Clopidogrel, Stroke, and why genetics is important for Indians now

Clopidogrel is an antiplatelet drug that helps to reduce the risk of serious cardiovascular thrombotic events such as stroke. In 2020 the state of Hawaii successfully sued the makers of clopidogrel for not disclosing that the drug may not be effective at providing anticoagulation against thrombotic events for some people, particularly those of East Asian and Pacific Island ancestry. The reason for this being a functional mutation in a gene (CYP2C19) that is present in over half of people of Chinese Ancestry 1, making it much more common than in people of European ancestry 2. Data has been limited for other populations though clopidogrel is commonly prescribed throughout the world3. This includes India, where the risk for serious cardiovascular events, including stroke is especially high, with more than a million people affected each year 4,5, making it the 4th leading cause of death and the 5th leading cause of disability in India 6. In terms of disability, in general, 20% of stroke survivors require institutional care after 3 months and 15-30% remain permanently disabled. The probability of a recurrent stroke after the first stroke is as high as 10% in the first month and 14% in the first year 7. The addition of clopidogrel to aspirin for at-risk populations reduces risk of stroke overall by 14-20% and risk of recurrence by 24% 7 and it has been estimated that 23 strokes are prevented per 1000 patients treated with clopidogrel in addition to standard aspirin therapy 8. However, the benefit will only apply if one is not insensitive to the drug. Unfortunately, the first sign of failed efficacy may be death or serious morbidity as the result of a stroke so it is important to identify those for whom alternate treatments should be considered.

This can be done at an individual or population level, thus empirically, an individual of European ancestry is more likely to benefit than one of Chinese ancestry based on the carriage rate of the ineffective gene.

In our work, we found that 38% of the Indians that we screened carried the CYP2C19 *2 or *3 variants, which are the commonest ones responsible for the lack of efficacy of the drug. This carrier rate of these variants was significantly higher than the 20-26% reported in people of European ancestry 9. It is important to note however that one study of patients in India with coronary artery disease treated with clopidogrel did not appear to have less efficacy regardless of genotype 10, raising the possibility of other, as yet unknown, factors that may be involved.

While the incidence is not as high as for those of Chinese ancestry, the genetic risk is nonetheless higher than for people of European ancestry, raising the possibility that testing and further studies on clopidogrel resistance should be considered in people of Indian origin.

References

  1. Liu G et al., The correlation between recurrent risk and CYP2C19 gene polymorphisms in patients with ischemic stroke treated with clopidogrel for prevention. Medicine (Baltimore). 2020;99(11):e19143.
  2. McDermott JH, Leach M, Sen D, Smith CJ, Newman WG, Bath PM. The role of CYP2C19 genotyping to guide antiplatelet therapy following ischemic stroke or transient ischemic attack. Expert Rev Clin Pharmacol. 2022 Jul;15(7):811-825. doi: 10.1080/17512433.2022.2108401. Epub 2022 Aug 4. PMID: 35912831; PMCID: PMC9612933.
  3. Choe JC, Cha KS, Ahn J,et al., Korea Acute Myocardial Infarction Registry–National Institutes of Health Investigators. Comparison of prescription rates and clinical outcomes in acute coronary syndrome patients who underwent percutaneous coronary intervention using different P2Y12 inhibitors in a large observational study. Int J Cardiol. 2019 Jan 1;274:21-26. doi: 10.1016/j.ijcard.2018.09.011. Epub 2018 Sep 5. PMID: 30224257.
  4. Prabhakaran D, Jeemon P, Roy A. Cardiovascular Diseases in India: Current Epidemiology and Future Directions. Circulation. 2016 Apr 19;133(16):1605-20. doi: 10.1161/CIRCULATIONAHA.114.008729. PMID: 27142605.
  5. Jones SP, Baqai K, Clegg A, et al. Stroke in India: A systematic review of the incidence, prevalence, and case fatality. Int J Stroke. 2022 Feb;17(2):132-140. doi: 10.1177/17474930211027834. Epub 2021 Jul 2. PMID: 34114912; PMCID: PMC8821978.
  6. Directorate General of Health Services: Ministry of Health and Family Welfare. National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases and Stroke. Government of India 2019, July
  7. Gouya G, Arrich J, Wolzt M, Huber K, Verheugt FW, Gurbel PA, Pirker-Kees A, Siller-Matula JM. Antiplatelet treatment for prevention of cerebrovascular events in patients with vascular diseases: a systematic review and meta-analysis. Stroke. 2014 Feb;45(2):492-503. doi: 10.1161/STROKEAHA.113.002590. Epub 2013 Dec 24. PMID: 24368560.
  8. Squizzato A, Bellesini M, Takeda A, Middeldorp S, Donadini MP. Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular events. Cochrane Database Syst Rev. 2017 Dec 14;12(12):CD005158. doi: 10.1002/14651858.CD005158.pub4. PMID: 29240976; PMCID: PMC6486024.
  9. Dean L, Kane M. Clopidogrel Therapy and CYP2C19 Genotype. 2012 Mar 8 [updated 2022 Dec 1]. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–. PMID: 28520346.
  10. Shetkar SS, Ramakrishnan S, Seth S, Chandna P, Verma SK, Bhargava B, Bahl VK. CYP 450 2C19 polymorphisms in Indian patients with coronary artery disease. Indian Heart J. 2014 Jan-Feb;66(1):16-24. doi: 10.1016/j.ihj.2013.10.001. Epub 2013 Nov 6. PMID: 24581091
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Dr. Jonathan Picker Chief Executive Office

