Direct Oral Anticoagulants (DOAC): Newly Identified Genes and Genetic Variants

Last Updated on

January 26, 2019 – Pharmacogenomic approaches are increasingly revealing newly identified genes and genetic variants that are at the base of remarkable inter-individual pharmacokinetic and pharmacodynamic variation of novel direct oral anticoagulants (DOAC).

Lately, DOACs have shown an upward prescribing trend due to seemingly favourable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring, be it in the clinic or by means of INR self-monitoring. Recent studies, however, have documented inter-individual variability in plasma drug levels of DOACs.

It is surprising, that until now, this inter-individual variability in the disposition of DOACs has not been taken more into serious consideration when prescribing DOAC’s, particularly under the heavily promoted premise that regular (and, yes, sometimes annoying for the patient) INR-monitoring would no longer be needed. In the clear, we are talking a very dangerous medical constellation, possibly life-threatening or fatal for an affected patient.

There exists an urgent need to thoroughly understand the pharmacogenomic background for the inter-individual variability of the disposition of DOACs in general and the four most commonly prescribed DOACs such as Dabigatran (Pradaxa), Rivaroxaban (Xarelto), Apixaban (Eliquis), and Edoxaban (Savaysa) in particular. In a recent and very important study,  published in the Journal of Personalised Medicine (JPM), an extensive search was performed on recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of individual patient’s disposition of DOACs. Additionally, commonly associated drug-drug interactions of DOACs were taken into account.

The study found that SNP’s in the CES1 gene and ABCB1 gene are the most common documented genetic variants that contribute to alteration in peak and trough levels of Dabigatran (Pradaxa) with demonstrated clinical impact. Furthermore, SNP’s in the ABCB1 gene are implicated in alteration of plasma drug levels of not only Rivaroxaban (Pradaxa) and Apixaban (Eliquis). Studies conducted with genetic variants in Factor Xa-, ABCB1-, SLCOB1-, CYP2C9-, and VKORC1-genes didn’t, in contrast, not reveal any significant association with plasma drug levels of Edoxaban (Savaysa). Pharmacokinetic drug-drug interactions of Dabigatran (Pradaxa) are mainly mediated by P-glycoprotein. Moreover, strong inhibitors and inducers of CYP3A4 and P-glycoprotein should be avoided in patients treated with Rivaroxaban (Pradaxa), Apixaban (Eliquis), and Edoxaban (Sawaysa). Among strong inhibitors of CYP3A4, you will find many co-medications, but also dietary ingredients such as grapefruit juice (see an extended table on possibly confounding factors here).

In conclusion, some of the inter-individual variability in the disposition of DOACs in the population is attributable to genetic variants of gene loci, also resulting in drug-drug interactions, which may be influenced by confounding factors such a dietary habits of patients under anticoagulant therapy. Under these conditions, the serious question arises if DOACs should in fact be prescribed and used by patients without obligation for a regular INR-monitoring. The possible risk associated seem somewhat high, under the conditions that they may be fatal. And, if something goes wrong, it may be of particular interest (and, by the way, most of the time ignored or selectively forgotten by prescribers and patients alike) that currently, a DOAC reversal agent is only approved by FDA for Dabigatran (Pradaxa), namely Idarucizumab (Praxbind).

See some further information on anticoagulation:

Print Friendly, PDF & Email

Tags: , , , , , , , , , , , , , , , , , , ,
About the Author
Joseph Gut - thasso Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

Your opinion


Hello Everyone out there,I am here to give my testimony about a Herbalist doctor who helped me . I was infected with HERPES SIMPLEX VIRUS five years ago, i went to many hospitals for cure but there was no solution, so I was thinking how can I get a solution out so that my body can be okay. One day I was in the river side thinking where I can go to get solution. so a lady walked to me telling me why am I so sad and i open up all to her telling her my problem, she told me that she can help me out, she introduce me to a doctor who uses herbal medication to cure HERPES SIMPLEX VIRUS and gave me his email, so i mail him. He told me all the things I need to do and also give me instructions to take, which I followed properly. Before I knew what is happening after two weeks the HERPES SIMPLEX VIRUS that was in my body got vanished . so if you are also heart broken and also need a help, you can also email him at or Contact him today on whatsapp number… Read more
3 weeks ago 3 weeks ago

thasso: conditions

thasso: tweets

thasso post: magazine

View my Flipboard Magazine.

thasso: categories

thasso: archives

thasso: simple chat

You must be a registered user to participate in this chat.

  • Mayo researchers recommend all women with breast cancer diagnosis under age 66 be offered genetic testing February 21, 2020
    A study by researchers at Mayo Clinic published this week in the Journal of Clinical Oncology suggests that all women with a breast cancer diagnosis under the age of 66 be offered germline genetic testing to determine if they have a gene mutation known to increase the risk of developing other cancers and cancers among […]
  • Cross-talk between enzymes that read and correct recipes in the cookbook of life February 21, 2020
    DNA is the hereditary material in humans, a unique cookbook of who we are. This is where you'll find the answer as to why you have your specific eye and hair colour, or perhaps why you sunburn easily.
  • Study finds certain genetic tests not useful in predicting heart disease risk February 21, 2020
    A Polygenic Risk Score—a genetic assessment that doctors have hoped could predict coronary heart disease (CHD) in patients—has been found not to be a useful predictive biomarker for disease risk, according to a Vanderbilt study published in the Journal of the American Medical Association.
  • Major discovery in the genetics of Down syndrome February 21, 2020
    Researchers at CHU Sainte-Justine and Université de Montréal have discovered a new mechanism involved in the expression of Down syndrome, one of the main causes of intellectual disability and congenital heart defects in children. The study's findings were published today in Current Biology.
  • MicroRNA exhibit unexpected function in driving cancer February 20, 2020
    Researchers long thought that only one strand of a double-stranded microRNA can silence genes. Though recent evidence has challenged that dogma, it's unclear what the other strand does, and how the two may be involved in cancer. New research from Thomas Jefferson University has revealed that both strands of some microRNA coordinate to act on […]
  • Ethnobotanical medicine is effective against the bacterium causing Lyme disease February 21, 2020
    A preclinical in vitro study shows that selected plant-based herbal medicines, especially Ghanaian quinine and Japanese knotweed, work better than antibiotics against the bacterium that causes Lyme disease. These findings represent an important step towards the development of treatments that might be better tolerated and more effective than the current standard of care.
  • Opportunity blows for offshore wind in China February 21, 2020
    If China is to meet and exceed its Paris Climate Agreement goal by 2030, it's going to need to find a way to increase its wind capacity. Researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) and Huazhong University of Science and Technology in China, found that offshore wind could […]
  • Alcohol-induced deaths in US February 21, 2020
    National vital statistics data from 2000 to 2016 were used to examine how rates of alcohol-induced deaths (defined as those deaths due to alcohol consumption that could be avoided if alcohol weren't involved) have changed in the US and to compare the results by demographic groups including sex, race/ethnicity, age, socioeconomic status and geographic location. […]
  • The integrated catalysts can simplify pharmaceutical manufacturing February 21, 2020
    Prof. In Su Lee and his research team from POSTECH developed catalytic platforms based on metal organic frameworks.
  • Shaping the rings of molecules February 21, 2020
    Canadian chemists discover a natural process to control the shape of 'macrocycles,' molecules of large rings of atoms, for use in pharmaceuticals and electronics.