As one of the best-selling drugs worldwide, Plavix, when taken with aspirin, is the standard therapy for acute coronary syndrome. This is especially true if the patient is treated with percutaneous coronary intervention (PCI), which often involves the placement of stents in the coronary arteries.
Plavix works by reducing the activity of platelets, small cell fragments in the blood that help to stop bleeding when an injury damages a blood vessel. Problems arise when platelets may aggregate in coronary arteries, where they may clog the vessels and, as a result, restrict blood supply to the heart. Such patients may suffer from a heart attack when the heart does not get enough oxygen supply from the blood.
There are three things a patient should know about Plavix. First, there has been compelling evidence showing that the effectiveness of Plavix is not guaranteed and results are remarkably variable among patients. Secondly, the FDA has added a warning to the Plavix label indicating that testing for CYP2C19 gene variants may identify patients who may not respond to the drug. And lastly, generic forms of this drug, known as clopidogrel, will be available as soon as the end of 2011.
It has been estimated that about 25% of patients do not benefit from the standard regimen of Plavix. In these patients, standard Plavix therapy had no effect in inhibiting platelet aggregation and, consequently, these patients are at an increased risk for recurrent cardiovascular events.
Genetic studies have shed light on the variability of Plavix response. Briefly, the benefit of Plavix depends on the activity of an enzyme in the patient, and the activity of this enzyme can be reliably inferred by knowing certain genotypes in the CYP2C19 gene.
In order to understand this, it helps to know that the chemical in the pink Plavix tablet is not the one that has therapeutic function. Once ingested, the chemical is converted to an active metabolite that carries out the actual anti-platelet function. This conversion relies heavily on an enzyme encoded by the CYP2C19 gene. Variations in the gene reduce function of the enzyme; therefore, in patients who have one or two of those variations, the ability to generate the active metabolite is compromised. These patients, when compared with those who do not have the genetic variants, have lower levels of the active metabolite, and they cannot enjoy the full benefit from Plavix.
The CYP2C19 genotypes have been repeatedly shown to affect the levels of the active metabolite, the function of platelets and the clinical outcomes in patients on Plavix. A meta-analysis of 23 studies, involving about 12,000 patients treated with Plavix, showed that people with at least one copy of the non-functional gene (CYP2C19*2) have a 30% increase in risk for major adverse cardiovascular events, like heart attack, when compared to people with two functional copies of the CYP2C19 gene. Recent data have suggested that the effect on clinical outcome may be most prominent in patients undergoing PCI.
In response to these data, the FDA has approved updates to the label of Plavix to include the pharmacogenetic information. The revised label states that genetic tests can be used in making clinical decisions and alternative treatment should be considered for those who do not have a fully functional copy of CYP2C19.
Pathway Genomics has incorporated CYP2C19 genotyping in its Drug Response (Medication) Insight genetic testing service. We currently test for two most common variants of CYP2C19, *2 and *3, which account for 85% of reduced function variants in Caucasians and 99% in Asians.
However, CYP2C19 genotyping is yet to be accepted as a routine practice for Plavix treatment. A major concern is that CYP2C19 genotypes account for only part of the variation in the response to Plavix and the clinical utility of the test has not been proven.
It is true that we have a long way to go before we can have a comprehensive algorithm to personalize anti-platelet therapy, but not all patients have the luxury to wait. This is especially true for patients who are to be managed with PCI. These patients are usually given Plavix to prevent blood clots from developing at the site of stenting (stent thrombosis). However, even with Plavix, stent thrombosis still clogs the coronary arteries in many people. It has been shown that CYP2C19 genotypes play a role in determining the risk for stent thrombosis; carriers of one reduced function allele of CYP2C19 have 2.67 times increased risk of stent thrombosis, compared to non-carriers, and those who do not have any fully functional copies of CYP2C19 have 3.97 times increased risk as do non-carriers.
About 30% of Caucasians have at least one reduced function CYP2C19 allele. Is it acceptable to give Plavix to patients undergoing PCI, knowing that it may not work well in about 30% of them? The question would be difficult to answer if we did not have alternative treatment strategies.
But we do.
In 2009, prasugrel (trade name, Effient), an alternative anti-platelet drug, was approved by the FDA for use in patients who are to be treated with PCI. The CYP2C19 enzyme is not as critical in the metabolism of prasugrel as in that of Plavix. Therefore, the drug is effective in patients with reduced CYP2C19 function. Prasugrel is not the best choice for everyone, because compared to Plavix, it is associated with an increased risk for bleeding. However, for many patients with reduced CYP2C19 function, the benefit of the enhanced effectiveness can offset the increased risk for bleeding.
This is how genotyping can make a difference. By testing for the CYP2C19 genotype, we can identify patients that are eligible for an alternative treatment.
Another strategy for patients with reduced CYP2C19 function is to use higher dosages of Plavix. The price of Plavix has been a concern for this strategy. However, there is the good news that generic equivalents of Plavix will soon be available, which will make this strategy more economical.
Genetic testing is still assumed to be expensive by many, but thanks to the rapid advances in technology and efforts of companies like Pathway, it is no longer true. The data in your genes are valuable health information similar to your family history or blood type — something you are willing to know and share with your doctor when necessary.
We certainly suggest that, in case you need anti-platelet therapy, you share with your doctor the Pathway test results of your CYP2C19 genotype.
Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2009 Jan 24;373(9660):309-17. Epub 2008 Dec 26. PubMed PMID: 19108880.
Fuster V, Sweeny JM. Clopidogrel and the reduced-function CYP2C19 genetic variant: a limited piece of the overall therapeutic puzzle. JAMA. 2010 Oct 27;304(16):1839-40. PubMed PMID: 20978263.
Holmes DR Jr, Dehmer GJ, Kaul S, Leifer D, O’Gara PT, Stein CM. ACCF/AHA clopidogrel clinical alert: approaches to the FDA “boxed warning”: a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol. 2010 Jul 20;56(4):321-41. Review. PubMed PMID: 20633831.
Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barthélémy O, Cayla G, Beygui F, Montalescot G. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol. 2010 Jul 6;56(2):134-43. PubMed PMID: 20620727.
Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D, Hod H. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 2004 Jun 29;109(25):3171-5. Epub 2004 Jun 7. PubMed PMID: 15184279.
Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009 Jan 22;360(4):354-62. Epub 2008 Dec 22. PubMed PMID: 19106084.
Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, Antman EM, Braunwald E, Sabatine MS. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet. 2010 Oct 16;376(9749):1312-9. PubMed PMID: 20801494.
Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, Cannon CP, Danchin N, Giusti B, Gurbel P, Horne BD, Hulot JS, Kastrati A, Montalescot G, Neumann FJ, Shen L, Sibbing D, Steg PG, Trenk D, Wiviott SD, Sabatine MS. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010 Oct 27;304(16):1821-30. PubMed PMID: 20978260.
Paré G, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Hirsh J, Simonsen K, Bhatt DL, Fox KA, Eikelboom JW. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med. 2010 Oct 28;363(18):1704-14. PubMed PMID: 20979470.
Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009 Aug 26;302(8):849-57. PubMed PMID: 19706858.
Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG, Ferrières J, Danchin N, Becquemont L; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009 Jan 22;360 (4):363-75. Epub 2008 Dec 22. PubMed PMID: 19106083.
Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, Husted S, Katus H, Steg PG, Shah SH, Becker RC; PLATO investigators. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010 Oct 16;376(9749):1320-8. PubMed PMID: 20801498.
Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15. Epub 2007 Nov 4. PubMed PMID: 17982182.