Chantal Pharand

Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients

AIMS We investigated the comparability of platelet function tests in quantifying platelet inhibition achieved by clopidogrel. METHODS AND RESULTS This pre-specified substudy of a randomized, double-blind trial included 116 patients with stable coronary artery disease requiring diagnostic angiography. Patients received clopidogrel for 1 (300 or 600 mg) or 7 days (300 + 75 or 150 mg daily) before the procedure. Blood samples obtained before clopidogrel initiation and before diagnostic coronary angiography were assayed using light transmission aggregometry [adenosine diphosphate (ADP) 5 and 20 microM as the agonist], whole-blood aggregometry (ADP 5 and 20 microM), PFA-100 (Collagen-ADP cartridge), and VerifyNow P2Y12. Although all assays studied were found sensitive to clopidogrel ingestion, none could distinguish categorically between patients who had, or not, ingested clopidogrel. Agreement between assays to identify patients with insufficient inhibition of platelet aggregation by clopidogrel was low. CONCLUSION The assessment of platelet function inhibition by clopidogrel is highly test-specific. Decision to increase clopidogrel dosage may vary on the basis of the assay used, thus highlighting the need for unambiguous guidelines with respect to assay selection, as platelet function assays are not interchangeable. At present, platelet function testing evaluating clopidogrel efficacy cannot be recommended in routine clinical practice.

Glycoprotein IIb/IIIa Receptor Blockade Improves Outcomes in Diabetic Patients Presenting With Unstable Angina/Non–ST-Elevation Myocardial Infarction Results From the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study

BackgroundDiabetic patients who present with unstable angina or non–ST-elevation myocardial infarction suffer a substantially greater incidence of subsequent infarction or death compared with nondiabetic patients. The present study was undertaken to examine whether diabetic patients in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) study appeared to benefit from platelet glycoprotein IIb/IIIa receptor–mediated inhibition of platelet aggregation by tirofiban. Methods and ResultsOf the 1570 PRISM-PLUS patients treated with either tirofiban plus heparin (n=773) or heparin alone (n=797), ≈23% in each treatment group were diabetic. A comparison of treatment outcomes in the diabetic subgroup revealed that the combination therapy compared with heparin alone was associated with reductions in the incidence of the composite primary end point of death, myocardial infarction (MI), or refractory ischemia at 2, 7, 30, and 180 days (7.7% versus 8.3%, 14.8% versus 21.8%, 20.1% versus 29.0%, and 32.0% versus 39.9%, respectively; P=NS) and in the incidence of MI or death (0.0% versus 3.1%, P =0.03; 1.2% versus 9.3%, P =0.005; 4.7% versus 15.5%, P =0.002; and 11.2% versus 19.2%, P =0.03). Tests for quantitative interaction between tirofiban therapy and diabetic status were significant. ConclusionsThe addition of tirofiban to heparin and aspirin appears effective in the prevention of major ischemic events, particularly MI or death, in diabetic patients presenting with unstable angina and non–ST-elevation MI.

Possibility of a rebound phenomenon following antiplatelet therapy withdrawal: A look at the clinical and pharmacological evidence

The importance of regular administration of antiplatelet drugs in patients suffering from coronary artery disease stands on firm grounds, as large meta-analyses have shown these therapies to drastically reduce the risk of death. Although the current guidelines published jointly by the American Heart Association, the American College of Cardiology, the Society for Cardiovascular Angiography and Interventions, the American College of Surgeons and the American Dental Association stress the hazards of premature discontinuation of antiplatelet drugs, abrupt withdrawal remains widespread, with potentially catastrophic consequences. In the limited state of knowledge on antiplatelet drug withdrawal, an early sound of alarm has risen from early thromboembolic complications reported after the interruption of treatment in patients who require antiplatelet therapy for prevention of ischemic vascular disease. Acute thrombotic complications are not immediate and usually follow interruption of aspirin or clopidogrel therapy after a mean delay of 8-25 days, a time lapse consistent with normal platelet turnover required to replace the platelet pool in circulation and suggestive of a rebound phenomenon. This review article describes the thrombotic risks associated with discontinuing antiplatelet therapy and the bleeding risks associated with continuing these drugs. By integrating the current understanding of the pharmacology of antiplatelet agents and the kinetics of platelet function recovery, this article unveils the possibility of a pharmacological rebound phenomenon which could lead to adverse ischemic events, and supports the warning against premature discontinuation of antiplatelet drugs issued in current guidelines.

