Clopidogrel and CYP2C19 in Acute Coronary Syndrome€¦ · Clopidogrel and CYP2C19 in Acute Coronary Syndrome Should pharmacogenetic testing be standard of care? •The author of

Clopidogrel and CYP2C19 in Acute Coronary Syndrome Should Pharmacogenetic Testing be Standard of Care?

September 22, 2017

Kelsey Melloy, PharmD PGY1 Pharmacy Resident Seton Healthcare Family

[email protected]

9/14/2017

1

ASCENSION TEXAS

Kelsey Melloy, PharmD

PGY1 Pharmacy Resident

Seton Healthcare Family

September 22, 2017

Clopidogrel and CYP2C19 in Acute

Coronary Syndrome Should pharmacogenetic testing be standard of

care?

• The author of this presentation has no conflicts of interest

to disclose

2

Conflict of Interest

• Review oral antiplatelet agents

• Explain the FDA black box warning for clopidogrel

pharmacogenetics

• Analyze the clinical impact of CYP2C19 polymorphisms

on clopidogrel efficacy

• Evaluate the evidence for genotype-guided antiplatelet

therapy

3

Objectives

• A 75 year old Chinese female weighing 55 kg presents

with an NSTEMI and is scheduled to undergo PCI

• Of note, the patient is taking St. John’s Wort

• Which antiplatelet option would you recommend?

• A. Clopidogrel

• B. Ticagrelor

• C. Prasugrel

• D. Order CYP2C19 genetic test

4

Meet the patient…

• Life-threatening situation from destabilization of

atherosclerotic plaque

- Includes STEMI, NSTEMI, and UA

• ACS occurs every 25 seconds in the United States

• 1.4 million patients hospitalized for ACS each year in the

United States

- 810,000 for MI

5

Acute Coronary Syndrome (ACS)

Meier P, et al. Heart. 2013;99:1488-1493.

Wachira JK, et al. S D Med. 2013;66:366-369.

Kumar A, et al. Mayo Clin Proc. 2009;84:917-938.

• 2013 ACCF/AHA STEMI Guidelines

- P2Y12 inhibitor load for PCI with stenting, then continued for at

least 12 months

• Clopidogrel, prasugrel, or ticagrelor (LOE B)

• 2014 AHA/ACC NSTEMI Guidelines

- P2Y12 inhibitor for at least 12 months for PCI with stenting

• Clopidogrel, prasugrel, or ticagrelor (class I, LOE B)

- Ticagrelor over clopidogrel in for early invasive or ischemia-guided

strategy (class IIa, LOE B)

6

Antiplatelet Therapy in ACS

Glenn NL, et al. JACC. 2011;58(24).

O’Gara PT, et al. Circulation. 2013;127(4).

Amsterdam EA, et al. Circulation. 2014;136(7).

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2

Clopidogrel

(Plavix)

Prasugrel

(Effient)

Ticagrelor

(Brilinta)

Dose LD: 300 or 600 mg

MD: 75 mg/d

LD: 60 mg

MD: 10 mg/d

(5 mg in < 60 kg)

LD: 180 mg

MD: 90 mg bid

Cost $ $$$ $$$

Metabolism Prodrug;

CYP2C19 (major),

CYP3A4 (minor)

Prodrug;

CYP2B6 (major),

CYP3A4 (minor)

CYP3A4 (major)

Contraindications Active bleeding Active bleeding,

prior stroke or

TIA

Active bleeding,

prior intracranial

hemorrhage

7

Comparison of Oral Antiplatelet Agents

Plavix (clopidogrel) [prescribing information]. Bridgewater, NJ: Bristol-Myers Squibb; July 2017.

Effient (prasugrel) [prescribing information]. Indianapolis, IN: Eli Lilly and Company; July 2016.

Brilinta (ticagrelor) [prescribing information]. Wilmington, DE: AztraZeneca; April 2017.

