LO ÚLTIMO EN CLOPIDOGREL ▲ FÁRMACO-GENÓMICA Y FÁRMACO-TERAPÉUTICA ► Clopidogrel, Pharmacogenomics and Drug Therapy: Where Are We? - February 9, 2015 [idioma inglés]

Genomics|Features|Clopidogrel

Clopidogrel

Clopidogrel, Pharmacogenomics and Drug Therapy: Where Are We? - February 9, 2015

OPHG classification of CYP2C19 for clopidogrel by level of evidence – Tier 2/Yellow 

A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverse clinical outcomes in clopidogrel users. 
Ruben L. Osnabrugge et al. Genetics in Medicine, June 19, 2014

Pilot study: incorporation of pharmacogenetic testing in medication therapy management services. 
Haga SB, et al. Pharmacogenomics. 2014 Nov;15(14):1729-1737.

CYP2C19 genotype has a greater effect on adverse cardiovascular outcomes following percutaneous coronary intervention and in Asian populations treated with clopidogrel: a meta-analysis. 
Sorich MJ, et al. Circ Cardiovasc Genet. 2014 Dec;7(6):895-902.

Clopidogrel: A multifaceted affair. 
Martínez-Quintana E, J Clin Pharmacol. 2015 Jan;55(1):1-9

Genomics|Genetic Testing|Tier 2

Genetic Testing

Tables

• Tier 1
• Tier 2
• Tier 3

Genomic Tests and Family History by Levels of Evidence

The CDC Office of Public Health Genomics ranks the following list for levels of evidence of genomic tests and family health history in practice . This approach was based on a paper by Khoury and updated in accordance with criteria presented by a 2014 paper in Clinical Pharmacology and Therapeutics. The criteria are  shown in the following figure to provide additional information to our readers. This list is updated on an ongoing basis andprovided only for informational purposes to researchers, healthcare providers, public health programs and others.

Green

• FDA label requires use of test to inform choice or dose of a drug
• CMS covers testing
• Clinical practice guidelines based on systematic review supports testing

Yellow

• FDA label mentions biomarkers*
• CMS coverage with evidence development
• Clinical practice guideline, not based on systematic review, supports use of test
• Clinical practice guideline finds insufficient evidence but does not discourage use of test
• Systematic review, without clinical practice guideline, supports use of test
• Systematic review finds insufficient evidence but does not discourage use of test
• Clinical practice guideline recommends dosage adjustment, but does not address testing

Red

• FDA label cautions against use
• CMS decision against coverage
• Clinical practice guideline recommends against use of test
• Clinical practice guideline finds insufficient evidence and discourages use of test
• Systematic review recommends against use
• Systematic review finds insufficient evidence and discourages use
• Evidence available only from published studies without systematic reviews, clinical practice guidelines, FDA label or CMS labels coverage decision

*Can be reassigned to Green of Red of one or more conditions in these categories apply 

Tier 2/Yellow category: represents genomic and family health history applications have synthesized evidence that is insufficient to support routine implementation in practice; however, existing evidence may provide information for informed decision making by providers and patients.

