Publications by authors named "Rolf P Kreutz"

40 Publications

Race-Related disparities in COVID-19 thrombotic outcomes: Beyond social and economic explanations.

EClinicalMedicine 2020 Dec 20;29:100647. Epub 2020 Nov 20.

Sinai Center for Thrombosis Research and Drug Development, Sinai Hospital of Baltimore, Baltimore, MD, United States.

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http://dx.doi.org/10.1016/j.eclinm.2020.100647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678450PMC
December 2020

Impact of the CYP2C19*17 Allele on Outcomes in Patients Receiving Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

Clin Pharmacol Ther 2021 03 2;109(3):705-715. Epub 2020 Oct 2.

Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, Florida, USA.

Genotyping for CYP2C19 no function alleles to guide antiplatelet therapy after percutaneous coronary intervention (PCI) improves clinical outcomes. Although results for the increased function CYP2C19*17 allele are also reported, its clinical relevance in this setting remains unclear. A collaboration across nine sites examined antiplatelet therapy prescribing and clinical outcomes in 3,342 patients after implementation of CYP2C19-guided antiplatelet therapy. Risk of major atherothrombotic and bleeding events over 12 months after PCI were compared across cytochrome P450 2C19 isozyme (CYP2C19) metabolizer phenotype and antiplatelet therapy groups by proportional hazards regression. Clopidogrel was prescribed to a similar proportion of CYP2C19 normal (84.5%), rapid (82.9%), and ultrarapid metabolizers (80.6%) (P = 0.360). Clopidogrel-treated normal metabolizers (20.4 events/100 patient-years; adjusted hazard ratio (HR) 1.00, 95% confidence interval (CI), 0.75-1.33, P = 0.993) and clopidogrel-treated rapid or ultrarapid metabolizers (19.1 events/100 patient-years; adjusted HR 0.95, 95% CI, 0.69-1.30, P = 0.734) exhibited no difference in major atherothrombotic events compared with patients treated with prasugrel or ticagrelor (17.6 events/100 patient-years). In contrast, clopidogrel-treated intermediate and poor metabolizers exhibited significantly higher atherothrombotic event risk compared with prasugrel/ticagrelor-treated patients (adjusted HR 1.56, 95% CI, 1.12-2.16, P = 0.008). When comparing clopidogrel-treated rapid or ultrarapid metabolizers to normal metabolizers, no difference in atherothrombotic (adjusted HR 0.97, 95% CI, 0.73-1.29, P = 0.808) or bleeding events (adjusted HR 1.34, 95% CI, 0.83-2.17, P = 0.224) were observed. In a real-world setting of genotype-guided antiplatelet therapy, the CYP2C19*17 allele did not significantly impact post-PCI prescribing decisions or clinical outcomes. These results suggest the CYP2C19 *1/*17 and *17/*17 genotypes have limited clinical utility to guide antiplatelet therapy after PCI.
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http://dx.doi.org/10.1002/cpt.2039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902344PMC
March 2021

Personalizing Antithrombotic Therapy in COVID-19: Role of Thromboelastography and Thromboelastometry.

Thromb Haemost 2020 11 17;120(11):1594-1596. Epub 2020 Jul 17.

Sinai Center of Thrombosis Research, Sinai Hospital of Baltimore, Baltimore, Maryland, United States.

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http://dx.doi.org/10.1055/s-0040-1714217DOI Listing
November 2020

Routine Venous Thromboembolism Prophylaxis May Be Inadequate in the Hypercoagulable State of Severe Coronavirus Disease 2019.

Crit Care Med 2020 09;48(9):e783-e790

Department of Surgery, Indiana University School of Medicine, Indianapolis, IN.

Objectives: The aim of this study was to determine the frequency of venous thromboembolism in critically ill coronavirus disease 2019 patients and associate a degree of inflammatory marker elevation to venous thromboembolism development.

Design: An observational study that identified patients with severe coronavirus disease 2019 between March 12, 2020, and March 31, 2020. Data reported are those available through May 6, 2020.

Setting: A multicenter study including three Indianapolis area academic hospitals.

Patients: Two-hundred forty consecutive patients with confirmed severe acute respiratory syndrome coronavirus 2 infection were admitted to one of three hospitals. One-hundred nine critically ill coronavirus disease 2019 patients admitted to the ICU were included in the analysis.

Interventions: All patients received routine subcutaneous chemical venous thromboembolism prophylaxis.

Measurements And Main Results: The primary outcome of this study was to determine the frequency of venous thromboembolism and the degree of inflammatory and coagulation marker elevation associated with venous thromboembolism development. Descriptive statistics outlined the frequency of venous thromboembolism at any time during severe coronavirus disease 2019. Clinical course and laboratory metrics were compared between patients that developed venous thromboembolism and patients that did not develop venous thromboembolism. Hypercoagulable thromboelastography was defined as two or more hypercoagulable parameters.

