IF:Cardiovascular
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Anti-Platelet Therapy
Problems 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 consensusbacked recommendation to avoid clopidogrel as ineffective
-
2.4x greater risk of cardiovascular event
• 28% of the population has a CYP2C19 variant resulting in consensusbacked recommendation to avoid clopidogrel due to risk of bleeding
• Clopidogrel has a pharmacogenetic recommendation in its label
Antiplatelet Activation Therapy: Clopidogrel
Clinical Fact
Economic Implication
Reference
30% of patients are resistant to
clopidogrel
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
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.
1.
2.
3.
4.
1,2
$19,330 per bleeding event. $40,790 non-fatal MI,
$27,314 non-fatal stroke
$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)
3,2
4,2
Working group on High-On Treatment of Platelet Reactivity. JACC 2010;56:919-933
Cost Effectiveness of PGx guided therapy in patients undergoing PCI. Pharmacotherapy 2012;32(4):332-332.
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;304:1821-1830
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 AntiPlatelet Therapy
Leading 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
Clopidogrel
~ 30% of patients have
deficiency in CYP2C19
– Decreased amount
of active metabolite
– High on-treatment
platelet reactivity
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Influence of CYP2C19 on Clopidogrel Response
Incidence of Adverse events in patients prescribed standard dosages of
Clopidogrel by CYP2C19 Phenotype.
PHENOTYPE
Stent Thrombosis
EM
CV death, MI,
Ischemic Stroke
8%
(BASELINE)
8.9%
1.4%
IM
10%
2.4%
PM
12.7%
5.7%
Mega et.al., JAMA. 2010;304(16);1821-1830.
0.9%
PGx Guideline for Clopidogrel
Scott et al 2013 CPIC Guideline update for 2C19 – clopidogrel.
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Anti-Platelet Activation Report
PGXL Tests and Reports on Kinetics and Dynamics
CYP2C19 *2/*2
CYP2C19
Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Poor Metabolizer Avoid
Clopidogrel**
Alternative Consideration
Adjust Dosage Adjustment
Prasugrel, Ticagrelor
Imipramine†
Sertraline†
decrease 30%
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.
Clopidogrel Therapy
Who 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 Drugs
Pharmacokinetics and Pharmacodynamics
Pharmacokinetics
What the body does to the drug
• Metabolism, bioavailability
• Pro-drugs and active drugs
• Washing the active agent from the body
Distribution
Pharmacodynamics
What the drug does to the body
• Therapeutic, sub-therapeutic, toxic
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%
Phenotypes
Categories 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
Phenotypes
•
Categories
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 Cardiovascular
Only Relevant if The Drug is Metabolized by CYP450
CARDIOLOGY
Anti-Arrhythmics, Anti-Hypertensives
Amlodipine
Norvasc
Carvedilol
Coreg
Diltiazem
Cardizem
Felodipine
Plendil
Flecainide
Tambocor
Lercanidipine
Zanidip
Losartan
Cozaar
Metoprolol
Toprol-XL
Nifedipine
Adalat
Nisoldipine
Sular
Nitrendipine
Various brands
Propafenone
Rythmol
Propanolol
Inderal, various
Quinidine
Various brands
Timolol
Blocadren
Verapamil
Various brands
CYP3A4/CYP3A5
CYP2D6
CYP3A4/CYP3A5
CYP3A4/CYP3A5
CYP2D6
CYP3A4/CYP3A5
CYP2C9
CYP2D6
CYP3A4/CYP3A5
CYP3A4/CYP3A5
CYP3A4/CYP3A5
CYP2D6
CYP2D6
CYP3A4/CYP3A5
CYP2D6
CYP3A4/CYP3A5
Pharmacogenetics in Cardiovascular
Only Relevant if The Drug is Metabolized by CYP450
CARDIOLOGY
Antithrombotics
Clopidogrel**
Rivaroxaban
Ticagrelor
Warfarin
Statins
Atorvastatin
Fluvastatin
Lovastatin
Mevastatin
Rosuvastatin
Simvastatin
Plavix
Xarelto
Brilinta
Coumadin
CYP2C19
CYP3A4/CYP3A5
CYP3A4/CYP3A5
CYP2C9
Lipitor, Caduet
Lescol
Mevacor, Advicor
Compactin
Crestor
Zocor, Vytorin,
Simcor
CYP3A4/CYP3A5
CYP2C9
CYP3A4/CYP3A5
CYP3A4/CYP3A5
CYP2C9
CYP3A4/CYP3A5
Consensus Recommendations
Our Report Suggests Specific Action For These Drugs
CYP2D6
Intermediate
Metabolizer
Propafenone