Appendix B

8

Clopidogrel FDA Warning


Appendix C

9

Clopidogrel Metabolism and Mechanism of Action

Clopidogrel • CYP1A2,

CYP2B6, CYP2C19

2-oxo-clopidogrel

• CYP2C9, CYP2B6, CYP3A4, CYP3A5, CYP2C19, PON1

Active metabolite

• Inhibits P2RY12 on platelet

Sangkuhl Katrin, Klein Teri E, Altman Russ B . Pharmacogenetics and genomics (2010).

Appendix D 10

CYP2C19 Variant Alleles and Frequencies

Scott SA, et al. Clinical Pharmacology & Therapeutics. 2013; 94(3): 317-323.

Functional Status Activity Level Alleles

Functional (wild-type) Normal *1

Loss-of-function (LOF) Little to none *2, *3, *4, *5, *6, *7, *8

Increased function Increased *17

Allele Caucasians Africans Asians

*2 15% 15% 29-35%

*3 <1% <1% 2-9%

Appendix E

Phenotype Genotype Clopidogrel

Implication

Frequency

Ultrarapid

metabolizer

(UM)

Homozygous or heterozygous

increased function (not loss of

function carrier)

Increased active

metabolite

5-30%

Extensive

metabolizer

(EM)

Homozygous normal function Normal active

metabolite

35-50%

Intermediate

metabolizer

(IM)

Heterozygous loss of function +

normal or increased function

Reduced active

metabolite

18-45%

Poor

metabolizer

(PM)

Homozygous loss of function Significantly

reduced active

metabolite

2-15%

11

CYP2C19 Polymorphisms and Clopidogrel


Appendix F 12

Pharmacokinetic Response to Clopidogrel Based on

CYP2C19 Phenotype

Mega JL, et al. N Engl J Med. 2009;360:354-362.

Clopidogrel active metabolite formation

Appendix G

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3

13

Pharmacodynamic Response to Clopidogrel Based on

CYP2C19 Phenotype


Reduction in platelet aggregation 24 hours after clopidogrel

Appendix H 14

CYP2C19 Genotype and Outcomes


Composite:

death from

cardiovascular

causes, MI, or

stroke

LOF Carriers (IMs + PMs)

Noncarriers

12.1%

8.0%

HR 1.53 (p = 0.01)

Appendix I

15

CYP2C19 Genotype and Stent Thrombosis


Noncarriers

2.6%

0.8%

HR 3.09 (p = 0.02)


Appendix J

How does clopidogrel compare to other

antiplatelet agents?

16

17

Clopidogrel vs. Prasugrel – TRITON-TIMI 38

Safety: non-CABG related major hemorrhage

2.4% 1.8% HR 1.32 (p = 0.03)

Primary: composite death from CV causes, MI, or stroke

9.9% 12.1% HR 0.81 (p < 0.001)

13,608 patients with moderate-to-high-risk ACS with scheduled PCI

Prasugrel 60 mg load then 10 mg/day Clopidogrel 300 mg load then 75mg/day

Wiviott SD, et al. N Engl J Med. 2007; 357: 2001-2015.

Outcome Prasugrel Clopidogrel HR (95% CI)

Cardiovascular death, MI, and stroke

Noncarrier 9.6% 9.8% 0.98 (0.80-1.20)

LOF carrier 8.5% 15.0% 0.57 (0.39-0.83)

Major or minor bleeding

Noncarrier 4.7% 3.4% 1.38 (1.00-1.93)

LOF carrier 5.5% 3.5% 1.60 (0.80-3.10)

18

TRITON-TIMI 38 Genetic Substudy

Sorich MJ, et al. J Thromb Haemost. 2010;8:1678-1684.

*Estimates of outcome risks over 15 months for patients with UA or NSTEMI scheduled for PCI

(excluded STEMI patients)

Conclusion

CYP2C19 genotype can distinguish which patients will receive extensive benefit

from prasugrel over clopidogrel

9/14/2017

4

19

Clopidogrel vs. Ticagrelor - PLATO

Safety: non-CABG related major bleeding

4.5% 3.8% HR 1.18 (p = 0.03)

Primary: composite death from CV causes, MI, or stroke

9.8% 11.7% HR 0.84 (p < 0.001)

18,624 patients admitted with ACS, with or without ST-segment elevation

Ticagrelor 180 mg load then 90 mg bid Clopidogrel 300-600 mg load then

75mg/day

Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.

