IF:Cardiovascular

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Anti-Platelet TherapyProblems and Implications

• >1 million coronary and peripheral stents placed each year- Clopidogrel is one of the most frequently prescribed drugs; $6B annually

• 36% of the population has a CYP2C19 variant resulting in consensus-backed recommendation to avoid clopidogrel as ineffective

- 2.4x greater risk of cardiovascular event

• 28% of the population has a CYP2C19 variant resulting in consensus-backed recommendation to avoid clopidogrel due to risk of bleeding

• Clopidogrel has a pharmacogenetic recommendation in its label

Antiplatelet Activation Therapy: ClopidogrelClinical Fact Economic Implication Reference

30% of patients are resistant to clopidogrel

$19,330 per bleeding event. $40,790 non-fatal MI, $27,314 non-fatal stroke

1,2

PGx guided antiplatelet activation yielded 1% to 4% reduced absolute risk of CV death, MI and stroke. 1% to 4.3% reduced absolute risk of stent thrombosis

3,2

PGx guided therapy in 2C19 IM’s and PM’s verses clopidogrel for all and prasugrel for all. 93% probability of greater net benefit verses clopidogrel for all.

$19,330 per bleeding event. $40,790 non-fatal MI, $27,314 non-fatal stroke. Cost of additional Quality Adjusted Life Years was $5K (typical benchmark is $50K for each additional QALY)

4,2

1. Working group on High-On Treatment of Platelet Reactivity. JACC 2010;56:919-9332. Cost Effectiveness of PGx guided therapy in patients undergoing PCI. Pharmacotherapy 2012;32(4):332-332.3. Reduced function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for

PCI: a meta-analysis. Journal of the American Medical Association. 2010;304:1821-18304. Risk-benefit assessment of prasugrel, clopidogrel, and genotype-guided therapy in patients undergoing percutaneous coronary

intervention. Clin Pharmacol Ther. 2012 May;91(5):829-837

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Pharmacogenetics in Anti-Platelet TherapyLeading Drugs are Metabolized by Genes in the CYP450 Superfamily

• Cytochrome P450 Enzymes- Enzymes bound to membranes within a cell (cyto)- Contain a heme pigment (chrome and P)- Heme pigment absorbs light at a wavelength of 450 nm

• More than 50 enzymes in CYP450- CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5- 90% of drugs are metabolized by these 6 enzymes

CYP2C19 - Clopidogrel

Clopidogrel (Plavix) is a PRODRUG

~ 30% of patients have deficiency in CYP2C19

– Decreased amount of active metabolite

– High on-treatment platelet reactivity

Clopidogrel

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Influence of CYP2C19 on Clopidogrel Response

Scott et al 2013 CPIC Guideline update for 2C19 – clopidogrel.

PGx Guideline for Clopidogrel

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Anti-Platelet Activation ReportPGXL Tests and Reports on Kinetics and DynamicsCYP2C19 *2/*2 CYP2C19 Phenotype

THERAPEUTIC IMPLICATIONS (adapted from published resources)

Poor Metabolizer Avoid Alternative Consideration Adjust Dosage Adjustment Clopidogrel** Prasugrel Imipramine† decrease 30% Sertraline† decrease 50%

CYP2C19 Poor Metabolizer (PM): This patient’s genotype is consistent with significantly reduced CYP2C19 enzymatic activity. PMs are at increased risk of drug-induced side effects due to diminished drug elimination of active drugs. Patients with no CYP2C19 function (PMs) taking clopidogrel lack adequate antiplatelet response and remain at risk for cardiovascular events, including thrombosis, myocardial infarction, stroke, and death. 

, Ticagrelor

Clopidogrel TherapyWho to Test?

• New patients with ACS having undergone PCI and considered for an antiplatelet prescription: Clopidogrel, prasugrel, ticagrelor

• Existing ACS patients scheduled for PCI and considered for antiplatelet therapy

• Existing ACS + PCI patients taking antiplatelet therapy, not previously tested

Biochemical and Physiological Effects of DrugsPharmacokinetics and Pharmacodynamics

PharmacokineticsWhat the body does to the drug• Metabolism, bioavailability• Pro-drugs and active drugs• Washing the active agent from the body

PharmacodynamicsWhat the drug does to the body• Therapeutic, sub-therapeutic, toxic

Distribution

Incidence of Variants Are Variants Rare or Common?