Flecainide
Metoprolol
Propafenone
35% of the
population
Poor Metabolizer

10% of the
population
Ultra Rapid
Metabolizer



3-6 % of the
Caucasian
population
29% of North
African and
Ethiopian
populations
6% of African
American
populations
Flecainide
Metoprolol
Propafenone
Metoprolol
Avoid or dose
adjustment
Dose Adjustment
Dose Adjustment
Avoid or dose
adjustment
Dose Adjustment
Dose Adjustment
Avoid
Dose Adjustment
Consensus Recommendations
Our Report Suggests Specific Action For These Drugs
2C19
Extensive
Metabolizer

Avoid
Clopidogrel
Efficacious, but
caution increased
bleed risk
2% of the
population
Ultra Rapid
Metabolizer

Clopidogrel
25% of the
population
Poor Metabolizer

Clopidogrel
Efficacious, consider
cost saving switch to
generic clopidogrel if
taking prasugrel or
ticagrelor
Avoid
45% of the
population
Intermediate
Metabolizer

Clopidogrel
28% of the
population
Consensus Recommendations
Our Report Suggests Specific Action For These Drugs
CYP2C9
Intermediate
Metabolizer

VKORC1
CYP3A4
SLCO1B1
Dose Adjustment
Warfarin
Dose Adjustment
Warfarin
Warfarin
Simvastatin
Atorvastatin
Lovastatin
Simvastatin
Atorvastatin
Simvastatin
Atorvastatin
Dose Adjustment
Dose Adjustment
Dose Adjustment
Dose Adjustment
Dose Adjustment
Dose Adjustment
Dose Adjustment
Avoid
Dose Adjustment
40% of the
population
Poor Metabolizer

Warfarin
3% of the
population
High Sensitivity A, A
Low Sensitivity G, G
*22 Decreased
Metabolizer
2.6-fold Increased
myopathy risk
>5-fold increased
myopathy risk
Anti-Coagulation
Problems 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-Coagulation
Problems 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 Therapy
Who 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 Cardiovascular
In 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
Phenotypes
Categories 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
Caucasians
African
Americans
Asians
High Sensitivity
13%
2%
81%
Intermediate
Sensitivity
47%
24%
18%
Low Sensitivity
40%
74%
1%
Pharmacogenetics of Warfarin
Only Relevant If the Drug is Metabolized by CYP450
Cardiovascular Activation Report
PGXL Tests and Reports on Kinetics and Dynamics
CYP2C9 *2/*3
CYP2C9
Phenotype
Poor Metabolizer
VKORC1 GA
VKORC1
Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Decreased metabolic clearance expected.
Adjust Dosage
Adjustment
Phenytoin†
Warfarin†
decrease 50%
Adjust based on multiple
factors
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Intermediate
Average VKORC1 enzyme expression and average warfarin dose requirement expected.
warfarin sensitivity
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?
Polypharmacy, Clinical Hx ADRs, Pre-therapeutic screening for all patients
Behavioral
Candidate for Psychotropic Rx
Pain
Candidate for Opioid Rx
CV
Candidate for AP, AC, Statin Rx
Psychotropic ADR or suboptimal response
Opioid ADR or sub-optimal
response
ACS-PCI, new warfarin initiation
Opioid abnormal UDT
Unstable INR
Bleeding, thrombotic event,
myopathy
Side effects to NSAIDs, muscle
relaxers, triptans
Effient, Brilinta, Pradaxa,
Xarelto Rx
More than 1 psychotropic Rx
Treatment resistant,
uncontrolled, hosp admission in
past 6 months
Pain
Patient
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CIPHER manages
the whole patient
Polypharmacy
Psychosis
ADHD
Chronic
Pain
Depression
Diabetes
Thrombosis
Hypertension
Stroke
Coronary Artery
Disease
Arrhythmia
Hyperlipidemia
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