Gene, Gene/Drug, Test, or Family History	Disorder/Indication	Use*	Synthesized Evidence Sources
Cancer—Breast
gene expression profiles	breast cancer	Recurrence:  risk prediction; prognostic	EGAPP (2009)
ER-alpha and PgR status/ER-alpha (ESR1)-modulating agents	invasive breast cancer and breast cancer	PGx - recurrence risk prediction; prognostic	NCCN Task Force (2011) NCCN Task Force (2009) ASCO/CAP (2010)
CYP2D6/tamoxifen	risk for primary breast cancer or breast cancer recurrence	PGx – informing therapeutic choice	BCBSA TEC (2014)
Cancer—Colorectal
first-degree family history of colorectal cancer at a younger age or multiple affected first-degree relatives	colorectal cancer screening	risk prediction	USPSTF (2008)
BRAF c.1799T>A (p.V600E)	colon cancer	prognostic	NCCN Task Force (2011) NCCN Guideline  [PDF 1.30 MB] (2013)
BRAF V600E/cetuximab, panitumumab	metastatic colorectal cancer	PGx	EGAPP  [PDF 456.16 KB](2013) NCCN Task Force (2011)
UGT1A1/irinotecan	Metastatic carcinoma of the colon or rectum	PGx	FDA-PGx Drug Information(2012) EGAPP (2009)
testing for Lynch syndrome	patients meeting revised Bethesda guidelines or Amsterdam criteria	diagnostic, screening	NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)
testing for Lynch syndrome	endometrial cancer in women under 50 years of age	diagnostic, screening	NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)
consideration of testing for Lynch syndrome	people with 5% or higher risk of Lynch syndrome based on any prediction model	diagnostic, screening	NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)
testing for Lynch syndrome	colorectal cancer diagnosed under 70 years of age, and those 70 and older who meet Bethesda guidelines	diagnostic, screening	NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)
testing for Lynch syndrome	colorectal cancer in patients younger than 50 years	diagnostic, screening	NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)
testing for Lynch syndrome	synchronous or metachronous colorectal or other Lynch syndrome-related tumors, at any age	diagnostic, screening	NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)
testing for Lynch syndrome	MSI-H histology in colorectal cancer patients younger than 60 years	diagnostic, screening	NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)
testing for Lynch syndrome	colorectal cancer in patient with relative (one or more first-degree) with Lynch syndrome related cancer that was diagnosed under age 50 years	diagnostic, screening	NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)
testing for Lynch syndrome	colorectal cancer in patient with relatives (two or more first- or second-degree) with Lynch syndrome related cancer at any age	diagnostic, screening	NCCN: Genetic/Familial High-Risk Assessment - Colorectal  (2014)
Cancer—Leukemia
FLT3-ITD	acute myeloid leukemia	predictive; prognostic	NCCN Task Force (2011) NCCN Guideline  [PDF 852.75 KB] (2013)
CEBPA mutation	acute myeloid leukemia	predictive; prognostic	NCCN Task Force (2011) NCCN Guideline  [PDF 852.78 KB] (2013)
NPM1 mutation	acute myeloid leukemia	predictive; prognostic	NCCN Task Force (2011) NCCN Guideline  [PDF 852.80 KB] (2013)
KIT mutation	acute myeloid leukemia	predictive; prognostic	NCCN Task Force (2011) NCCN Guideline  [PDF 852.70 KB] (2013)
Philadelphia chromosome/busulfan	chronic myelogenous leukemia	PGx	FDA-PGx Drug Information(2003)
UGT1A1*28homozygotes/nilotinib	Philadelphia chromosome positive chronic myeloid leukemia	PGx	FDA-PGx Drug Information(2013)
FIP1L1-PDGFRα kinase/imatinib	hypereosinophilic syndrome and/or chronic eosinophilic leukemia	PGx-dose	FDA-PGx Drug Information(2013)
TPMT/thiopurines (mercaptopurine)	acute lymphatic leukemia	PGx-dose	CPIC (2011) FDA-PGx Drug Information(2011)
TPMT/thiopurines (thioguanine)	acute, non-lymphocytic leukemias	PGx-dose	CPIC (2011) FDA-PGx Drug Information(2004)
Cancer—Lung
KRAS mutations [except c38G>A]/anti-EGFR therapy	non–small cell lung cancer	predictive; prognostic	NCCN Task Force (2011)
Cancer—Melanoma
G6PD/dabrafenib	unresectable or metastatic melanoma	PGx	FDA-PGx Drug Information(2014)
family history of skin cancer	skin cancer screening in adults	risk prediction	USPSTF (2009)
Cancer—Other
DPD testing/5-FU (capecitabine)	Dukes’ C colon cancer, metastatic colorectal cancer, metastatic breast cancer	PGx	FDA-PGx Drug Information(2013)
family history of bladder cancer	bladder cancer screening	risk prediction	USPSTF (2011)
c-Kit D816V/imatinib	aggressive systemic mastocytosis	PGx	FDA-PGx Drug Information(2013)
TPMT/cisplatin	metastatic testicular tumors, metastatic ovarian tumors, advanced bladder cancer	PGx	FDA-PGx Drug Information(2011)
