Cardiology

Pharmacogenetics in Cardiology– Benefits of Precision Prescribing

Cardiologists are frequently challenged when they consult with patients who are already taking multiple medications. Our partners at YouScript can help specialist physicians chart a safer, more effective course when they need to make treatment changes or prescribe additional medications.

Take the example of a patient with a recent history of myocardial infarction, currently on 8 different medications. The patient complains of several non-specific side effects, but doesn’t know which drugs are causing the symptoms. Making dose adjustments or prescribing different medications is difficult, and further complicated by the fact that several U.S. Food and Drug Administration (FDA)-approved medications with cardiology indications carry pharmacogenetic information on their labeling (see table, below). A growing number have warnings about genetic factors leading to altered patient response.

Until recently, cardiologists had little choice but to prescribe medications without knowing in advance how their patients might respond. Today, YouScript makes it possible for physicians to know, before they prescribe, which medications will be most effective based on individual genetic profiles – and which ones will not.

Cardiac Medicines with Significant Pharmacogenetic Information on the FDA Label

DrugBiomarkerDrugBiomarker
carvedilolCYP2D6propafenoneCYP2D6
clopidogrelCYP2C19propranololCYP2D6
isosorbide and hydralazineNAT1;NAT2quinidine / dextromethorphanCYP2D6
metoprololCYP2D6ticagrelorCYP2C19
prasugrelCYP2C19warfarinCYP2C9 and VKORC1

Warfarin Dosing

Genetic variants detected by the tests are found in approximately half of patients and are the major contributor to variation in warfarin dose requirement.

The two genes CYP2C9 and VKORC1 are a model for the application of pharmacogenetic data because one controls the metabolism of the drug and the other controls the effective concentration requirement at the site of action.

  • CYP2C9 is the most important enzyme in the metabolism of warfarin and greatly affects the half-life and time to a stable dose. Without genetic testing it is not known if INR test results represent a steady state or one that is climbing.
CYP2C9 genotypeTime to stable dose
*1/*1 extensive(normal) metabolizer3 – 5 days
*1/*2 or *1/*3 intermediate metabolizer6 – 8 days
*1/*3, *2/*2, *3/*3 intermediate or poor metabolizer12 -15 days

 

  • Vitamin K epoxide reductase complex subunit 1, VKORC1, is the site of action of warfarin. The level of the enzyme is under genetic control according to the DNA sequence present in the control region of the gene. The more enzyme present, the more warfarin required.
  • This graph illustrates the genotype based maintenance dose for a 160 cm tall, 66 year old female without significant drug interactions or other impairments. GG, GA and AA are the VKORC1 genotypes *1/*1 etc. are the CYP2C9 genotypes.

warfarin

Here’s what a blue ribbon FDA advisory panel has to say about the genetics of warfarin. View meeting notes >

  • Use lower doses of warfarin for patients with genetic variations in CYP2C9 and or VKORC1 that lead to reduced activities.
  • Genotyping patients prior to warfarin therapy may reduce adverse events and improve achievement of stable INR.
  • Monitoring of the patient’s INR is still required and genetic testing for CYP2C9 and VKORC1 is not a replacement for INR monitoring.

The FDA and others are sponsoring clinical trials to prove the extent to which using DNA testing will reduce the morbidity and mortality associated with warfarin induced adverse bleeding events. Many scientists believe that the use of this testing will dramatically improve warfarin efficacy and safety. In addition, the FDA has  updated the label to include genetic testing information (view release >).

YouScript Helps You Achieve Optimal Prescribing

Many important medicines used to treat cardiac conditions are metabolized by CYP2D6, CYP2C9, CYP2C19, CYP3A4 or CYP3A5. Genetic variations in these cytochromes are extremely common. This genetic variability is one of the most important considerations in determining how an individual patient will respond to specific medications.

The YouScript software tests for all clinically significant genetic variants in the enzymes responsible for metabolizing the majority of medications: CYP2D6, CYP2C9 (including VKORC1), CYP2C19, CYP3A4, and CYP3A5.