Outcome Ticagrelor Clopidogrel HR

Cardiovascular death, MI, and stroke

Noncarrier 8.3% 9.4% 0.86 (p = 0.0608)

LOF carrier 8.3% 10.7% 0.77 (p = 0.0380)

Non-CABG major bleeding

Noncarrier 3.4% 3.1% 1.08 (p = 0.5500)

LOF carrier 4.1% 3.0% 1.39 (p = 0.1100)

20

PLATO Genetic Substudy

Wallentin L, et al. Lancet. 2010;376(9749):1320-8.

Conclusion

Ticagrelor more efficacious regardless of CYP2C19 polymorphism and

eliminates the need for genetic testing before dual antiplatelet treatment

• 2011 ACCF/AHA/SCAI PCI Guidelines - Testing might be considered to identify patients at high risk for poor

clinical outcomes

- If PM status identified, consider alternate P2Y12 therapy

- Routine genetic testing not recommended

• 2013 ACCF/AHA STEMI Guidelines - Acknowledges possibility of relationship between CYP2C19

polymorphisms and clopidogrel

- No mention of pharmacogenetic testing

• 2014 AHA/ACC NSTEMI Guidelines - Routine genetic testing not recommended

21

What do guidelines say about testing?

Glenn NL, et al. JACC. 2011;58(24).

O’Gara PT, et al. Circulation. 2013;127(4).

Amsterdam EA, et al. Circulation. 2014;136(7).

• CYP2C19 intermediate and poor metabolizer status

associated worse outcomes with clopidogrel

- Black box warning/ FDA safety alert

• Prasugrel and ticagrelor are much more expensive and

cannot be used in certain patients

• Guidelines still do not recommend testing

22

What We Know

23

Does pharmacogenetic testing improve

outcomes?

24

RAPID Gene Study

• Single-center, prospective, randomized, blinded, N=200

• Rapid genotyping vs. standard treatment

Study Design

• Inclusion: age 18-75 undergoing PCI for NSTEMI or stable ACS

• Exclusion: warfarin or dabigatran use, history of stroke or TIA, weight < 60 kg, platelets < 100,000, known bleeding diathesis, Hct < 30%, severe liver dysfunction, or CrCl < 30 ml/min

Patient Population

• Proportion of CYP2C19*2 carriers with high on-treatment platelet reactivity (P2Y12 reactivity units (PRU) > 234) after 1 week of dual antiplatelet therapy

Primary Outcome

Roberts JD, et al. Lancet 2012;379:1705-11.

9/14/2017

5

N=200

Rapid genotyping

(n=102)

CYP2C19*2 carriers (n=23)

Prasugrel 10 mg daily

CYP2C19*2 noncarriers

(n=74)

Clopidogrel 75 mg daily

Standard treatment

(n=98)

Clopidogrel 75 mg daily

CYP2C19*2 23 carriers

73 noncarriers

25

RAPID Gene Study


Rapid Genotyping

(n=91)

Standard Treatment

(n=96)

P-value

Primary Outcome

Patients with PRU

> 234 at day 7

9 (10%) 16 (17%) 0.0672

Secondary Outcomes

Patients with PRU

> 208 at day 7

14 (15%) 30 (31%) 0.0008

26

RAPID Gene Study


PRU: P2Y12 reactivity units

CYP2C19*2

Subgroup

Rapid Genotyping

(n=23)

Standard Treatment

(n=23)

P-value

Patients with PRU

> 234 at day 7

0 (0%) 7 (30%) 0.0092

Authors’ Conclusions

• Point-of-care genetic testing after PCI can be done

effectively at the bedside

• Treatment of CYP2C19*2 carriers with prasugrel can

reduce high on-treatment platelet reactivity

27

RAPID Gene Study


RAPID Gene Study

Strengths

• Prospective

• Genotype-guided vs.