Cardiovascular
family history relevant to dyslipidemia (otherwise undefined)	lipid screening in  infants, children, adolescents, or young adults (up to age 20)	risk prediction	USPSTF (2007)
first-degree family history of abdominal aortic aneurysm requiring surgical repair	abdominal aortic aneurysm screening	risk prediction	USPSTF (2005)
SLCO1B1/simvastatin	dyslipidemia	PGx-dose	CPIC (2012)
CYP2C9, VKORC1/warfarin	venous thrombosis, pulmonary embolism, thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement, myocardial infarction	PGx-dose	CMS CED (2009) ACMG (2008) FDA-PGx Drug Information CPIC (2011)
CYP2D6/metoprolol	hypertension, angina pectoris, heart failure	PGx	FDA-PGx Drug Information(2012)
CYP2D6/carvedilol	chronic heart failure, left ventricular dysfunction following myocardial infarction, hypertension	PGx	FDA-PGx Drug Information(2012)
CYP2D6/carvedilol	chronic heart failure, left ventricular dysfunction following myocardial infarction, hypertension	PGx	FDA-PGx Drug Information(2011)
CYP2D6/propafenone	atrial fibrillation	PGx	FDA-PGx Drug Information(2011)
CYP2C19/clopidogrel	non-ST-segment elevation acute coronary syndrome, ST-elevation myocardial infarction, myocardial infarction, stroke, peripheral arterial disease	PGx	FDA-PGx Drug Information(2013) CPIC (2013) AHRQ (2013)
CYP2C19/prasugrel	acute coronary syndrome managed with percutaneous coronary intervention	PGx	FDA-PGx Drug Information(2013)
CYP2C19/tricagrelor	acute coronary syndrome	PGx	FDA-PGx Drug Information(2013)
LDLR/pravastatin	hypercholesterolemia	PGx	FDA-PGx Drug Information(2012)
F5, SERPINC1/eltrombopag	thrombocytopenia	PGx	FDA-PGx Drug Information(2012)
Endocrine disorders
G6PD/chlorpropamide	glycemic control, type 2 diabetes in adults	PGx	FDA-PGx Drug Information(2011)
G6PD/glimepiride	glycemic control, type 2 diabetes in adults	PGx	FDA-PGx Drug Information(2013)
G6PD/glipizide	glycemic control, type 2 diabetes in adults	PGx	FDA-PGx Drug Information(2013)
G6PD/glyburide	glycemic control, type 2 diabetes in adults	PGx	FDA-PGx Drug Information(2013)
Gastroenterology
CYP2C19/pantoprazole	gastroesophageal reflux disease, pathological hypersecretory conditions	PGx-dose	FDA-PGx Drug Information(2013)
CYP2C19/omeprazole	duodenal ulcer, gastric ulcer, gastroesophageal reflux disease	PGx	FDA-PGx Drug Information(2013)
CYP2C19/esomeprazole	gastroesophageal reflux disease, NSAID-associated gastric ulcer, duodenal ulcer recurrence, pathological hypersecretory conditions	PGx	FDA-PGx Drug Information(2012)
CYP2C19/rabeprazole	gastroesophageal reflux disease, duodenal ulcers, pathological hypersecretory conditions	PGx	FDA-PGx Drug Information(2013)
CYP2C19, CYP1A2/dexlansoprazole	erosive esophagitis, heartburn	PGx	FDA-PGx Drug Information(2013)
Infectious Disease
G6PD/chloroquine phosphate	malaria, extraintestinal amebiasis	PGx	FDA-PGx Drug Information(2013)
G6PD/dapsone (tablet)	leprosy	PGx	FDA-PGx Drug Information DailyMed (2011)
G6PD/mafenide acetate (for 5% topical solution)	bacterial infections	PGx	FDA-PGx Drug Information(1998)
G6PD/nitrofurantoin	antibacterial, specific urinary tract infections	PGx	FDA-PGx Drug Information(2013)
G6PD/primaquine	vivax malaria, radical cure (prevention of relapse)	PGx	FDA-PGx Drug Information(2008)
G6PD/quinine sulfate	uncomplicatedPlasmodium falciparum malaria	PGx	FDA-PGx Drug Information(2013)
G6PD/sulfamethoxazole & trimethoprim	bacterial infections	PGx	FDA-PGx Drug Information(2013)
IL28B/boceprevir	chronic hepatitis C genotype 1	PGx	FDA-PGx Drug Information(2013)
IL28B/telaprevir	chronic hepatitis C genotype 1	PGx	FDA-PGx Drug Information(2013)
IL28B/peginterferon alfa-2b	chronic hepatitis C	PGx	FDA-PGx Drug Information(2013)
CYP2C19/voriconazole	invasive aspergillosis, candidemia and disseminated candidiasis, esophageal candidiasis,Scedosporium apiospermum andFusarium spp. infection	PGx-dose	FDA-PGx Drug Information(2011)
Neurology
CYP2C19/clobazam	seizures associated with Lennox-Gastaut syndrome	PGx-dose	FDA-PGx Drug Information(2013)
HLA-B*1502/phenytoin	generalized tonic-clonic status epilepticus and for seizures that occur during neurosurgery; testing pertains to risk for certain serious dermatologic reactions, which may be higher in patients of Chinese or Asian ancestry	PGx	FDA-PGx Drug Information(2013)
HLAB*1502/ carbamazepine	epilepsy, other seizure disorders, trigeminal neuralgia, bipolar disorder	PGx-dose	CPIC (2013)
CYP2D6, CYP2C19/diazepam	epilepsy	PGx	FDA-PGx Drug Information(2005)
CYP2D6/dextromethorphan and quinidine	pseudobulbar affect	PGx, PGx-dose	FDA-PGx Drug Information(2010)
Psychiatry
parental history of depression	major depressive disorder screening in adolescents	risk prediction	USPSTF (2009)
