Relation of Low Response to Clopidogrel Assessed With Point-of-Care Assay to Periprocedural Myonecrosis in Patients Undergoing Elective Coronary Stenting for Stable Angina Pectoris

doi:10.1016/j.amjcard.2008.02.054

The American Journal of Cardiology

Volume 101, Issue 12, 15 June 2008, Pages 1700-1703

https://doi.org/10.1016/j.amjcard.2008.02.054 Get rights and content

Impaired responses to antiplatelet therapy assessed by laboratory tests are associated with an increased risk of recurrent ischemic events after percutaneous coronary intervention (PCI). This study was designed to determine the relation between responses to aspirin and clopidogrel as assessed by a point-of-care assay (Verify Now, Accumetrics, San Diego, California) and periprocedural myocardial infarction (PMI) in patients undergoing elective PCI for stable angina. One hundred twenty-two consecutive patients undergoing elective coronary stenting prospectively received aspirin 500 mg and clopidogrel 600 mg ≥12 hours before PCI. Clopidogrel response was measured with P2Y12 reaction units (PRUs) and percent inhibition P2Y12 from baseline (percent inhibition P2Y12) and aspirin response with aspirin reaction units (ARUs). Troponin T level was considered positive if it was >0.03 ng/ml. Responses to aspirin and clopidogrel were correlated (r = 0.42, p <0.0001). PMI occurred in 27 patients (22%) who showed significantly lower percent inhibition P2Y12 (25.3 ± 26 vs 38.3 ± 25, p = 0.01) and a trend toward higher PRU values (221 ± 87 vs 193 ± 94, p = 0.21). We did not find any difference for aspirin response as assessed by ARUs in patients with or without PMI (460 ± 82 vs 454 ± 73, p = 0.82). Stratification of percent inhibition P2Y12 isolated a quartile of clopidogrel nonresponders (inhibition P2Y12 <15%) with significantly higher incidence of PMI (44% vs 15%, odds ratio 4.6, 95% confidence interval 1.9 to 11.5, p = 0.001). In conclusion, point-of-care assessment of clopidogrel response reliably predicted PMI after low- to medium-risk elective PCI for stable angina.

Section snippets

Methods

Patients >18 years old with stable angina or a positive functional study finding with a planned PCI procedure of a de novo lesion in a native coronary artery were prospectively eligible for inclusion. Exclusion criteria were a left ventricular ejection fraction <30%, acute coronary syndrome in the previous month, previous MI in the target vessel–related territory, positive biomarkers before PCI, a platelet count <100,000 G/L, history of bleeding diathesis, chronic total occlusion, intrastent

Results

From May to October 2007, 122 consecutive patients who fulfilled the enrollment criteria were included. Demographic data of the population are presented in Table 1, Table 2. Overall occurrence of PMI was 22% (n = 27) in the entire population. Demographic, clinical, and therapeutic parameters were similar in the groups with and without PMI (Table 1, Table 2). Mean time between loading doses of antiplatelet therapy and blood sampling was 15.7 ± 2.1 hours in the entire population and were similar

Discussion

In the present study, low response to clopidogrel using a point-of-care assay was associated with an increased risk of PMI after elective PCI. Several preprocedural treatment strategies have evolved in an attempt to lower the rate of PMI.¹⁷ The concept of clopidogrel pretreatment with a standard loading dose of 300 mg has been validated in large clinical trials.2, 18 However, recent data have suggested the benefit of a higher loading dose of clopidogrel (600 mg) on the level of platelet

Acknowledgment

Assistance of our research nurses team in executing this study is gratefully acknowledged.