Main Results: One-hundred nine patients developed severe coronavirus disease 2019 requiring ICU care. The mean (± SD) age was 61 ± 16 years and 57% were male. Seventy-five patients (69%) were discharged home, 7 patients (6%) remain in the hospital, and 27 patients (25%) died. Venous thromboembolism was diagnosed in 31 patients (28%) 8 ± 7 days after hospital admission, including two patients diagnosed with venous thromboembolism at presentation to the hospital. Elevated admission D-dimer and peak D-dimer were associated with venous thromboembolism development (p < 0.05). D-dimer greater than 2,600 ng/mL predicted venous thromboembolism with an area under the receiver operating characteristic curve of 0.760 (95% CI, 0.661-0.858; p < 0.0001), sensitivity of 89.7%, and specificity of 59.5%. Twelve patients (11%) had thromboelastography performed and 58% of these patients had a hypercoagulable study. The calculated coagulation index was hypercoagulable in 50% of patients with thromboelastography.

Conclusions: These data show that coronavirus disease 2019 results in a hypercoagulable state. Routine chemical venous thromboembolism prophylaxis may be inadequate in preventing venous thromboembolism in severe coronavirus disease 2019.
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http://dx.doi.org/10.1097/CCM.0000000000004466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302085PMC
September 2020

IL-1R (Interleukin-1 Receptor) Signaling and Attenuated Hepatic CYP (Cytochrome P450) 2C Expression: Explanation for Higher Rate of Clopidogrel Resistance in Patients With Diabetes Mellitus?

Authors:
Rolf P Kreutz

Arterioscler Thromb Vasc Biol 2020 06 27;40(6):1429-1431. Epub 2020 May 27.

From the Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis.

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http://dx.doi.org/10.1161/ATVBAHA.120.314446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263358PMC
June 2020

Impact of Routine Platelet Reactivity Testing with VerifyNow Assay on Antiplatelet Choice After Percutaneous Coronary Intervention.

Clin Pharmacol 2020 16;12:35-41. Epub 2020 Apr 16.

Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA.

Background: High on-treatment ADP platelet reactivity (HPR) measured by VerifyNow P2Y12 assay (VN) is an established risk factor for ischemic events after percutaneous coronary intervention (PCI). We hypothesized that routine use of VN at time of PCI in clinical practice may affect choice of P2Y12 antiplatelet therapy at discharge.

Methods: In a single center retrospective analysis, we examined the influence of VN testing on choice of P2Y12 inhibitor post PCI in routine clinical practice. Assessment of HPR was used routinely in clinical care during the time period of analysis at discretion of clinical providers. Subjects with PRU>208 after the loading dose of clopidogrel or during clopidogrel steady state were switched to alternate P2Y12 inhibitors.

Results: We identified 1001 patients with PCI during the time period specified. A total of 252 subjects underwent VN testing. Among those, 43% were found to have HPR on clopidogrel and were switched to alternate therapies (prasugrel [n=60], ticagrelor [n=48]). Patients who had VN platelet function testing were more likely to be discharged on clopidogrel as compared to those who did not have VN assay done (57% vs. 50%, p=0.039). There was no significant difference in 1-year net-MACE (CVD, MI, stent thrombosis, BARC 2 or higher bleeding) using tailored antiplatelet therapy (VN testing) as compared to standard of care group (adjusted HR:0.92, 95% CI: 0.54-1.5, p=0.74).

Conclusion: Routine use of VN assay in personalized antiplatelet treatment decision-making after PCI is associated with lower likelihood of using novel P2Y12 inhibitors.
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http://dx.doi.org/10.2147/CPAA.S242675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170549PMC
April 2020

Intensified P2Y12 inhibition for high-on treatment platelet reactivity.

J Thromb Thrombolysis 2020 Oct;50(3):619-627

Department of Medicine, Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.

High on treatment platelet reactivity (HPR) during treatment with clopidogrel has been consistently found to be strong risk factor for recurrent ischemic events after percutaneous coronary intervention (PCI). Insufficient P2Y12 receptor inhibition contributes to HPR measured by the VerifyNow (VN) assay. Prasugrel and ticagrelor are more potent P2Y12 inhibitors than clopidogrel and commonly substituted for clopidogrel when HPR is documented, however benefit of VN guided intensified antiplatelet therapy is uncertain. We identified patients who had undergone platelet reactivity testing after PCI with VN after pretreatment with clopidogrel (n = 252) in a single center observational analysis. Patients who had HPR defined as PRU > 208 were switched to alternate P2Y12 inhibitors. Primary clinical endpoint was 1-year post PCI combined cardiovascular death, myocardial infarction (MI), and stent thrombosis. One hundred and eight (43%) subjects had HPR and were switched to prasugrel (n = 60) and ticagrelor (n = 48). Risk of recurrent 1-year primary endpoint remained higher for HPR patients switched to either ticagrelor or prasugrel as compared to subjects who had low on treatment platelet reactivity (n = 144) (LPR) on clopidogrel [Hazard Ratio: 3.5 (95% CI 1.1-11.1); p = 0.036)]. Propensity score matched analysis demonstrated higher event rates in patients with HPR on alternate P2Y12 inhibitor as compared to patients with LPR (log-rank: p = 0.044). The increased risk of recurrent events associated with HPR measured by VN is not completely attenuated by switching to more potent P2Y12 inhibitors. Non-P2Y12 mediated pathways likely contribute to increased incidence of thrombotic events after PCI in subjects with HPR.
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http://dx.doi.org/10.1007/s11239-020-02075-xDOI Listing
October 2020

Prediction of Ischemic Events after Percutaneous Coronary Intervention: Thrombelastography Profiles and Factor XIIIa Activity.