family history of depression	depression screening in adults	risk prediction	USPSTF (2009)
CYP2D6/amitriptyline	depression	PGx-dose	CPIC (2013) FDA-PGx Drug Information
CYP2D6/desipramine	depression	PGx-dose	CPIC (2013) FDA-PGx Drug Information(2012)
CYP2D6/fluoxetine	major depressive disorder, obsessive compulsive disorder, bulimia nervosa, panic disorder	PGx	FDA-PGx Drug Information(2009)
CYP2D6/imipramine	depression	PGx-dose	CPIC (2013) FDA-PGx Drug Information(2012)
CYP2D6/nortriptyline	depression	PGx-dose	CPIC (2013) FDA-PGx Drug Information(2012)
CYP2D6/trimipramine	depression	PGx-dose	CPIC (2013) FDA-PGx Drug Information(2012)
CYP2D6/venlafaxine	major depressive disorder, social anxiety disorder	PGx, PGx-dose	FDA-PGx Drug Information(2012)
CYP2C19, CYP2D6/citalopram	depression	PGx-dose	FDA-PGx Drug Information(2012)
CYP2D6/aripiprazole	schizophrenia, bipolar I disorder, major depressive disorder, autistic disorder	PGx-dose	FDA-PGx Drug Information(2013)
CYP2D6/clozapine	schizophrenia, schizoaffective disorder	PGx-dose	FDA-PGx Drug Information(2013)
CYP2D6/iloperidone	schizophrenia	PGx-dose	FDA-PGx Drug Information(2013)
CYP2D6/risperidone	schizophrenia, bipolar I disorder, autistic disorder	PGx-dose	FDA-PGx Drug Information(2012)
CYP2D6/atomoxetine	attention-deficit/hyperactivity disorder	PGx-dose	FDA-PGx Drug Information(2013)
CYP2D6/clomipramine	obsessive-compulsive disorder	PGx-dose	CPIC (2013) FDA-PGx Drug Information(2012)
CYP2D6, CYP2C19/fluvoxamine	obsessive compulsive disorder	PGx	FDA-PGx Drug Information(2012)
CYP2D6, CYP2C19/doxepin	insomnia	PGx-dose	CPIC (2013) FDA-PGx Drug Information(2010)
CYP2D6/modafinil	narcolepsy, obstructive sleep apnea, and shift work disorder	PGx-dose	FDA-PGx Drug Information(2010)
Rheumatology
CYP2C19/carisoprodol	musculoskeletal conditions	PGx	FDA-PGx Drug Information(2013)
CYP2C9/celecoxib	osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, acute pain, primary dysmenorrhea	PGx-dose	FDA-PGx Drug Information(2011)
CYP2C9/flurbiprofen	rheumatoid arthritis, osteoarthritis	PGx	FDA-PGx Drug Information(2010)
TPMT/thiopurines (azathioprine)	renal homotransplantation, rheumatoid arthritis	PGx-dose	CPIC (2011) FDA-PGx Drug Information(2011)
Other
family history of developmental dysplasia of the hip	developmental dysplasia of the hip screening in infants	risk prediction	USPSTF (2006)
family history of diabetes	gestational diabetes screening	risk prediction	USPSTF (2008)
family history of neonatal jaundice	Hyberbilirubinemia screening in infants; prevention of chronic bilirubin encephalopathy	risk prediction	USPSTF (2009)
family history of age-related macular degeneration	visual acuity screening in older adults	risk prediction	USPSTF (2009)
family history of chronic kidney disease	chronic kidney disease screening	risk prediction	USPSTF (2012)
family history for common diseases	common diseases	risk prediction	NIH State of the Science (2009)
CYP2D6/tolterodine	overactive bladder	PGx	FDA-PGx Drug Information(2012)
HPRT1/mycophenolic acid	organ rejection	PGx	FDA-PGx Drug Information(2013)
CYP2C19/drospirenone and ethinyl estradiol	pregnancy prevention, premenstrual dysphoric disorder, moderate acne	PGx	FDA-PGx Drug Information(2012)
UGT1A1/indacaterol	chronic obstructive pulmonary disease, including chronic bronchitis and/or emphysema	PGx	FDA-PGx Drug Information(2012)
CYP2D6/codeine	pain	PGx-dose	CPIC (2012) FDA-PGx Drug Information(2013)
CYP2D6/tramadol and acetaminophen	acute pain	PGx	FDA-PGx Drug Information(2013)
CYP2D6/cevimeline	dry mouth in patients with Sjögren’s Syndrome	PGx	FDA-PGx Drug Information(2013)
DPD/fluorouracil cream	multiple actinic or solar keratoses	PGx	FDA-PGx Drug Information(2003)
G6PD/dapsone (gel)	acne vulgaris	PGx	FDA-PGx Drug Information(2009)
G6PD/dapsone (tablet)	dermatitis herpetiformis	PGx	FDA-PGx Drug Information DailyMed (2011)
G6PD/(polyethylene glycol 3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate, & ascorbice acid for oral solution)	laxative, preparation for colonoscopy in adults	PGx	FDA-PGx Drug Information(2013)
G6PD/sodium nitrite	life-threatening, acute cyanide poisoning	PGx	FDA-PGx Drug Information(2012)
G6PD/succimer	lead poisoning, pediatric	PGx	FDA-PGx Drug Information(2007)
next generation sequencing/whole genome sequence	various rare familial diseases	diagnostic	BCBS TEC  [PDF 210.52 KB](2013)
various molecular, cytogenetic biochemical and other tests**	single gene disorders and chromosomal abnormalities where diagnosis and management may require use of genetic tests even without formal evidence synthesis and reviews by evidence panels	diagnosis, management, carrier testing	NIH GTR (2013)