traditional selection

• Compared LOF carriers to

LOF carriers

Weaknesses

• Universal clopidogrel load

• Only tested for CYP2C19*2

• Surrogate endpoint

• Primary outcome timing

• 95% of study population of

western European ancestry

28

29

Genotyping-Approach vs. Conventional Approach in

Chinese Patients

• Single-center, prospective, randomized, open-label, N=132

• CYP2C19 genotype-guided P2Y12 antiplatelet therapy in ACS

Study Design

• Inclusion: ACS (STEMI, UA/NSTEMI) +/- PCI, Chinese

• Exclusion: P2Y12 blocker w/in 6 months, chronic renal failure on HD or plan for HD, serious hepatic disease, CI to clopidogrel or ticagrelor, pregnant

Patient Population

• Platelet reactivity at 24 hours and 1 month after first loading dose of clopidogrel

Primary Outcome

Tam CC, et al. Journal of International Medical Research. 2017;45:134-146.

30


Chinese Patients

Clopidogrel loading dose

Genotype-guided

CYP2C19*2/3 Carrier

Ticagrelor 180 mg load

Ticagrelor 90 mg bid

Noncarrier

Clopidogrel 75 mg/day

Traditional

Clopidogrel 75 mg/day


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6

On-treatment

platelet reactivity

Genotype-guided Standard P value

HTPR at 24 hours 6/65 (9.2%) 27/67 (40.3%) <0.001

HTPR at 1 month 4/62 (6.5%) 20/62 (32.3%) <0.001

31


Chinese Patients

Intermediate metabolizers

HTPR at 24 hours 0/33 (0.0%) 12/27 (44.4%) NR

HTPR at 1 month 0/31 (0.0%) 10/27 (37.0%) NR

Poor metabolizers

HTPR at 24 hours 0/7 (0.0%) 5/8 (62.5%) NR

HTPR at 1 month 0/6 (0.0%) 5/7 (71.4%) NR

HTPR: high on-treatment platelet reactivity = P2Y12 reaction units > 208

NR: not reported


Authors’ conclusions

• Rapid genotyping-guided approach for selecting P2Y12

blockers is feasible

• Genotype-guided approach reduces the incidence of high

on-treatment platelet reactivity

32


Chinese Patients



Chinese Patients

Strengths

• Prospective

• Use of genotype-guidance

randomized

• High risk patient population

Weaknesses

• Surrogate endpoint

• PRU cutoff > 208

• Small sample size

• Patient population not

generalizable

• LOF patients loaded with

clopidogrel and ticagrelor

33 34

Prospective Clinical Implementation of CYP2C19

Genotype Guided Antiplatelet Therapy After PCI

• Prospective, multicenter

• CYP2C19 genotype-guided antiplatelet therapy post-PCI

Study Design

• Average patient: early 60s, male, white, unstable ACS w/PCI

• 54 PMs + 518 IMs 572 (31.5%) actionable genotypes

Patient Population

• Major adverse cardiac events (MACE): death, MI, or stroke within 12 months following index PCI

Primary Outcome

Cavallari LH, IGNITE Investigators. AHA’s Scientific Sessions. 2016.

