platelet Count and Platelet Reactivity

Angiology ◽

10.1177/0003319717736407 ◽

2017 ◽

Vol 69 (6) ◽

pp. 490-496 ◽

Cited By ~ 7

Author(s):

Monica Verdoia ◽

Patrizia Pergolini ◽

Roberta Rolla ◽

Lucia Barbieri ◽

Alon Schaffer ◽

...

Keyword(s):

Platelet Count ◽

Antiplatelet Therapy ◽

Dual Antiplatelet Therapy ◽

Platelet Reactivity ◽

Adenosine Diphosphate ◽

Inverse Association ◽

Median Percentage ◽

Potential Marker ◽

Median Percentage Change ◽

Acid Test

The immature platelet count (IPC) is a potential marker of platelet reactivity. We assessed the relationship between IPC during chronic dual antiplatelet therapy (DAPT) and the response to antiplatelet drugs (acetylsalycilic acid + clopidogrel/ticagrelor). We included 286 patients: 167 (58.4%) patients received ticagrelor and 119 (41.6%) received clopidogrel. At a median follow-up of 46.5 days, the variation in IPC displayed an absolute median (interquartile range [IQR]) of −11.9 × 103/µL (−182.7 to 160.8), corresponding to a median percentage change in IPC ([%ΔIPC] IQR) of −0.3% (−21.9% to 35.5%), with an increase in IPC levels in those on ticagrelor and a decrease in IPC levels in those on clopidogrel. We observed an inverse association of lower platelet reactivity at different tests and a higher increase in IPC ( r = −0.14, P = .04 for arachidonic acid test; r = −0.12, P = .05 for collagen test; and r = −0.13, P = .02 for adenosine diphosphate test [ADP]). The rate of poor effectiveness of ADP antagonists was the only independent predictor of a ΔIPC above the third tertile (odds ratio [95% confidence interval] = 0.55 [0.32-0.99]; P = .048). We showed that in patients treated with chronic DAPT, an increase in IPC is significantly related to lower levels of platelet reactivity.

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Antithrombotic Therapy in the Prevention of Stroke

Biomedicines ◽

10.3390/biomedicines9121906 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1906

Author(s):

Shyamal Bir ◽

Roger E. Kelley

Keyword(s):

Secondary Prevention ◽

Antiplatelet Therapy ◽

Anticoagulant Therapy ◽

Stroke Prevention ◽

Antithrombotic Therapy ◽

Dual Antiplatelet Therapy ◽

Recurrent Stroke ◽

Oral Anticoagulants ◽

Minor Stroke ◽

Potential Clinical Benefit

Overview: Ischemic stroke is a leading cause of death and disability throughout the world. Antithrombotic therapy, which includes both antiplatelet and anticoagulant agents, is a primary medication of choice for the secondary prevention of stroke. However, the choices vary with the need to incorporate evolving, newer information into the clinical scenario. There is also the need to factor in co-morbid medical conditions as well as the cost ramifications for a particular patient as well as compliance with the regimen. Pertinent Updates: In the acute setting, dual antiplatelet therapy from three weeks to up to three months has become recognized as a reasonable approach for patients with either minor stroke or transient ischemic attack or those with symptoms associated with higher-grade intracranial stenosis. This approach is favored for non-cardioembolic stroke as a cardiogenic mechanism tends to be best managed with attention to the cardiac condition as well as anticoagulant therapy. Risk stratification for recurrent stroke is important in weighing potential risk versus benefits. For example, prolonged dual antiplatelet therapy, with a combination such as aspirin and clopidogrel or aspirin and ticagrelor, tends to have negation of the potential clinical benefit of stroke prevention, over time, by the enhanced bleeding risk. Anticoagulant choices are now impacted by newer agents, initially identified as novel oral anticoagulants (NOACs), which also became associated with “non-vitamin K” agents as they are no longer considered novel. Alternatively, they are now often identified as direct oral anticoagulants (DOACs). They tend to be viewed as superior or non-inferior to warfarin with the caveat that warfarin is still viewed as the agent of choice for stroke prevention in patients with mechanical heart valves. Conclusion: Based upon cumulative information from multiple clinical trials of secondary prevention of stroke, there is an increasing array of approaches in an effort to provide optimal management. Antithrombotic therapy, including in combination with anticoagulant therapy, continues to evolve with the general caveat that “one size does not fit all”. In view of this, we desire to provide an evidence-based approach for the prevention of stroke with antithrombotic agents.