Dr. Jonathan Picker is an affiliate faculty member and clinical geneticist at Boston's Children's Hospital, Harvard Medical School.

With 25 years of experience in Pediatrics and Genetics, Dr. Picker specializes in the interface of clinical care and applied genetic and genomic research. Dr. Picker's research spans diagnostic tools in genetics to descriptive analysis of rare disorders to molecular neuroscience. He was the co-founder and Director of the first Pediatric Pharmacogenomic clinic in the USA; as well as Director of the Harvard Medical School Advanced Human Genetics Training Program Course.

Dr. Picker is the recipient of various prestigious awards, including the first Sidney R. Baer Jr. Prize for Mental health Research. He has authored numerous research papers involving informative cases, molecular biology, behavioral neuroscience, applied clinical genetic guidelines as well as invited reviews and chapters.

Dr. Picker holds a bachelor's degree of Medical Biology in Genetics, and an MBChB in Medicine from Aberdeen University, UK. He also holds an MS in Genetics and Biochemistry and a PhD in Molecular Biology from Newcastle University, UK.

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Kushagra SharmaPresident & Board Member

Kushagra Sharma is a seasoned business leader with a career spanning entrepreneurship as well as general management, Kushagra has deep expertise in developing and executing business plans in start-ups as well as large corporations. He is responsible for the revenue growth of the business, strategic planning, and partnerships at Anuva.

Before joining Anuva, he was responsible for the strategy and project execution in launching 4G digital services for Reliance Jio in India. Kushagra has previously served in leadership roles in companies like British Telecom, MTS Sistema Shyam, Grail Research and Evalueserve.

He holds a bachelor's degree from Indian Institute of Technology, Delhi and an MBA from INSEAD, Fontainebleau.

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Dr. Asmi ShahVice President of Data and Technology

Dr. Asmi Shah brings in her data science expertise in dealing with big data, managing and standardizing multidisciplinary large scale biological datasets in the field of drug discovery through genomics and phenomics. She is responsible for the research and development of end to end software products and workflows.

Before joining Anuva, she contributed to the research of drug discovery done with the use of high content/throughput screening on various zebrafish assays at University of Heidelberg in Germany and at Harvard Medical School, USA. She has also taken up various technical roles in product management and software R&D with different corporate industries such as Intel, Rambus and Inform Technologies in the USA and with data analytics startups in India.

Dr. Shah holds a bachelor’s degree from Saurashtra University, India, an MS from San Jose State University, USA and has pursued her PhD from University of Heidelberg, Germany under a Marie Curie fellowship.

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Naveen Tewari

Naveen Tewari is the Founder & CEO of the InMobi group of companies. He brings his immense expertise with successfully setting up and running tech-first companies to provide strategic and tactical guidance to Anuva.

He holds a bachelor’s degree from Indian Institute of Technology, Kanpur and an MBA from Harvard Business School.

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Abhishek Kumar Chairman & Executive Director

Abhishek Kumar brings in extensive experience of acquiring, merging, carving out and repositioning companies globally. He founded Joulon - a KKR company, and has led large scale distributed businesses globally.

He holds a bachelor’s degree from Indian Institute of Technology, Kanpur and an MBA from Harvard Business School.