Gene EM IM PM UM Total

CYP2D6 53% 35% 10% 2% 47%

CYP2C19 36% 32% 4% 28% 64%

CYP2C9 57% 40% 3% NA 43%

CYP3A4 87% 12% 1% NA 13%

CYP3A5 1% 18% 81% NA 99%

PhenotypesCategories of People With Specific CYP450 Variants (polymorphism)

• Effective Metabolizer (EM): • Normal Genetics• Two good copies of the genetic code required for metabolism

• Intermediate Metabolizer (IM): • Reduced enzymatic activity• One good copy and one bad copy of code required for metabolism• May render the drug a No-Go or require a dose adjustment

PhenotypesCategories of People With Specific CYP450 Variants (polymorphism)

• Poor Metabolizer (PM): • Complete lack of enzymatic activity• Two bad copies of the code required for metabolism• Usually renders a drug a No-Go

• Ultra Rapid Metabolizer (UM): • Higher-than-average enzymatic activity• Two bad copies causing much higher than normal metabolism• May render the drug a No-Go or require a dose adjustment

Pharmacogenetics in CardiovascularOnly Relevant if The Drug is Metabolized by CYP450

CARDIOLOGY Anti-Arrhythmics, Anti-Hypertensives Amlodipine Norvasc CYP3A4/CYP3A5 Carvedilol Coreg CYP2D6 Diltiazem Cardizem CYP3A4/CYP3A5 Felodipine Plendil CYP3A4/CYP3A5 Flecainide Tambocor CYP2D6 Lercanidipine Zanidip CYP3A4/CYP3A5 Losartan Cozaar CYP2C9 Metoprolol Toprol-XL CYP2D6 Nifedipine Adalat CYP3A4/CYP3A5 Nisoldipine Sular CYP3A4/CYP3A5 Nitrendipine Various brands CYP3A4/CYP3A5 Propafenone Rythmol CYP2D6 Propanolol Inderal, various CYP2D6 Quinidine Various brands CYP3A4/CYP3A5 Timolol Blocadren CYP2D6 Verapamil Various brands CYP3A4/CYP3A5

Pharmacogenetics in CardiovascularOnly Relevant if The Drug is Metabolized by CYP450

CARDIOLOGY Antithrombotics Clopidogrel** Plavix CYP2C19 Rivaroxaban Xarelto CYP3A4/CYP3A5 Ticagrelor Brilinta CYP3A4/CYP3A5 Warfarin Coumadin CYP2C9 Statins Atorvastatin Lipitor, Caduet CYP3A4/CYP3A5 Fluvastatin Lescol CYP2C9 Lovastatin Mevacor, Advicor CYP3A4/CYP3A5 Mevastatin Compactin CYP3A4/CYP3A5 Rosuvastatin Crestor CYP2C9 Simvastatin Zocor, Vytorin,

Simcor CYP3A4/CYP3A5

Consensus RecommendationsOur Report Suggests Specific Action For These Drugs

CYP2D6 Intermediate Metabolizer 35% of the

population

Propafenone Avoid or dose adjustment

Flecainide Dose Adjustment

Metoprolol Dose Adjustment

Poor Metabolizer 10% of the

population

Propafenone Avoid or dose adjustment

Flecainide Dose Adjustment

Metoprolol Dose Adjustment

Ultra Rapid Metabolizer 3-6 % of the

Caucasian population

29% of North African and Ethiopian populations

6% of African American populations

Propafenone Avoid

Metoprolol Dose Adjustment

Consensus RecommendationsOur Report Suggests Specific Action For These Drugs

2C19 Extensive Metabolizer 45% of the

population

Clopidogrel Efficacious, consider cost saving switch to generic clopidogrel if taking prasugrel or ticagrelor

Intermediate Metabolizer 25% of the

population

Clopidogrel Avoid

Poor Metabolizer 2% of the

population

Clopidogrel Avoid

Ultra Rapid Metabolizer 28% of the

population

Clopidogrel Efficacious, but caution increased bleed risk

Consensus RecommendationsOur Report Suggests Specific Action For These Drugs

CYP2C9 Intermediate Metabolizer 40% of the

population

Warfarin Dose Adjustment

  Poor Metabolizer 3% of the

population

Warfarin Dose Adjustment

VKORC1 High Sensitivity A, A Warfarin Dose AdjustmentLow Sensitivity G, G Warfarin Dose Adjustment

CYP3A4 *22 Decreased Metabolizer

Simvastatin Dose AdjustmentAtorvastatin Dose AdjustmentLovastatin Dose Adjustment

SLCO1B1 2.6-fold Increased myopathy risk

Simvastatin Dose AdjustmentAtorvastatin Dose Adjustment

>5-fold increased myopathy risk

Simvastatin AvoidAtorvastatin Dose Adjustment

Anti-CoagulationProblems and Implications

• 25 million warfarin prescriptions (2010)• Warfarin has a narrow therapeutic window and a wide range of

patient responses- Patients who are seemingly similar can require 10-20 fold

difference in dosage• Anti-Coagulation agents consistently rank at the top of the mist of

most dangerous prescribed medications- 179,855 serious or fatal drug reactions (2011)

• 20% of those hospitalized had bleeding events- Cost to treat: $13,500 per event (2006)- If receive thrombosis: $39,500 per event (2006)- Clopidogrel is one of the most frequently prescribed drugs; $6B annually

Continued…

Anti-CoagulationProblems and Implications

• Pharmacogenetic guidance lowered bleeding events by 43%- Reduced hospitalization for all causes 33%

• Warfarin has a pharmacogenetics warning in the label

…Continued

Warfarin TherapyWho to Test?