Use of OTC and Herbal Products in Patients with Cardiovascular Disease

BACKGROUND: The use of nonprescription and herbal products by the public is rising, resulting in an increased potential for adverse reactions or drug interactions in cardiac patients. OBJECTIVE: To describe the utilization patterns for nonprescription medications and herbal products in patients with cardiovascular disease across Canada. METHODS: Patients admitted to 8 teaching hospitals during the winter of 1998/1999 were interviewed by a pharmacist using a structured survey instrument. RESULTS: Interviews were conducted with 306 patients (mean age 66 y; 60% men). The majority (74%) had coronary artery disease; however, hypertension, congestive heart failure, and arrhythmias were also common. The most common product categories used were pain relievers (51%), single-entity vitamin/mineral (38%), multivitamin/mineral (23%), antacids (21%), laxatives (17%), and herbals (17%). As compared with western (28%) and central Canada (26%), fewer patients in the Atlantic region (11%) reported daily use of multivitamin/mineral products. Overall, the usage of specific single-entity vitamin/mineral products was most commonly vitamin E (24%), vitamin C (16%), calcium (9%), and B vitamins (8%). Central Canada reported the highest rates (25%) of daily or weekly use of herbal products. The most common herbal products used were garlic (13%), cayenne pepper (2%), and ginseng (2%). More than half of the patients consulted with their pharmacist at least occasionally regarding the use of these products. CONCLUSIONS: Canadian patients with cardiovascular disease commonly report the use of herbal products and vitamins. Allied health professionals need to be aware of the widespread use of these products and their potential for adverse reactions and drug interactions.

Assessment of VerifyNow P2Y12 assay accuracy in evaluating clopidogrel-induced platelet inhibition.

The emergence of point-of-care assays enabling bedside testing such as the VerifyNow P2Y12 system might prove useful in clinical settings. The aim of this study was to evaluate the ability of the VerifyNow P2Y12 assay to estimate the inhibition of platelet aggregation provided by clopidogrel in the absence of baseline off-drug aggregation data. Sixty-eight patients with coronary artery disease scheduled to initiate clopidogrel therapy underwent platelet aggregation testing by VerifyNow P2Y12 at baseline and after clopidogrel administration. The inhibition reported by the VerifyNow assay (relative to thrombin receptor activating peptide-induced platelet aggregation, serving as baseline) was compared with that calculated with the actual adenosine diphosphate-induced baseline obtained with the same methodology. The postclopidogrel thrombin receptor activating peptide-induced aggregation showed a great discordance with that induced by adenosine diphosphate before clopidogrel with a bias of 24 units (95% limits of agreement from −142 to 190 units). Moreover, the inhibition reported by the assay overestimated the standard before-and-after testing data by an average of 8% (95% limits of agreement from −49% to 65%), making its use without a true baseline comparator unsatisfactory. The VerifyNow P2Y12 assay fails to accurately quantify platelet inhibition achieved by clopidogrel compared with before-and-after testing. Further studies are required to establish the clinical usefulness of the VerifyNow P2Y12 assay to accurately predict the occurrence of major adverse cardiovascular events in patients with reduced clopidogrel efficacy before it can be implemented in clinical practice. At present, the use of this assay in clinical care cannot be recommended for monitoring clopidogrel therapy.

Heterogeneity in platelet cyclooxygenase inhibition by aspirin in coronary artery disease

BACKGROUND Platelets, long believed to be incapable of de novo protein synthesis, may retain their ability to form the cyclooxygenase (COX) enzyme once it has been inactivated by aspirin. This may explain the inefficacy of the drug to induce sustained platelet inhibition in certain patients. We evaluated the stability of platelet inhibition following once-daily enteric-coated aspirin administration. METHODS Platelet responsiveness to aspirin was evaluated in 11 stable coronary artery disease patients on chronic aspirin therapy before and 1, 3, 8, and 24h after observed ingestion of 80-mg enteric-coated aspirin. Inhibition of the COX pathway was measured pharmacologically through plasma thromboxane (Tx) B(2) levels, and functionally by light transmission aggregometry in response to arachidonic acid. COX-independent platelet activity was measured in response to adenosine diphosphate, epinephrine and collagen. RESULTS Plasma TxB(2) levels showed profound inhibition of TxA(2) formation, which was stable throughout 24h, in all but 1 subject. This subject had optimal response to aspirin (inhibition of platelet TxA(2) production within 1h), but recovered the ability to synthesize TxA(2) within 24h of aspirin ingestion. Arachidonic acid-induced platelet aggregation closely mirrored TxB(2) formation in this patient, portraying a functional ability of the platelet to aggregate within 24h of aspirin ingestion. COX-independent platelet aggregation triggered TxA(2) production to a similar extent in all patients, likely through signal-dependent protein synthesis. CONCLUSIONS COX-dependent platelet activity is recovered in certain individuals within 24h of aspirin administration. Further research should consider increasing aspirin dosing frequency to twice daily, to allow sustained inhibition in such subjects.