TH Open 2018 Apr;2(2):e173-e181

Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana, United States.

Background: High plasma fibrin clot strength (MA) measured by thrombelastography (TEG) is associated with increased risk of cardiac events after percutaneous coronary interventions (PCIs). Factor XIIIa (FXIIIa) cross-links soluble fibrin, shortens clot formation time (TEG-K), and increases final clot strength (MA).

Methods: We analyzed platelet-poor plasma from patients with previous PCI. Kaolin-activated TEG (R, K, MA) in citrate platelet-poor plasma and FXIIIa were measured ( = 257). Combined primary endpoint was defined as recurrent myocardial infarction (MI) or cardiovascular death (CVD). Relationship of FXIIIa and TEG measurements on cardiac risk was explored.

Results: FXIIIa correlated with TEG-MA ( = 0.002) and inversely with TEG-K ( < 0.001). High MA (≥35.35 mm; = 0.001), low K (<1.15 min; = 0.038), and elevated FXIIIa (≥83.51%; = 0.011) were associated with increased risk of CVD or MI. Inclusion of FXIIIa activity and low TEG-K in risk scores did not improve risk prediction as compared with high TEG-MA alone.

Conclusion: FXIIIa is associated with higher plasma TEG-MA and low TEG-K. High FXIIIa activity is associated with a modest increase in cardiovascular risk after PCI, but is less sensitive and specific than TEG-MA. Addition of FXIIIa does not provide additional risk stratification beyond risk associated with high fibrin clot strength phenotype measured by TEG.
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http://dx.doi.org/10.1055/s-0038-1645876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419750PMC
April 2018

Pharmacogenomics of Novel Direct Oral Anticoagulants: Newly Identified Genes and Genetic Variants.

J Pers Med 2019 Jan 17;9(1). Epub 2019 Jan 17.

Department of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a relatively new area of research. There is a need to understand the role of pharmacogenomics in the interpatient variability of the four most commonly prescribed DOACs, namely dabigatran, rivaroxaban, apixaban, and edoxaban. We performed an extensive search of recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of DOACs. Additionally, we also focused on commonly associated drug-drug interactions of DOACs. CES1 and ABCB1 SNPs are the most common documented genetic variants that contribute to alteration in peak and trough levels of dabigatran with demonstrated clinical impact. ABCB1 SNPs are implicated in alteration of plasma drug levels of rivaroxaban and apixaban. Studies conducted with factor Xa, ABCB1, SLCOB1, CYP2C9, and VKORC1 genetic variants did not reveal any significant association with plasma drug levels of edoxaban. Pharmacokinetic drug-drug interactions of dabigatran are mainly mediated by p-glycoprotein. Strong inhibitors and inducers of CYP3A4 and p-glycoprotein should be avoided in patients treated with rivaroxaban, apixaban, and edoxaban. We conclude that some of the inter-individual variability of DOACs can be attributed to alteration of genetic variants of gene loci and drug-drug interactions. Future research should be focused on exploring new genetic variants, their effect, and molecular mechanisms that contribute to alteration of plasma levels of DOACs.
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http://dx.doi.org/10.3390/jpm9010007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463033PMC
January 2019

Next generation MicroRNA sequencing to identify coronary artery disease patients at risk of recurrent myocardial infarction.

Atherosclerosis 2018 11 3;278:232-239. Epub 2018 Oct 3.

Department of Clinical Pharmacology, Indiana University School of Medicine, United States; Krannert Institute of Cardiology, Indiana University School of Medicine, United States. Electronic address:

Background And Aims: Variation in micro-RNA (miRNA) levels in blood has been associated with alterations of physiological functions of the cardiovascular system. Circulating miRNA have the potential to become reliable biomarkers for risk stratification and early detection of cardiovascular events. Recurrent thrombotic events in patients with established coronary artery disease (CAD) demonstrate the need for personalized approaches to secondary prevention, especially in light of recent novel treatment approaches.

Methods: In a single center cohort study, whole blood samples were collected from 437 subjects undergoing cardiac catheterization, who were followed for recurrent cardiovascular events during a mean follow up of 1.5 years. We selected a case cohort (n = 22) with recurrent thrombotic events on standard medical therapy (stent thrombosis (n = 6) or spontaneous myocardial infarction (MI) (n = 16)) and a matched cohort with CAD, but uneventful clinical follow up (n = 26), as well as a control group with cardiovascular risk factors, but without angiographic CAD (n = 24). We performed complete miRNA next generation sequencing of RNA extracted from whole blood samples (including leukocytes and platelets).

Results: A differential pattern of miRNA expression was found among controls, CAD patients with no events, and CAD patients with recurrent events. MiRNA previously associated with MI, CAD, endothelial function, vascular smooth muscle cells, platelets, angiogenesis, heart failure, cardiac hypertrophy, arrhythmia, and stroke were found variably expressed in our case-control cohorts. Seventy miRNA (FDR <0.05) were linked to the risk of recurrent myocardial infarction and future stent thrombosis, as compared to CAD patients with subsequently uneventful follow up.