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Periprocedural Myocardial Injury: Pathophysiology, Prognosis, and Prevention
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Citation Excerpt :
In fact, post-PCI HPR was significantly and independently correlated with an increase in high-sensitivity troponin (hs-TnT) [74]. It has been suggested that point-of-care assessment of PR after clopidogrel can identify non-responders and allow for more tailored antiplatelet therapy [72,75]. Furthermore, PR is not just an inherent value but seems to be inducible by the environment.
The definition and clinical implications of myocardial infarction occurring in the setting of percutaneous coronary intervention have been the subject of unresolved controversy. The definitions of periprocedural myocardial infarction (PMI) are many and have evolved over recent years. Additionally, the recent advancement of different imaging modalities has provided useful information on a patients' pre-procedural risk of myocardial infarction. Nonetheless, questions on the benefit of different approaches to prevent PMI and their practical implementation remain open. This review aims to address these questions and to provide a current and contemporary perspective.
The use of intravenous tPA for the treatment of severe frostbite
2017, Burns
tPA and anticoagulation for treatment of severe frostbite have been reported suggesting differences in imaging techniques, route of tPA administration and management of patients after tPA infusion. This is a report of our results following a protocol of Tc-99m scanning, intravenous tPA administration, followed by either systemic anticoagulation or antiplatelet therapy.
Patients admitted to our burn center between February 13, 2015 and February 13, 2016 for frostbite who met inclusion criteria were treated with Tc-99m scan and intravenous tPA followed by systemic anticoagulation or antiplatelet therapy. Inclusion criteria included rewarming had not started more than 24 h prior to the scan and no contraindications to the use of tPA.
Fifteen patients met inclusion criteria and 12 were treated according to the protocol. Nine received scans with 2 showing normal perfusion. Seven displayed perfusion defects and received intravenous tPA. Five recovered fully after tPA. Two who showed improved but abnormal scans after tPA experienced bleeding complications necessitating stopping heparin/Coumadin. Those two went on to partial amputation of digits.
The use of intra-arterial or intravenous tPA along with angiography or Tc-99m scanning followed by systemic anticoagulation or antiplatelet therapy may be beneficial to patients suffering frostbite.
Impact of initial clinical presentation on clopidogrel low response
2013, Archives of Cardiovascular Diseases
Large interindividual variability exists in clopidogrel response. Clopidogrel low response correlates with poor prognosis after percutaneous coronary intervention. Some authors also suggest intraindividual variability over time.
To assess the impact of initial clinical presentation on clopidogrel low response.
In this prospective study, clopidogrel response was assessed in 100 patients. Fifty patients presenting with acute coronary syndromes (ACS group) were compared with 50 patients with stable coronary artery disease matched 1:1 for age, sex, body mass index and diabetes (stable group). All patients were tested 18–24 h after a 600 mg loading dose of clopidogrel using the VerifyNow-P2Y12 test (results expressed as platelet reaction units [PRUs]). Patients under chronic clopidogrel therapy or treated with glycoprotein IIb/IIIa inhibitors, bivalirudin or thrombolytics were excluded.
Mean age was 61 ± 12 years in each group; 28% of patients in each group were diabetic; mean body mass index was 27.6 ± 5.6 kg/m² in the ACS group and 27.9 ± 5.9 kg/m² in the stable group (p = 0.80). Mean PRU values were 197 ± 81 in the ACS group and 159 ± 94 in the stable group (p = 0.03). By multivariable analysis, the ACS group was significantly associated with a higher PRU value (p = 0.02). There were significantly more clopidogrel low responders (PRU value > 230) in the ACS group (38% vs. 18%; p = 0.04).
Our study confirms that initial clinical presentation, especially ACS, is a strong predictor of clopidogrel low response; this suggests that the evolution of coronary artery disease for one patient influences the clopidogrel response over time. These results are in accordance with recent trials showing a benefit for more aggressive antiplatelet therapy in ACS patients.