Genetic determinants of response to aspirin: Appraisal of 4 candidate genes

INTRODUCTION Intersubject variability in platelet response to aspirin could be related to genetic factors that regulate platelet enzymes or receptors. This study evaluates the impact of the selected polymorphisms in the COX-1 gene, the CYP5A1 gene, the P2RY1 receptor gene, and the GPIIbIIIa receptor gene on platelet response to aspirin and risk of suffering from major adverse cardiovascular and cerebrovascular events (MACCE). MATERIALS AND METHODS 192 Caucasian patients with stable coronary artery disease treated with daily aspirin were recruited and followed for 3 years. Platelet aggregation was measured by light transmission aggregometry with arachidonic acid (1.6 mM) and adenosine diphosphate (5, 10 or 20 μM) used as agonists. Genotyping was performed by standard PCR methods. RESULTS Arachidonic acid-induced platelet aggregation was unaffected by the COX-1 22C/T and by the Pl(A1/A2) polymorphisms. However, carriers of the 1622 G/G genotype of the P2RY1 gene had significantly higher levels of arachidonic acid-induced platelet aggregation compared with non-carriers (AA 2.0%, AG 2.0% vs. GG 9.0%, p=0.047). Carrying the 1622 G/G genotype increased the risk of inadequate platelet response to aspirin, defined as arachidonic acid-induced aggregation ≥ 20%, by a factor of 8.5 (1.4 - 53.3, p=0.022) and the risk of 3-year MACCE by a factor of 7 (1.4 - 34.7, p=0.017). CONCLUSION The 1622A/G mutation of the P2RY1 gene could contribute to inadequate platelet response to aspirin and is associated with an increased risk of suffering from MACCE.

Platelet count, not oxidative stress, may contribute to inadequate platelet inhibition by aspirin

BACKGROUND Several patient characteristics have been shown to increase the risk of inadequate platelet inhibition by aspirin, yet underlying mechanisms remain mostly unknown. We explored whether oxidative stress, via isoprostane formation, was associated with inadequate platelet response to aspirin. Additionally, we sought to investigate whether individual pre-selected demographic, hematological or biochemical parameters further increased the risk of inadequate platelet response to aspirin. METHODS Two hundred consecutive subjects suffering from stable coronary artery disease and under daily aspirin therapy were enrolled in our study. Inadequate platelet response to aspirin was defined as residual platelet aggregation>or=20% per arachidonic acid-induced light transmission aggregometry. Morning urinary samples were used to determine levels of isoprostanes (8-iso-PGF2alpha) using an enzyme immunoassay. RESULTS Eight subjects were deemed to present inadequate platelet response to aspirin. Wide intersubject variability was observed in urinary 8-iso-PGF2alpha levels. However, levels were similar between aspirin responders and non-responders. Patients with inadequate platelet response to aspirin had higher platelet counts and received the lowest daily aspirin dose when compared to responders, suggesting subtherapeutic aspirin therapy due to increased platelet production. Only platelet count remained independently predictive of inadequate platelet response to aspirin in a multiple logistic regression model. CONCLUSIONS Urinary 8-iso-PGF2alpha levels, a reflection of systemic oxidative stress, did not appear to contribute to impaired platelet responsiveness to aspirin, while increased platelet production may partly explain this phenomenon.

Potential Anaphylactic Shock with Abciximab Readministration

A 46‐year‐old woman developed an anaphylactic reaction during percutaneous coronary intervention after she was pretreated with prednisone and diphenhydramine for a known allergy to iodine. She developed pruritus, edema, and nausea, which were followed by bradycardia and shock, minutes after administration of a bolus and standard‐dose infusion of abciximab. The reaction was treated successfully with epinephrine, methoxamine, hydrocortisone, atropine, furosemide, sodium bicarbonate, diphenhydramine, and ranitidine.

Evaluation of the platelet count drop method for assessment of platelet function in comparison with "gold standard" light transmission aggregometry.

INTRODUCTION Hyporesponsiveness to antiplatelet agents has been linked to an increased risk of major adverse cardiovascular events. However, light transmission aggregometry (LTA), the gold standard methodology for assessing platelet function, requires expertise and is labour-intensive, which render its use in clinical settings impractical. We assessed whether platelet count drop (PCD), a technique widely available in any haematology laboratory, could replace LTA in testing for inhibition of platelet aggregation induced by antiplatelet agents. MATERIALS AND METHODS One hundred and sixty-one coronary artery disease patients taking aspirin alone and 91 patients taking a combination of aspirin and clopidogrel were enrolled. Platelet aggregation was measured by LTA and PCD stimulated with 1.6 mM of arachidonic acid (AA) for aspirin and 5 and 20 microM of adenosine diphosphate (ADP) for clopidogrel. RESULTS Correlation between AA-induced LTA and PCD was nonexistent (r=-0.043, p=0.587), while correlation between ADP-induced LTA and PCD was low (r=0.374, p<0.0001 for ADP 5 microM and r=0.402, p<0001 for ADP 20 microM ). PCD, whether stimulated with AA or ADP, overestimated platelet aggregation as assessed by LTA, by 13-18%. The wide 95% limits of agreement suggest that the assays can disagree significantly in individual patients. CONCLUSIONS Although the PCD method is widely available in non-specialized laboratories, our results demonstrate that there is poor correlation with the current gold standard, i.e. LTA. Thus, PCD should not be used in replacement of LTA to assess antiplatelet responsiveness.