Conclusions: MiRNA next generation sequencing demonstrates altered fingerprint profile of whole blood miRNA expression among subjects with subsequent recurrent thrombotic events on standard medical therapy ('non-responders'), as compared to subjects with no recurrent cardiovascular events. MiRNA profiling may be useful to identify high risk subjects and provide additional insights into disease mechanisms not currently attenuated with standard medical therapy used in CAD treatment.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350783PMC
November 2018

A comprehensive review and meta-analysis of risk factors for statin-induced myopathy.

Eur J Clin Pharmacol 2018 Sep 22;74(9):1099-1109. Epub 2018 May 22.

Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

Purpose: To aid prescribers in assessing a patient's risk for statin-induced myopathy (SIM), we performed a comprehensive review of currently known risk factors and calculated aggregated odds ratios for each risk factor through a meta-analysis.

Methods: This meta-analysis was done through four phases: (1) Identification of the relevant primary literature; (2) abstract screening using inclusion and exclusion criteria; (3) detailed review and data extraction; and (4) synthesis and statistical analysis.

Results: Out of 44 papers analyzed from 836 papers searched from MEDLINE, 18 different potential risk factors were collected, divided into three categories: three demographics (11 papers), ten clinical factors (31 papers), and five pharmacogenetics/biomarkers (12 papers). Risk factors significant for myopathy and/or rhabdomyolysis included age, gender, diabetes, renal impairment, cardiovascular disease, certain interacting drugs, and mutations of the SLCO1B1 gene, which encodes a transporter protein in the liver. Several factors, such as gender, race, cardiovascular disease, and the GATM gene, which encodes a protein for creatine synthesis, appeared to be protective in terms of the outcomes of interest.

Conclusions: This comprehensive assessment of risk factors can help support clinicians in reducing the incidence of SIM in their patient population on statins.
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http://dx.doi.org/10.1007/s00228-018-2482-9DOI Listing
September 2018

Fibrin Clot Strength in Patients with Diabetes Mellitus Measured by Thrombelastography.

J Diabetes Res 2018 4;2018:4543065. Epub 2018 Feb 4.

Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA.

Background: Patients with diabetes mellitus (DM) exhibit increased risk of recurrent myocardial infarction. Maximal clot strength measured by thrombelastography (TEG) is a risk factor for recurrent ischemic events. We hypothesized that diabetic subjects exhibit increased fibrin clot strength in platelet-poor plasma and that glycemic control correlates with maximal fibrin clot strength.

Methods: We collected plasma samples from subjects with known or suspected coronary artery disease undergoing cardiac catheterization ( = 354). We measured kaolin-activated TEG in platelet-poor citrate plasma. Time to fibrin formation (R), clot formation time (K), and maximal fibrin clot strength (MA) were recorded.

Results: Plasma fibrin MA was increased among subjects with DM ( = 152) as compared to non-DM ( = 202) (37.0 ± 8 versus 34.1 ± 8 mm; < 0.001). Hemoglobin A1c (HbA1c) ( = 0.22; = 0.001) and fibrinogen ( = 0.29; < 0.001) correlated with fibrin MA. In multivariable regression analysis, DM remained significantly associated with plasma MA after adjustment for fibrinogen level ( = 0.003).

Conclusions: Subjects with diabetes mellitus exhibit increased maximal fibrin clot strength measured by TEG in platelet-poor plasma.
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http://dx.doi.org/10.1155/2018/4543065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817329PMC
September 2018

Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy.

Clin Pharmacol Ther 2018 10 30;104(4):664-674. Epub 2018 Jan 30.

Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes, which are both related to the CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions.
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http://dx.doi.org/10.1002/cpt.1006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019555PMC
October 2018

Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

JACC Cardiovasc Interv 2018 01 1;11(2):181-191. Epub 2017 Nov 1.

Department of Medicine, University of Maryland, Baltimore, Maryland.

Objectives: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI).

Background: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI.

Methods: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights.

Results: Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60).

Conclusions: These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.
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http://dx.doi.org/10.1016/j.jcin.2017.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775044PMC
January 2018

Common genetic polymorphisms of adenosine A2A receptor do not influence response to regadenoson.

Pharmacogenomics 2017 Apr 30;18(6):523-529. Epub 2017 Mar 30.

Department of Medicine, Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Aim: Hemodynamic response to regadenoson varies greatly, and underlying mechanisms for variability are poorly understood. We hypothesized that five common variants of adenosine A2A receptor (ADORA2A) are associated with altered response to regadenoson.

Methods: Consecutive subjects (n = 357) undergoing resting regadenoson nuclear stress imaging were enrolled. Genotyping was performed using Taqman-based assays for rs5751862, rs2298383, rs3761422, rs2267076 and rs5751876.

Results: There was no significant difference in heart rate or blood pressure between different genotypes following regadenoson administration. There was also no significant difference in myocardial ischemia detected by nuclear perfusion imaging as defined by summed difference score, or in self-reported side effects among the genotypes tested.

Conclusion: The common A2A variants studied are not associated with variability in hemodynamic response to regadenoson or variability in detection of ischemia with nuclear perfusion stress imaging.
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http://dx.doi.org/10.2217/pgs-2016-0178DOI Listing
April 2017

Fibrin clot strength measured by thrombelastography and outcomes after percutaneous coronary intervention.

