Abstract Title

GENETIC POLYMORPHISMS AFFECTING CLOPIDOGREL METABOLISM

Presenter Name

Adityanant Jain, MS, DO

Abstract

49 yo Asian male with history of coronary artery disease, hyperlipidemia, complete heart block, unstable angina pectoris and gout presents with four prior myocardial infarctions within the prior year indicating rapid stent restenosis despite being on dual anti-platelet therapy with clopidogrel and aspirin. Family history is very positive for myocardial infarctions and death on his paternal side. Patient is a lifetime non-smoker, employed as a hospital pharmacist and had no other cardiac risk factor besides family history. Physical exam was unremarkable, BMI 24.84, vital signs all normal. LDL was above goal at 83 and HDL was 61. A lipoprotein subfractionation, apolipoproteins, inflamatory markers, and genetic markers including LPA Aspirin, KIF6 Genotype, and CYP2C19 were obtained. Patient was noted to be homozygous KIF6 Arg/Arg and CYP2C19*2/*2. KIF6 Arg/Arg is associated with HR 1.50 for recurrent MI by the CARE trial, and clopidogrel is a pro-drug that requires CYP2C19 activation to be efficatious. The patient was changed to ticagrelor which has similar efficacy however does not require CYP2C19 activation. This case study strongly indicates a potential benefit for genetic screening for CYP2C19 on patients being placed on dual antiplatelet therapy with clopidogrel and aspirin. Further it shows the value of research in basic sciences to understand the causes variable responses to drugs in vivo.

Purpose (a):

To demonstrate a case of severe cardiovascular complications in a young and otherwise healthy patient with no high risk behaviours likely due to a genetic polymorphism affecting his ability to activate clopidogrel.

Methods (b):

Labs were drawn in the office and performed by Quest Lab and results were discussed with the patient who participated in decision making regarding his subsequent medication selection.

Results (c):

HR = "High Risk" LR = "Low Risk" MR = "Medium Risk"

LPA Aspirin Genotype Ile/Ile (non-carrier)

KIF6 Genotype Arg/Arg (High Risk-CV disease)

9p21 rs10757278 ag

9p21 rs1333049 gc

ApoE Genotype E2/E3 (Apo E2 carrier)

LPA Intron 25 Genotype tt (non-carrier)

CYP2C19 *2/*2 (poor metabolizer)

4q25 AF Risk Genotype

rs2200733 tt (High Risk carrier - Afib & CVA)

rs10033464 gg (non-carrier)

HS-CRP 0.5

LP PLA2 181(LR)

Fibrinogen Antigen 267 ≤ 350 (LR)

Vitamin D, 25-OH, Total 18 ≥ 30 (HR)

Vitamin D, 25-OH, D3 18

Vitamin D, 25-OH, D2 <4

Homocystine 16.1

Apolipoprotein A1 166 >176 (MR)

Apolipoprotein B 62(MR)

Apolipoprotein B/A1 0.37

Lipoprotein (a) 46(LR)

Lipoprotein Subfractionation

LDL Phenotype A (LR)

LDL, Particle Size 225.6 (LR) >255.5

LDL Particles, Tot 1234 (LR) <1260

LDL, Very Small 304 (LR) <398

LDL, Med & Small 397 (MR) <369

HDL, Small 28160 (LR) >28133

HDL, Large 8028 (MR) >9386

IDL, Small 223 (HR) >315

IDL, Large 179 (LR) <198

VLDL, Small 72 (LR) <124

VLDL, Medium 46 (LR) <61

VLDL, Large 13 (LR) <17

Conclusions (d):

Our patient had multiple risk factors for underlying cardiovascular disease – including his KIF6 Arg/Arg genotype and strong family history. Although his CYP2C19*2/CYP2C19*2 genotype was not responsible for his underlying disease; significant evidence exists demonstrating that loss of function mutation being associated with adverse cardiovascular outcomes while on clopidogrel. Currently gene testing is not currently standard of care.

Previous studies have not categorically shown cost-effectiveness of gene testing, however genetic testing technology is becoming increasingly affordable. Cost-effective gene testing and the availability of alternatives to clopidogrel suggests that identification of patients with loss of function mutations is in the best interest of patient care. If a patient has a thrombotic event on clopidogrel, it is appropriate to either determine CYP2C19 genotype or empirically initiate alternative antiplatelet therapy.

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GENETIC POLYMORPHISMS AFFECTING CLOPIDOGREL METABOLISM

49 yo Asian male with history of coronary artery disease, hyperlipidemia, complete heart block, unstable angina pectoris and gout presents with four prior myocardial infarctions within the prior year indicating rapid stent restenosis despite being on dual anti-platelet therapy with clopidogrel and aspirin. Family history is very positive for myocardial infarctions and death on his paternal side. Patient is a lifetime non-smoker, employed as a hospital pharmacist and had no other cardiac risk factor besides family history. Physical exam was unremarkable, BMI 24.84, vital signs all normal. LDL was above goal at 83 and HDL was 61. A lipoprotein subfractionation, apolipoproteins, inflamatory markers, and genetic markers including LPA Aspirin, KIF6 Genotype, and CYP2C19 were obtained. Patient was noted to be homozygous KIF6 Arg/Arg and CYP2C19*2/*2. KIF6 Arg/Arg is associated with HR 1.50 for recurrent MI by the CARE trial, and clopidogrel is a pro-drug that requires CYP2C19 activation to be efficatious. The patient was changed to ticagrelor which has similar efficacy however does not require CYP2C19 activation. This case study strongly indicates a potential benefit for genetic screening for CYP2C19 on patients being placed on dual antiplatelet therapy with clopidogrel and aspirin. Further it shows the value of research in basic sciences to understand the causes variable responses to drugs in vivo.