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Effect of Physical Exercise on Platelet Reactivity in Patients with Dual Antiplatelet Therapy

International Journal of Sports Medicine ◽

10.1055/a-0631-3302 ◽

2018 ◽

Vol 39 (08) ◽

pp. 646-652

Author(s):

Stefan Brunner ◽

Konstantinos Rizas ◽

Wolfgang Hamm ◽

Michael Mehr ◽

Korbinian Lackermair

Keyword(s):

Physical Exercise ◽

Antiplatelet Therapy ◽

Maximal Exercise ◽

Dual Antiplatelet Therapy ◽

Platelet Reactivity ◽

Adenosine Diphosphate ◽

Cycle Ergometer ◽

Platelet Activity ◽

Artery Disease ◽

Maximal Exercise Capacity

AbstractIt is known that physical exercise may increase platelet activity. However, the effect of exercise on platelet reactivity in patients on dual antiplatelet therapy has not been investigated yet. In our study, 21 patients with coronary artery disease on dual antiplatelet therapy and 10 controls were enrolled. We performed an exercise test using a cycle ergometer and determined the adenosine diphosphate-induced platelet reactivity before and immediately after exercise testing. Additionally, we analysed maximal exercise capacity and an electrocardiogram. Further, we assessed chromogranin A and P-selectin levels and platelet counts.

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Review of Toyoda K, et al. Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high-risk ischemic stroke in Japan. Lancet Neurol. 2019 Jun;18(6):539-548

Surgical Neurology International ◽

10.25259/sni_83_2020 ◽

2020 ◽

Vol 11 ◽

pp. 53

Author(s):

Benjamin W. Y. Lo ◽

Satoru Miyawaki ◽

Hitoshi Fukuda ◽

Masaomi Koyanagi

Keyword(s):

Randomized Controlled Trial ◽

Ischemic Stroke ◽

High Risk ◽

Secondary Prevention ◽

Antiplatelet Therapy ◽

Dual Antiplatelet Therapy ◽

Controlled Trial ◽

Antiplatelet Agent ◽

Dual Therapy ◽

Randomized Controlled

Background: Prior meta-analyses showed that treatment with cilostazol, with or without aspirin, significantly reduced the incidence of recurrent ischemic stroke, occurrence of hemorrhagic stroke, and frequency of other serious vascular adverse events. Methods: This review highlights the value of the randomized controlled trial (RCT) by Toyoda et al. entitled, “Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high-risk ischemic stroke in Japan: a multicenter, open-label, randomized controlled trial.” Here, dual therapy consisting of cilostazol and another antiplatelet agent was used to prevent secondary ischemic stroke in high-risk Japanese patients. Results: Patients on dual therapy consisting of cilostazol/aspirin or cilostazol/clopidogrel had significantly lower frequencies of recurrent stroke. However, there were significant differences in the incidence of attendant hemorrhagic complications utilizing mono or dual therapy. Conclusion: This RCT demonstrated the safety of dual therapy, consisting of cilostazol/aspirin or cilostazol/ clopidogrel, in preventing secondary ischemic stroke in a high-risk Japanese population. Further studies are required to generalize these findings to other patient populations worldwide.

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Comparison of outcome of patients with acute minor ischaemic stroke treated with intravenous t-PA, DAPT or aspirin

Stroke and Vascular Neurology ◽

10.1136/svn-2019-000319 ◽

2020 ◽

pp. svn-2019-000319

Author(s):

Peng Wang ◽

Mengyuan Zhou ◽

Yuesong Pan ◽

Xia Meng ◽

Xingquan Zhao ◽

...

Keyword(s):

Functional Outcome ◽

Antiplatelet Therapy ◽

Dual Antiplatelet Therapy ◽

National Institutes Of Health ◽

Minor Stroke ◽

Post Hoc Analysis ◽

Intravenous Tissue Plasminogen Activator ◽

Tissue Plasminogen ◽

Ischemic Attack ◽

Post Hoc

BackgroundWhether to treat minor stroke with intravenous tissue plasminogen activator (t-PA) treatment or antiplatelet therapy is a dilemma. Our study aimed to explore whether intravenous t-PA treatment, dual antiplatelet therapy (DAPT) and aspirin have different efficacies on outcomes in patients with minor stroke.MethodsA post hoc analysis of patients with acute minor stroke treated with intravenous t-PA within 4.5 hours from a nationwide multicentric electronic medical record and patients with acute minor stroke treated with DAPT and aspirin from the Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack Database. Minor stroke was defined by a score of 0–3 on the National Institutes of Health Stroke Scale at randomisation. Favourable functional outcome (defined as modified Rankin Scale (mRS) score of 0–1 or 0–2 at 3 months).ResultsCompared with those treated with intravenous t-PA, no significant association with 3-month favourable functional outcome (defined as mRS score of 0–1) was found neither in patients treated with aspirin (87.8% vs 89.4%; OR, 0.83; 95% CI, 0.46 to 1.50; p=0.53) nor those treated with DAPT (87.4% vs 89.4%; OR, 0.84; 95% CI, 0.46 to 1.52; p=0.56). Similar results were observed for the favourable functional outcome defined as mRS score of 0–2 at 3 months.ConclusionsIn our study, no significant advantage of intravenous t-PA over DAPT or aspirin was found. Due to insufficient sample size, our study is probably unable to draw such a conclusion that that intravenous t-PA was superior or non-superior to DAPT.

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