*Pharmacogenomic applications have been classified in the Use column as either PGx (which may relate to drug choice, prevention of adverse events, or other uses of the information gained through testing), or PGx-dose (when specific dosing-related guidance is provided, or mention of a potential effect on dose is noted in the evidence sources cited). Additional Use categories include: screening, cascade testing, risk prediction, diagnostic, and prognostic.

**This entry includes many genetic disorders for which there are no evidence-based recommendations, clinical guidelines or systematic reviews. However, a systematic search for evidence-based recommendations and reviews has not been conducted to date by our office. We expect further refinements in this classification in the near future.

Source Abbreviations: Agency for Healthcare Research and Quality (AHRQ), American College of Medical Genetics and Genomics (ACMG), American Society of Clinical Oncology (ASCO), Centers for Medicare and Medicaid Services (CMS), Clinical Pharmacogenetics Implementation Consortium (CPIC), Evaluation of Genomic Applications in Practice and Prevention (EGAPP), National Comprehensive Cancer Network (NCCN), National Institute for Health and Care Excellence (NICE), National Institutes of Health (NIH), Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC), US Department of Health and Human Services (DHHS), US Food and Drug Administration (FDA), United States Preventive Services Task Force (USPSTF)

Other Abbreviations: estrogen receptor (ER), progesterone receptor (PgR), pharmacogenomics (PGx), single-nucleotide polymorphism (SNP)