35



*p<0.0001 for alternative therapy between LOF and NON-LOF groups

ƚPrasugrel >60% of alternative therapy

LOF = loss of function carrier


36





CLOP = clopidogrel

ALT = alternative

8.0%

4.6%

Appendix K

9/14/2017

7

37




Authors’ conclusions

• Genotype-guided approach feasible

• Higher risk for MACE in CYP2C19 LOF treated with

clopidogrel vs. alternative

• Genotyping can improve clinical outcomes after PCI



Strengths

• Genotype-guided antiplatelet

selection

• Prospective

• Real world setting

• Antiplatelet selection up to

physician

Limitations

• Use of genotype-guidance

not randomized

• High dose clopidogrel

• Outcomes based on carrier

status

• Limited study information

available

38

39

Summary of Evidence

Trial Overall Conclusion

Roberts, et al Genotyping reduces high on-treatment platelet

reactivity at day 7 in CYP2C19*2 carriers

Tam, et al Genotyping reduces high on-treatment platelet

reactivity at 24 hours and 1 month

Cavallari, et al Genotyping reduces risk for MACE outcomes




40

Ongoing Trial

2700 STEMI patients

undergoing PCI

CYP2C19 genotyping

2C19 LOF prasugrel or

ticagrelor

Wild-type clopidogrel

Routine ticagrelor or prasugrel

41

POPular Genetics Study

Bergmeijer TO, et al. Am Heart J. 2014;168(1)16-22.e1

• Clinical benefit

- Death, recurrent MI, definite stent thrombosis, stroke, platelet

inhibition and patient outcomes

• Safety

- Clinical benefit and major or minor bleeding

• Cost-effectiveness

• Quality of life

42

POPular Genetics Study Endpoints

Bergmeijer TO, et al. Am Heart J. 2014;168(1)16-22.e1

9/14/2017

8

• A 75 year old Chinese female weighing 55 kg presents

with an NSTEMI and is scheduled to undergo PCI

• Of note, the patient is taking St. John’s Wort

• Which antiplatelet option would you recommend?

• A. Clopidogrel

• B. Ticagrelor

• C. Prasugrel

• D. Order CYP2C19 genetic test

43

Back to the patient…

• Data not strong enough to support testing everyone

• Use genetic information when available

• Consider testing higher risk ethnicities

44

Recommendation

• Antiplatelet agents are not one size fits all

• Clopidogrel response variation can be partly explained by CYP2C19 polymorphisms

• CYP2C19 LOF carriers at higher risk for poor outcomes

• Evidence to support genotyping all patients is still limited - Surrogate endpoints, small sample size, focused on feasibility

• Watch for results of the POPular Genetics Study

45

Conclusion

Evan J. Peterson, PharmD, BCPS

Clinical Pharmacy Specialist – Cardiology

Seton Medical Center Austin

Tamara B. Knight, PharmD, BCPS

Clinical Pharmacy Specialist – Internal Medicine

Seton Northwest Hospital

46

Acknowledgements

ASCENSION TEXAS

Kelsey Melloy, PharmD

PGY1 Pharmacy Resident

Seton Healthcare Family

September 22, 2017

Clopidogrel and CYP2C19 in Acute

Coronary Syndrome Should pharmacogenetic testing be standard of

care?

9

Appendix A: Abbreviations Appendix B: Comparison of Oral Antiplatelet Agents Appendix C: Clopidogrel FDA Warning Appendix D: Clopidogrel Metabolism and Mechanism of Action Appendix E: CYP2C19 Variant Alleles and Frequencies Appendix F: CYP2C19 Polymorphisms and Clopidogrel Appendix G: Pharmacokinetic Response to Clopidogrel Based on CYP2C19 Phenotype Appendix H: Pharmacodynamic Response to Clopidogrel Based on CYP2C19 Phenotype Appendix I: CYP2C19 Genotype and Outcomes Appendix J: CYP2C19 Genotype and Stent Thrombosis Appendix K: Cumulative MACE Rate Based on CYP2C19 Phenotype

10

Appendix A: Abbreviations

ACCF: American College of Cardiology Foundation

ACS: acute coronary syndrome

AHA: American Heart Association

ALT: alternative

CABG: coronary artery bypass grafting

CLOP: clopidogrel

CV: cardiovascular

CYP: cytochrome P450

EM: extensive metabolizer (normal metabolizer)