Thromb Haemost 2017 01 3;117(2):426-428. Epub 2016 Nov 3.

Rolf P. Kreutz, M. D., FACC, FAHA, FSCAI, Associate Professor of Clinical Medicine, Krannert Institute of Cardiology, Indiana University School of Medicine, 1801 N. Senate Blvd., MPC2, ME400, Indianapolis, IN 46202-1228, USA, Tel.: +1 317 962 0500, E-mail:

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http://dx.doi.org/10.1160/TH16-10-0496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459604PMC
January 2017

Simultaneous administration of high-dose atorvastatin and clopidogrel does not interfere with platelet inhibition during percutaneous coronary intervention.

Clin Pharmacol 2016 3;8:45-50. Epub 2016 Jun 3.

Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA.

Background: Reloading with high-dose atorvastatin shortly before percutaneous coronary interventions (PCIs) has been proposed as a strategy to reduce periprocedural myonecrosis. There has been a concern that statins that are metabolized by cytochrome P450 3A4 may interfere with clopidogrel metabolism at high doses. The impact of simultaneous administration of high doses of atorvastatin and clopidogrel on the efficacy of platelet inhibition has not been established.

Methods: Subjects (n=60) were randomized to receive atorvastatin 80 mg together with clopidogrel 600 mg loading dose (n=28) versus clopidogrel 600 mg alone (n=32) at the time of PCI. Platelet aggregation was measured at baseline, 4 hours after clopidogrel loading dose, and 16-24 hours after clopidogrel loading dose by light transmittance aggregometry using adenosine diphosphate as agonist.

Results: Platelet aggregation was similar at baseline in both the atorvastatin and the control groups (adenosine diphosphate 10 µM: 57%±19% vs 61%±21%; P=0.52). There was no significant difference in platelet aggregation between the atorvastatin and the control groups at 4 hours (37%±18% vs 39%±21%; P=0.72) and 16-24 hours post-clopidogrel loading dose (35%±17% vs 37%±18%; P=0.75). No significant difference in incidence of periprocedural myonecrosis was observed between the atorvastatin and control groups (odds ratio: 1.02; 95% confidence interval 0.37-2.8).

Conclusion: High-dose atorvastatin given simultaneously with clopidogrel loading dose at the time of PCI does not significantly alter platelet inhibition by clopidogrel. Statin reloading with high doses of atorvastatin at the time of PCI appears to be safe without adverse effects on platelet inhibition by clopidogrel (ClinicalTrials.gov: NCT00979940).
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http://dx.doi.org/10.2147/CPAA.S98790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902146PMC
June 2016

AMPD1 polymorphism and response to regadenoson.

Pharmacogenomics 2015 Nov 10;16(16):1807-15. Epub 2015 Nov 10.

Department of Medicine, Krannert Institute of Cardiology, Indiana University School of Medicine, 1800 N. Capitol Ave, MPC2, ME-400, Indianapolis, IN 46202, USA.

Aims:  AMPD1 c.34C > T (rs17602729) polymorphism results in AMPD1 deficiency. We examined the association of AMPD1 deficiency and variability of hemodynamic response to regadenoson.

Subjects & Methods: Genotyping for c.34C>T was performed in 267 patients undergoing regadenoson cardiac stress testing.

Results: Carriers of c.34C >T variant exhibited higher relative changes in systolic blood pressure (SBP) compared with wild-type subjects ([%] SBP change to peak: 12 ± 25 vs 5 ± 13%; p = 0.01) ([%] SBP change to nadir: -3 ± 15 vs -7 ± 11%; p = 0.04). Change in heart rate was similar between groups, but side effects were more common in carriers of the variant (+LR = 4.2; p = 0.04).

Conclusion: AMPD1 deficiency may be involved in the modulation of regadenoson's systemic effects.
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http://dx.doi.org/10.2217/pgs.15.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826562PMC
November 2015

Variations in Clinical Presentation, Risk Factors, Treatment, and Prognosis of Spontaneous Coronary Artery Dissection.

J Invasive Cardiol 2015 Aug;27(8):363-9

Krannert Institute of Cardiology, Indiana University School of Medicine, 1800 N. Capitol Ave, ME-400, Indianapolis, IN 46202 USA.

Spontaneous coronary artery dissection (SCAD) has been considered a rare cause of acute coronary syndrome (ACS) in younger patients without known cardiovascular risk factors. However, recent studies have reported a higher incidence of SCAD in patients presenting with ACS with use of advanced invasive imaging modalities. In light of increasing awareness, the diagnosis of SCAD has increased significantly. We conducted a single-center retrospective analysis of cases with reported SCAD during a 10-year period between 2003 and 2013. Ten cases of SCAD were identified after review of coronary angiograms and clinical records. Basic demographic details, comorbidities, initial presentation, length of dissection, specific vessels involved in dissection, initial management, subsequent outcome, and incidence of recurrence were documented. All patients were female, with mean age of 42 years. One-third of cases occurred in the peripartum period. All patients presented with acute coronary syndromes. The left anterior descending artery was the predominant vessel involved in 80% of the patients on initial presentation. Out of 10 patients, 6 were managed conservatively, 2 had emergent coronary artery bypass graft, and 2 had percutaneous coronary intervention with placement of stents. Three of the 6 patients undergoing medical management after the initial presentation had recurrence within the same hospitalization.
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August 2015

Caffeine Consumption and Heart Rate and Blood Pressure Response to Regadenoson.