• New warfarin patients initiating therapy – These patients are at the highest risk of serious adverse events during the first month of taking warfarin.

• Patients already taking warfarin and having difficulties stabilizing within the therapeutic INR range for reasons that are unexplained by environmental factors. These patients may be more easily managed if their phenotype is known.

• Patients already taking warfarin who are scheduled for a surgical procedure.

Pharmacogenetics in CardiovascularIn Addition to CYP450, PGXL Also Tests for VKORC1

• Cytochrome P450 Enzymes- Enzymes bound to membranes within a cell (cyto)- Contain a heme pigment (chrome and P)- Heme pigment absorbes light at a wavelength of 450 nm

• More than 50 enzymes in CYP450- CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5- 90% of drugs are metabolized by these 6 enzymes

• VKORC1 predicts warfarin sensitivity

PhenotypesCategories of People With Specific CYP450 Variants (polymorphism)

• Effective Metabolizer (EM)- Normal genetics- Two good copies of the genetic code required for metabolism

• Intermediate Metabolizer (IM)- Reduced enzymatic activity- One good copy, one bad copy of code required for metabolism- May render the drug a no-go or require dose adjustment

• Poor Metabolizer (PM)- Complete lack of enzymatic activity- Two bad copies of required code- May render the drug a no-go or require dose adjustment

Incidence of Variants Are Variants Rare or Common?

Gene EM IM PM UM Total

CYP2D6 53% 35% 10% 2% 47%

CYP2C19 36% 32% 4% 28% 64%

CYP2C9 57% 40% 3% NA 43%

CYP3A4 87% 12% 1% NA 13%

CYP3A5 1% 18% 81% NA 99%

VKORC1 CaucasiansAfrican

AmericansAsians

High Sensitivity 13% 2% 81%

Intermediate Sensitivity

47% 24% 18%

Low Sensitivity 40% 74% 1%

Pharmacogenetics of WarfarinOnly Relevant If the Drug is Metabolized by CYP450

Cardiovascular Activation ReportPGXL Tests and Reports on Kinetics and Dynamics

CYP2C9 *2/*3 CYP2C9 Phenotype

THERAPEUTIC IMPLICATIONS (adapted from published resources)

Poor Metabolizer Decreased metabolic clearance expected. Adjust Dosage Adjustment Phenytoin† decrease 50%

Warfarin† Adjust based on multiple factors

VKORC1 GA VKORC1 Phenotype

THERAPEUTIC IMPLICATIONS (adapted from published resources)

Intermediate warfarin sensitivity

Average VKORC1 enzyme expression and average warfarin dose requirement expected.

WARFARIN DOSE INFORMATION Estimated time to steady-state: Delayed, 16-22 days

Estimated warfarin maintenance dose requirement: 3.9 mg/day‡ _ CYP2C9 Poor Metabolizer (PM): This patient’s genotype is consistent with significantly reduced CYP2C9 enzymatic activity. Reduced CYP2C9 activity leads to lower dose requirement (e.g., warfarin) due to decreased clearance, increased elimination half-life, and increased time to reach steady-state blood concentrations. VKORC1 Intermediate Warfarin Sensitivity: ‡The warfarin maintenance dose estimate was derived using a published formula that accounts for age, gender, weight, and CYP2C9 and VKORC1 genotypes. This estimate should be viewed as an example of how this information can be taken into consideration by the physician as part of the overall patient management strategy.

Incorporating PGX: Considerations for whom to test?

CVCandidate for AP, AC, Statin Rx

ACS-PCI, new warfarin initiation

Unstable INRBleeding, thrombotic event,

myopathy

Effient, Brilinta, Pradaxa, Xarelto Rx

Pain Patient

PainCandidate for Opioid Rx

Opioid ADR or sub-optimal response

Opioid abnormal UDT

Side effects to NSAIDs, muscle relaxers, triptans

BehavioralCandidate for Psychotropic Rx

Psychotropic ADR or sub-optimal response

More than 1 psychotropic Rx

Treatment resistant, uncontrolled, hosp admission in

past 6 months

Polypharmacy, Clinical Hx ADRs, Pre-therapeutic screening for all patients

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Polypharmacy

Diabetes

Hyperlipidemia

Coronary Artery Disease

HypertensionThrombosisStroke

Depression

Psychosis

ADHD

Arrhythmia

ChronicPain

CIPHER manages the whole patient

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