FDA: Federal Drug Administration

HD: hemodialysis

HR: hazard ratio

HTPR: high on-treatment platelet reactivity

IM: intermediate metabolizer

LD: loading dose

LOE: level of evidence

LOF: loss of function

MACE: major adverse cardiac events

MD: maintenance dose

MI: myocardial infarction

MPA: maximal platelet aggregation

NR: not reported

NSTEMI non-ST elevated myocardial infarction

PCI: percutaneous coronary intervention

PM: poor metabolizer

PRU: P2Y12 reactivity units

STEMI: ST elevated myocardial infarction

TIA: transient ischemic attack

UA: unstable angina

UM: ultra-rapid metabolizer

Clopidogrel

(Plavix)

Prasugrel

(Effient)

Ticagrelor

(Brilinta)

Dose LD: 300 or 600 mg

MD: 75 mg/d

LD: 60 mg

MD: 10 mg/d

(5 mg in < 60 kg)

LD: 180 mg

MD: 90 mg bid

Cost $ $$$ $$$

Metabolism Prodrug;

CYP2C19 (major),

CYP3A4 (minor)

Prodrug;

CYP2B6 (major),

CYP3A4 (minor)

CYP3A4 (major)

Contraindications Active bleeding Active bleeding,

prior stroke or

TIA

Active bleeding,

prior intracranial

hemorrhage

11

Appendix B: Comparison of Oral Antiplatelet Agents


Effient (prasugrel) [prescribing information]. Indianapolis, IN: Eli Lilly and Company; July 2016.

Brilinta (ticagrelor) [prescribing information]. Wilmington, DE: AztraZeneca; April 2017.

12

Appendix C: Clopidogrel FDA Warning


13

Appendix D: Clopidogrel Metabolism and Mechanism of

Action

Clopidogrel • CYP1A2,

CYP2B6, CYP2C19

2-oxo-clopidogrel

• CYP2C9, CYP2B6, CYP3A4, CYP3A5, CYP2C19, PON1

Active metabolite

• Inhibits P2RY12 on platelet

Sangkuhl Katrin, Klein Teri E, Altman Russ B . Pharmacogenetics and genomics (2010).

14

Appendix E: CYP2C19 Variant Alleles and Frequencies


Functional Status Activity Level Alleles

Functional (wild-type) Normal *1

Loss-of-function (LOF) Little to none *2, *3, *4, *5, *6, *7, *8

Increased function Increased *17

Allele Caucasians Africans Asians

*2 15% 15% 29-35%

*3 <1% <1% 2-9%

Phenotype Genotype Clopidogrel

Implication

Frequency

Ultrarapid

metabolizer

(UM)

Homozygous or heterozygous

increased function (not loss of

function carrier)

Increased active

metabolite

5-30%

Extensive

metabolizer

(EM)

Homozygous normal function Normal active

metabolite

35-50%

Intermediate

metabolizer

(IM)

Heterozygous loss of function +

normal or increased function

Reduced active

metabolite

18-45%

Poor

metabolizer

(PM)

Homozygous loss of function Significantly

reduced active

metabolite

2-15%

15

Appendix F: CYP2C19 Polymorphisms and Clopidogrel


16

Appendix G: Pharmacokinetic Response to Clopidogrel

Based on CYP2C19 Phenotype


Clopidogrel active metabolite formation

17

Appendix H: Pharmacodynamic Response to Clopidogrel

Based on CYP2C19 Phenotype


Reduction in platelet aggregation 24 hours after clopidogrel

18

Appendix I: CYP2C19 Genotype and Outcomes


Composite:

death from

cardiovascular

causes, MI, or

stroke


Noncarriers

12.1%

8.0%

HR 1.53 (p = 0.01)

19

Appendix J: CYP2C19 Genotype and Stent Thrombosis


Noncarriers

2.6%

0.8%

HR 3.09 (p = 0.02)


20

Appendix K: Prospective Clinical Implementation of

CYP2C19 Genotype Guided Antiplatelet Therapy After PCI



CLOP = clopidogrel

ALT = alternative

8.0%

4.6%

Documents

Clopidogrel and CYP2C19 in Acute Coronary Syndrome€¦ · Clopidogrel and CYP2C19 in Acute Coronary Syndrome Should pharmacogenetic testing be standard of care? •The author of