Investigating the Mechanisms of Hyporesponse to Antiplatelet Approaches

Hyporesponsiveness, or resistance, to antiplatelet therapy may be a major contributor to poorer outcomes among cardiac patients and may be attributed to an array of mechanisms—both modifiable and unmodifiable. Recent evidence has uncovered clinical, cellular, and genetic factors associated with hyporesponsiveness. Patients with severe acute coronary syndromes (ACS), type 2 diabetes, and increased body mass index appear to be the most at risk for hyporesponsiveness. Addressing modifiable mechanisms may offset hyporesponsiveness, while recognizing unmodifiable mechanisms, such as genetic polymorphisms and diseases that affect response to antiplatelet therapy, may help identify patients who are more likely to be hyporesponsive. Hyporesponsive patients might benefit from different dosing strategies or additional antiplatelet therapies. Trials correlating platelet function test results to clinical outcomes are required. Results from these studies could cause a paradigm shift toward individualized antiplatelet therapy, improving predictability of platelet inhibition, and diminishing the likelihood for hyporesponsiveness. Copyright © 2008 Wiley Periodicals, Inc.

[1]  K. Harjai,et al.  Impact of angina class on inhibition of platelet aggregation following clopidogrel loading in patients undergoing coronary intervention: Do we need more aggressive dosing regimens in unstable angina? , 2003, Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions.

[2]  R. Califf,et al.  Randomized, Double-Blind, Placebo-Controlled, International Trial of the Oral IIb/IIIa Antagonist Lotrafiban in Coronary and Cerebrovascular Disease , 2003, Circulation.

[3]  Harald Langer,et al.  Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. , 2006, European heart journal.

[4]  P. Järemo,et al.  Individual variations of platelet inhibition after loading doses of clopidogrel , 2002, Journal of internal medicine.

[5]  S. Yusuf,et al.  Effects of Aspirin Dose When Used Alone or in Combination With Clopidogrel in Patients With Acute Coronary Syndromes: Observations From the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Study , 2003, Circulation.

[6]  S. Yusuf,et al.  Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. , 2001, The New England journal of medicine.

[7]  S. Yusuf,et al.  Aspirin-Resistant Thromboxane Biosynthesis and the Risk of Myocardial Infarction, Stroke, or Cardiovascular Death in Patients at High Risk for Cardiovascular Events , 2002, Circulation.

[8]  M. Gawaz,et al.  Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement , 2003, Thrombosis and Haemostasis.

[9]  J. Akkerman,et al.  Platelet Inhibition by Insulin Is Absent in Type 2 Diabetes Mellitus , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[10]  P. R. R. Ecurrent,et al.  EFFECTS OF CLOPIDOGREL IN ADDITION TO ASPIRIN IN PATIENTS WITH ACUTE CORONARY SYNDROMES WITHOUT ST-SEGMENT ELEVATION , 2001 .

[11]  M. Furman,et al.  Residual Arachidonic Acid–Induced Platelet Activation via an Adenosine Diphosphate–Dependent but Cyclooxygenase-1– and Cyclooxygenase-2–Independent Pathway: A 700-Patient Study of Aspirin Resistance , 2006, Circulation.

[12]  C. Macaya,et al.  Platelet aggregation according to body mass index in patients undergoing coronary stenting: should clopidogrel loading-dose be weight adjusted? , 2004, The Journal of invasive cardiology.

[13]  H. Hod,et al.  Clopidogrel Resistance Is Associated With Increased Risk of Recurrent Atherothrombotic Events in Patients With Acute Myocardial Infarction , 2004, Circulation.

[14]  J. Heikkilä,et al.  Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions. , 2004, European heart journal.

[15]  A. Connor,et al.  The way I see it: House officers need formal career development , 2002 .

[16]  C. Macaya,et al.  Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. , 2005, Diabetes.

[17]  P. Gurbel,et al.  The difference between clopidogrel responsiveness and posttreatment platelet reactivity. , 2005, Thrombosis research.

[18]  A. Mattioli,et al.  Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients , 2002, BMJ : British Medical Journal.

[19]  P. Morange,et al.  Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting. , 2006, Journal of the American College of Cardiology.

[20]  F. Neumann,et al.  Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. , 2006, Journal of the American College of Cardiology.

[21]  P. Watkins,et al.  Contribution of Hepatic Cytochrome P450 3A4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance , 2004, Circulation.

[22]  R. Collins,et al.  Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial , 2005, The Lancet.

[23]  C. Macaya,et al.  Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment. , 2006, Journal of the American College of Cardiology.

[24]  C. Lau,et al.  Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment. , 2004, Journal of the American College of Cardiology.

[25]  P. Gurbel,et al.  Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate? , 2007, Journal of the American College of Cardiology.

[26]  Eric J Topol,et al.  Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. , 2002, JAMA.

[27]  Deepak L. Bhatt.  Aspirin resistance: more than just a laboratory curiosity. , 2004, Journal of the American College of Cardiology.

[28]  Kevin P. Bliden,et al.  Clopidogrel for Coronary Stenting Response Variability, Drug Resistance, and the Effect of Pretreatment Platelet Reactivity , 2003, Circulation.

[29]  G. Davı̀,et al.  Platelet activation in type 2 diabetes mellitus , 2004, Journal of thrombosis and haemostasis : JTH.

[30]  Paul B. Watkins,et al.  Atorvastatin Reduces the Ability of Clopidogrel to Inhibit Platelet Aggregation: A New Drug–Drug Interaction , 2003, Circulation.

[31]  A. Kastrati,et al.  Impact of body mass index on platelet aggregation after administration of a high loading dose of 600 mg of clopidogrel before percutaneous coronary intervention. , 2007, The American journal of cardiology.

[32]  E. Trabetti,et al.  Contribution of Gene Sequence Variations of the Hepatic Cytochrome P450 3A4 Enzyme to Variability in Individual Responsiveness to Clopidogrel , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[33]  J. Granada,et al.  CLINICAL RESEARCH Interventional Cardiology Aspirin and Clopidogrel Drug Response in Patients Undergoing Percutaneous Coronary Intervention The Role of Dual Drug Resistance , 2006 .

[34]  S. Anand.  Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Eikelboom JW, Hirsh J, Weitz J, Johnston M, Yi Q, Yusuf S. Circulation 2002; 105: 1650- 1655. , 2002 .

[35]  P. Gurbel,et al.  The stratification of platelet reactivity and activation in patients with stable coronary artery disease on aspirin therapy. , 2003, Thrombosis research.

[36]  L. Waskell,et al.  The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[37]  Justin T. Newcomer,et al.  Evaluation of Dose-Related Effects of Aspirin on Platelet Function: Results From the Aspirin-Induced Platelet Effect (ASPECT) Study , 2007, Circulation.

[38]  V. Knappertz,et al.  Aspirin and clopidogrel resistance: an emerging clinical entity. , 2006, European heart journal.

[39]  Timi Study,et al.  Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation , 2005 .

[40]  A. Bura,et al.  Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. , 2006, Blood.

[41]  L. Christiaens,et al.  Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate. , 2002, Thrombosis research.

[42]  J. Eikelboom,et al.  Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. , 2002, The New England journal of medicine.

[43]  P. Gurbel.  The relationship of platelet reactivity to the occurrence of post-stenting ischemic events: emergence of a new cardiovascular risk factor. , 2006, Reviews in cardiovascular medicine.

[44]  Catherine Sudlow,et al.  Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients , 2002, BMJ : British Medical Journal.

[45]  G. Karthikeyan.  Clopidogrel and metoprolol in myocardial infarction , 2006, The Lancet.