Une mauvaise réponse biologique au clopidogrel est associée à un pronostic défavorable des patients après angioplastie coronaire percutanée (ACP). Il est clairement démontré qu’il existe une large variabilité interindividuelle dans la réponse au clopidogrel. Certains auteurs suggèrent également la présence d’une variabilité intraindividuelle au cours du temps.
Nous avons analysé l’impact de la présentation clinique initiale sur la réponse au clopidogrel.
Dans cette étude prospective, la réponse biologique au clopidogrel a été analysée chez 100 patients. Au total, 50 patients présentant initialement un syndrome coronaire aigu (groupe SCA) ont été appariés 1:1 à 50 patients présentant un angor stable (groupe stable) sur l’âge, le sexe, l’indice de masse corporelle et le diabète. Tous les patients ont été testés par le test du VerifyNow-P2Y12 (résultats exprimés en platelet reaction unit [PRU]) entre 18 et 24 heures après une dose de charge de 600 mg de clopidogrel. Les patients traités au long cours par clopidogrel, ceux ayant reçu un fibrinolytique, de la bivalirudine ou un inhibiteur du récepteur Gp IIb/IIIa ont été systématiquement exclus de cette étude.
L’âge moyen était de 61 ± 12 ans dans chaque groupe. Au total, 28% des patients étaient diabétiques dans chaque groupe et l’indice de masse corporelle était de 27,6 ± 5,6 et 27,9 ± 5,9 kg/m² dans le groupe « SCA » et dans le groupe « stable », respectivement (p = ns). Les valeurs de PRU moyennes étaient de 197 ± 80 et 159 ± 94 dans le groupe « SCA » et dans le groupe « stable », respectivement (p = 0,033). En analyse multivariée, le groupe « SCA » était significativement associé à des valeurs de PRU plus élevées (p = 0,018). Il y avait significativement plus de « mauvais répondeurs » (définis comme une valeur de PRU > 230) dans le groupe « SCA » (18% vs 38%; p = 0,04).
Cette étude confirme que la présentation clinique initiale, notamment le SCA, est un facteur prédictif puissant de mauvaise réponse au clopidogrel. Elle suggère également que l’évolution de la maladie coronaire pour un patient donné influence la réponse au clopidogrel au cours du temps. Ces résultats sont en accord avec les récents essais montrant un bénéfice à une thérapeutique antiagrégante plaquettaire plus agressive dans le SCA.
Response variability to P2Y<inf>12</inf> receptor inhibitors: Expectations and reality
2013, JACC: Cardiovascular Interventions
P2Y₁₂ inhibitors are widely used in patients with acute coronary syndromes and in the secondary prevention of thrombotic events in vascular diseases. Within the past few years, several pharmacological, genetic, and clinical limitations of the second-generation thienopyridine clopidogrel have raised major concerns. High on-treatment platelet reactivity, which is common in clopidogrel-treated patients, and its clinical implications led to the development of the more effective platelet P2Y₁₂ inhibitors prasugrel (a third-generation thienopyridine) and ticagrelor (a cyclopentyl-triazolo-pyrimidine). The pharmacokinetics and pharmacodynamics of prasugrel and ticagrelor indicate that they provide more consistent, more rapid, and more potent platelet inhibition than clopidogrel, which translates into improved ischemic outcomes. Nevertheless, higher efficacy, which is reflected by low on-treatment platelet reactivity, increases the risk of major bleeding events. Therefore, cardiologists might be facing a new challenge in the future: to individualize the level of platelet inhibition in order to decrease thrombotic events without increasing bleeding. The current review focuses on the use of platelet function testing and pharmacogenomic testing in order to identify patients who either do not respond to or are at risk of not responding sufficiently to P2Y₁₂ inhibitors. Moreover, this paper discusses randomized trials, which so far have failed to show that tailored antiplatelet therapy improves clinical outcome, and treatment options for patients with high on-treatment platelet reactivity.
Influence of platelet reactivity and inflammation on peri-procedural myonecrosis in East Asian patients undergoing elective percutaneous coronary intervention
2013, International Journal of Cardiology
Citation Excerpt :