PLoS One 2015 22;10(6):e0130487. Epub 2015 Jun 22.

Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Background: Current guidelines recommend that caffeinated products should be avoided for at least 12 hours prior to regadenoson administration. We intended to examine the effect of caffeine consumption and of timing of last dose on hemodynamic effects after regadenoson administration for cardiac stress testing.

Methods: 332 subjects undergoing regadenoson stress testing were enrolled. Baseline characteristics, habits of coffee/caffeine exposure, baseline vital signs and change in heart rate, blood pressure, percent of maximal predicted heart rate, and percent change in heart rate were prospectively collected.

Results: Non-coffee drinkers (group 1) (73 subjects) and subjects who last drank coffee >24 hours (group 3) (139 subjects) prior to regadenoson did not demonstrate any difference in systolic blood pressure, heart rate change, maximal predicted heart rate and percent change in heart rate. Systolic blood pressure change (15.2±17.1 vs. 7.2±10.2 mmHg, p = 0.001), heart rate change (32.2±14 vs. 27.3±9.6 bpm, p = 0.038) and maximal predicted heart rate (65.5±15.6 vs. 60.7±8.6%, p = 0.038) were significantly higher in non-coffee drinkers (group 1) compared to those who drank coffee 12-24 hours prior (group 2) (108 subjects). Subjects who drank coffee >24 hours prior (group 3) exhibited higher systolic blood pressure change (13±15.8 vs. 7±10.2, p = 0.007), and heart rate change (32.1±15.3 vs. 27.3±9.6, p = 0.017) as compared to those who drank coffee 12-24 hours prior to testing (group 2).

Conclusions: Caffeine exposure 12-24 hours prior to regadenoson administration attenuates the vasoactive effects of regadenoson, as evidenced by a blunted rise in heart rate and systolic blood pressure. These results suggest that caffeine exposure within 24 hours may reduce the effects of regadenoson administered for vasodilatory cardiac stress testing.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130487PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476756PMC
April 2016

Platelet factor XIIIa release during platelet aggregation and plasma clot strength measured by thrombelastography in patients with coronary artery disease treated with clopidogrel.

Platelets 2015 15;26(4):358-63. Epub 2014 May 15.

Krannert Institute of Cardiology .

It has been estimated that up to half of circulating factor XIIIa (FXIIIa) is stored in platelets. The release of FXIIIa from platelets upon stimulation with adenosine diphosphate (ADP) in patients with coronary artery disease treated with dual antiplatelet therapy has not been previously examined. Samples from 96 patients with established coronary artery disease treated with aspirin and clopidogrel were examined. Platelet aggregation was performed by light transmittance aggregometry in platelet-rich plasma (PRP), with platelet-poor plasma (PPP) as reference, and ADP 5 µM as agonist. Kaolin-activated thrombelastography (TEG) was performed in citrate PPP. PRP after aggregation was centrifuged and plasma supernatant (PSN) collected. FXIIIa was measured in PPP and PSN. Platelet aggregation after stimulation with ADP 5 µM resulted in 24% additional FXIIIa release in PSN as compared to PPP (99.3 ± 27 vs. 80.3 ± 24%, p < 0.0001). FXIIIa concentration in PSN correlated with maximal plasma clot strength (TEG-G) (r = 0.48, p < 0.0001), but not in PPP (r = 0.15, p = 0.14). Increasing quartiles of platelet-derived FXIIIa were associated with incrementally higher TEG-G (p = 0.012). FXIIIa release was similar between clopidogrel responders and non-responders (p = 0.18). In summary, platelets treated with aspirin and clopidogrel release a significant amount of FXIIIa upon aggregation by ADP. Platelet-derived FXIIIa may contribute to differences in plasma TEG-G, and thus, in part, provide a mechanistic explanation for high clot strength observed as a consequence of platelet activation. Variability in clopidogrel response does not significantly influence FXIIIa release from platelets.
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http://dx.doi.org/10.3109/09537104.2014.916793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736138PMC
February 2016

Factor XIII Val34Leu polymorphism and recurrent myocardial infarction in patients with coronary artery disease.

J Thromb Thrombolysis 2014 Oct;38(3):380-7

Krannert Institute of Cardiology, Indiana University School of Medicine, 1800 N. Capitol Ave, ME-400, Indianapolis, IN, 46202, USA,