Perez et al. reported an association of a higher ‘BASE’ value with myocardial damage (p = 0.043) in non-ST-elevation ACS patients undergoing PCI [15]. Cuisset et al. showed significantly lower percent inhibition (25 ± 26% vs. 38 ± 25%; p = 0.01) but no difference in PRU (221 ± 87 vs. 193 ± 94; p = 0.21) in stable CAD patients with vs. without PMI [13]. In the recent large, prospective ADAPT-DES (Assessment of Dual Antiplatelet Therapy with Drug Eluting Stents) registry [30], ‘percent inhibition’ showed greater predictive value for 1-month definite/probable stent thrombosis compared with ‘PRU’ assessed by ROC curve analysis (AUC, 0.720 vs. 0.679).
The contribution of multiple risk factors to peri-procedural myocardial infarction (PMI) in East Asians remains controversial. To assess the influence of clinical or laboratory covariates on PMI in these patients.
Stable patients (n = 341) undergoing elective percutaneous coronary intervention (PCI) were enrolled. Platelet reactivity was measured by conventional aggregometry and VerifyNow. Inflammation markers and lipid profile were determined by standard methods. PMI was defined according to Universal definition (troponin I or CK-MB ≥ 3 times the 99th percentile of the upper reference limit).
PMI (defined by troponin I and CK-MB) occurred in 47 (13.8%) and 30 (8.8%) patients, respectively. There was no significant difference in ADP-induced platelet reactivity between patients with vs. without PMI. Patients with PMI (troponin I) had higher levels of 6 μg/mL collagen-induced platelet aggregation (PA) and VerifyNow ‘BASE’ compared with those without PMI. The combination of ‘6 μg/mL collagen-induced PA > 40%’ + ‘BASE > 318’ (odds ratio, 14.08; 95% confidence intervals, 1.68 to 111.11; p = 0.015) or ‘WBC > 6550/mm³’ + ‘C-reactive protein > 2.3 mg/L’ (odds ratio, 7.75; 95% confidence intervals, 2.49 to 24.39; p < 0.001) was associated with an increased risk of PMI (troponin I). The greatest likelihood ratio was observed when cholesterol, inflammation marker and platelet function were combined together.
This is the first study to demonstrate that heightened platelet responsiveness to collagen and thrombin may be a risk factor for myonecrosis in patients undergoing elective PCI. The utility of the combining measures of platelet function, inflammation and cholesterol to enhance risk stratification and thus facilitate personalized therapy deserves further study.
Nuisance and alarming bleeding do not correlate with on-treatment platelet reactivity
2013, Cardiovascular Revascularization Medicine
We hypothesized that patients with a history of either alarming or nuisance bleeding events, compared to those with no history of bleeding, would have lower levels of on-treatment platelet reactivity (aspirin and a thienopyridine).
In total, 42 patients with no bleeding, 34 with nuisance bleeding, and 14 with alarming bleeding underwent platelet reactivity testing 1 month to 1 year after PCI with light transmission aggregometry (LTA 5 and 20 μM adenosine disphosphate [ADP]), vasodilator stimulated phosphoprotein phosphorylation (VASP) and VerifyNow P2Y12. Clinical and demographic characteristics of the 3 groups were generally similar, except that patients with alarming bleeding were less likely to be Caucasian; only 6 patients (6.7%) were taking prasugrel. There was considerable overlap between no bleeding, nuisance bleeding and alarming bleeding groups with respect to on-treatment platelet reactivity. Furthermore, there was no difference in the median platelet reactivity values for all assays. Prevalence of high on-treatment platelet reactivity did not differ among the 3 groups; 32.6% of patients had high on-treatment platelet reactivity as measured by LTA with 5 μM ADP (P= .91); 40.0% as measured by VASP (P= .35); and 35.6% as measured by VerifyNow P2Y12 (P= .61).
The use of platelet reactivity assays to identify patients on thienopyridine therapy at higher risk of bleeding is an unfounded strategy.

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Coronary artery diseaseRelation of Low Response to Clopidogrel Assessed With Point-of-Care Assay to Periprocedural Myonecrosis in Patients Undergoing Elective Coronary Stenting for Stable Angina Pectoris

Section snippets

Methods

Results

Discussion

Acknowledgment

Lancet

J Am Coll Cardiol

J Thromb Haemost

J Am Coll Cardiol

J Am Coll Cardiol

J Thromb Haemost

J Thromb Haemost

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Am J Cardiol

Coronary artery disease
Relation of Low Response to Clopidogrel Assessed With Point-of-Care Assay to Periprocedural Myonecrosis in Patients Undergoing Elective Coronary Stenting for Stable Angina Pectoris