Factor XIII (FXIII) is necessary for cross linking of fibrin strands and generation of stable fibrin clot. FXIII Val34Leu is a common genetic single nucleotide polymorphism that has been associated with accelerated fibrin stabilization and reduced rate of fibrinolysis. The contribution of Val34Leu to long term risk of recurrent myocardial infarction (MI) in patients with coronary stenting has not been conclusively established. The objective of the study was to examine the effects of Val34Leu on fibrin generation, platelet aggregation, and long term clinical outcomes in patients with coronary artery disease treated with dual antiplatelet therapy. Patients with angiographically documented coronary artery disease who were treated with aspirin and clopidogrel were enrolled (n = 211). Light transmittance aggregometry and plasma fibrin clot formation using thrombelastography (TEG) were determined. Genotyping of Val34Leu was performed using Taqman assay. Clinical events during follow up were recorded. Homozygous carriers of 34 Leu variant had significantly shorter fibrin clot formation time as compared to wild type individuals (TEG K: 1.27 ± 0.3 vs. 1.68 ± 1.1 min, p = 0.011). The Val34Leu variant was associated with gene dose dependent increased risk of MI (log rank, p = 0.002) or occurrence of composite of MI and CV death (log rank, p = 0.005) with highest event rates observed in homozygous carriers of 34 Leu. In summary, FXIII Val34Leu polymorphism was associated with increased rate of fibrin stabilization in homozygous carriers of the variant and may increase risk of recurrent MI and death in patients with angiographically established coronary artery disease treated with dual antiplatelet therapy.
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http://dx.doi.org/10.1007/s11239-014-1059-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295494PMC
October 2014

Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response.

Clin Pharmacol 2013 9;5:185-92. Epub 2013 Dec 9.

Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Recent candidate gene studies using a human liver bank and in vivo validation in healthy volunteers identified polymorphisms in cytochrome P450 (CYP) 3A4 gene (CYP3A4*22), Ah-receptor nuclear translocator (ARNT), and peroxisome proliferator-activated receptor-α (PPAR-α) genes that are associated with the CYP3A4 phenotype. We hypothesized that the variants identified in these genes may be associated with altered clopidogrel response, since generation of clopidogrel active metabolite is, partially mediated by CYP3A activity. Blood samples from 211 subjects, of mixed racial background, with established coronary artery disease, who had received clopidogrel, were analyzed. Platelet aggregation was determined using light transmittance aggregometry (LTA). Genotyping for CYP2C19*2, CYP3A4*22, PPAR-α (rs4253728, rs4823613), and ARNT (rs2134688) variant alleles was performed using Taqman® assays. CYP2C19*2 genotype was associated with increased on-treatment platelet aggregation (adenosine diphosphate 20 μM; P=0.025). No significant difference in on-treatment platelet aggregation, as measured by LTA during therapy with clopidogrel, was demonstrated among the different genotypes of CYP3A4*22, PPAR-α, and ARNT. These findings suggest that clopidogrel platelet inhibition is not influenced by the genetic variants that have previously been associated with reduced CYP3A4 activity.
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http://dx.doi.org/10.2147/CPAA.S53151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3862586PMC
December 2013

Plasma and whole blood clot strength measured by thrombelastography in patients treated with clopidogrel during acute coronary syndromes.

Thromb Res 2013 Aug 3;132(2):e94-8. Epub 2013 Aug 3.

Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Introduction: Treatment with clopidogrel, a selective platelet P2Y12 receptor antagonist, reduces risk of recurrent ischemic events in patients with acute coronary syndrome (ACS), by limiting platelet aggregation and activation. Stable whole blood clot formation requires activation of platelets, generation of fibrin and final fibrin crosslinks. In this study we intended to compare plasma and whole blood thrombelastography (TEG) measurements in patients during ACS.

Materials And Methods: Whole blood and plasma samples from 32 patients with non-ST segment elevation myocardial infarction (NSTEMI) were collected after administration of clopidogrel. Whole blood and plasma fibrin clot strength (MA) were determined by TEG. Platelet aggregation was determined by light transmittance aggregometry (LTA) using adenosine 5'-diphosphate (ADP), thrombin receptor activation peptide (TRAP), or collagen as agonists. Fibrinogen and C-reactive protein (CRP) concentrations were measured by ELISA.

Results: Heightened plasma fibrin clot strength was associated with increased platelet reactivity stimulated by ADP (ρ=0.536; p=0.002), TRAP (ρ=0.481; p=0.007), and collagen (ρ=0.538; p=0.01). In contrast to plasma fibrin MA, whole blood MA did not correlate with platelet aggregation. Platelet count was the primary contributor to the difference in thrombin induced whole blood MA and plasma fibrin MA. Increasing levels of CRP were associated with increased plasma fibrin clot strength and platelet reactivity.

Conclusions: Our data suggest that inflammation is associated with increased plasma fibrin clot strength and lower platelet inhibition by clopidogrel during ACS. Platelet count is a main contributor to additional contractile force of whole blood TEG as compared to plasma TEG during treatment with clopidogrel.
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http://dx.doi.org/10.1016/j.thromres.2013.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028119PMC
August 2013

C-reactive protein and fibrin clot strength measured by thrombelastography after coronary stenting.

Blood Coagul Fibrinolysis 2013 Apr;24(3):321-6

Krannert Institute of Cardiology, Indiana University School of Medicine, 1800 N. Capitol Avenue, Indianapolis, IN 46202, USA.

Inflammation is implicated in the progression of coronary artery disease and the molecular processes of inflammation and thrombosis are closely intertwined. Elevated levels of C-reactive protein (CRP) have been associated with an elevated risk of adverse ischaemic events after coronary stenting and hypercoagulability. Heightened whole blood clot strength measured by thrombelastography (TEG) has been associated with adverse ischaemic events after stenting. We intended to examine the relationship of CRP to plasma fibrin clot strength in patients after coronary stenting. Plasma fibrin clot strength was measured by TEG in 54 patients 16-24 h after undergoing elective percutaneous coronary intervention (PCI). Coagulation was induced in citrated plasma by addition of kaolin and CaCl2. Plasma levels of CRP and fibrinogen were measured by enzyme-linked immunoassay. Increasing quartiles of CRP were associated with increasing levels of maximal plasma fibrin clot strength measured by TEG (P < 0.001) and increasing BMI (P = 0.04). Patients in the highest quartile of CRP had significantly higher maximal fibrin clot strength (G) than the patients in the lowest quartile (G: 3438 ± 623 vs. 2184 ± 576 dyn/cm, P < 0.0001). Fibrinogen concentration was not significantly different across quartiles of CRP (P = 0.97). Patients with established coronary artery disease undergoing coronary stenting who have elevated CRP after PCI exhibit heightened maximal plasma fibrin clot strength as compared with those with low CRP. Thrombotic risk associated with elevated CRP may be linked to procoagulant changes and high tensile fibrin clot strength independent of fibrinogen concentration.
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http://dx.doi.org/10.1097/MBC.0b013e32835cc193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028117PMC
April 2013

Spontaneous coronary artery dissection in a 14-year-old.

Am J Emerg Med 2013 Feb 15;31(2):461.e5-7. Epub 2012 Nov 15.

Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

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http://dx.doi.org/10.1016/j.ajem.2012.08.014DOI Listing
February 2013

Protease activated receptor-1 (PAR-1) mediated platelet aggregation is dependent on clopidogrel response.

Thromb Res 2012 Aug 28;130(2):198-202. Epub 2012 Mar 28.

Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Introduction: Clopidogrel inhibits ADP mediated platelet aggregation through inhibition of the P2Y12 receptor by its active metabolite. Thrombin induces platelet aggregation by binding to protease activated receptor-1 (PAR-1), and inhibition of PAR-1 has been evaluated in patients treated with clopidogrel to reduce ischemic events after acute coronary syndromes. Residual PAR-1 mediated platelet aggregation may be dependent on extent of clopidogrel response.

Material And Methods: Platelet aggregation was measured in 55 patients undergoing elective PCI at 16-24 hours after 600 mg clopidogrel loading dose by light transmittance aggregometry using ADP 20 μM and thrombin receptor agonist peptide (TRAP) at 15 μM and 25 μM as agonists. Genomic DNA was genotyped for common CYP2C19 variants.

Results: Increasing quartiles of 20 μM ADP induced platelet aggregation after clopidogrel loading were associated with increasing levels of TRAP mediated platelet aggregation. Patients in the highest quartile (clopidogrel non-responders) of post treatment ADP aggregation had significantly higher TRAP mediated aggregation than the patients in the lowest quartile (clopidogrel responders) [TRAP 15 μM: 79.6 ± 5% vs. 69.5 ± 8%, p<0.001].

Conclusions: Non-responders to clopidogrel show increased residual platelet aggregation induced by TRAP, whereas clopidogrel responders exhibit attenuated response to TRAP. Addition of PAR-1 antiplatelet drugs may be most effective in patients with reduced clopidogrel response and high residual TRAP mediated platelet aggregation.
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http://dx.doi.org/10.1016/j.thromres.2012.02.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3965578PMC
August 2012

Influence of paraoxonase-1 Q192R and cytochrome P450 2C19 polymorphisms on clopidogrel response.

Clin Pharmacol 2012 20;4:13-20. Epub 2012 Feb 20.

Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA.

Background: The metabolic activation of clopidogrel is a two-step process. It has been suggested that paraoxonase-1 (PON1) is a rate-limiting enzyme in the conversion of 2-oxo- clopidogrel to an active thiol metabolite. Conflicting results have been reported in regard to (1) the association of a common polymorphism of PON1 (Q192R) with reduced rates of coronary stent thrombosis in patients taking clopidogrel and (2) its effects on platelet inhibition in patient populations of European descent.

Methods: Blood samples from 151 subjects of mixed racial background with established coronary artery disease and who received clopidogrel were analyzed. Platelet aggregation was determined with light transmittance aggregometry and VerifyNow(®) P2Y12 assay. Genotyping for cytochrome P450 2C19 (CYP2C19)*2 and *3 and PON1 (Q192R) polymorphisms was performed.

Results: Carriers of CYP2C19*2 alleles exhibited lower levels of platelet inhibition and higher on-treatment platelet aggregation than noncarriers. There was no significant difference in platelet aggregation among PON1 Q192R genotypes. Homozygous carriers of the wild-type variant of PON1 (QQ192) had similar on-treatment platelet reactivity to carriers of increased-function variant alleles during maintenance clopidogrel dosing, as well as after administration of a clopidogrel 600 mg loading dose.

Conclusion: CYP2C19*2 allele is associated with impaired platelet inhibition by clopidogrel and high on-treatment platelet aggregation. PON1 (Q192R) polymorphism does not appear to be a significant determinant of clopidogrel response.
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http://dx.doi.org/10.2147/CPAA.S27822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3304338PMC
August 2012
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