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Multicenter Study
. 2018 Jan 22;11(2):181-191.
doi: 10.1016/j.jcin.2017.07.022. Epub 2017 Nov 1.

Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention

Larisa H Cavallari  1 , Craig R Lee  2 , Amber L Beitelshees  3 , Rhonda M Cooper-DeHoff  4 , Julio D Duarte  5 , Deepak Voora  6 , Stephen E Kimmel  7 , Caitrin W McDonough  8 , Yan Gong  8 , Chintan V Dave  9 , Victoria M Pratt  10 , Tameka D Alestock  3 , R David Anderson  11 , Jorge Alsip  12 , Amer K Ardati  13 , Brigitta C Brott  12 , Lawrence Brown  14 , Supatat Chumnumwat  5 , Michael J Clare-Salzler  15 , James C Coons  16 , Joshua C Denny  17 , Chrisly Dillon  18 , Amanda R Elsey  8 , Issam S Hamadeh  8 , Shuko Harada  19 , William B Hillegass  20 , Lindsay Hines  21 , Richard B Horenstein  3 , Lucius A Howell  22 , Linda J B Jeng  3 , Mark D Kelemen  3 , Yee Ming Lee  5 , Oyunbileg Magvanjav  8 , May Montasser  3 , David R Nelson  23 , Edith A Nutescu  24 , Devon C Nwaba  3 , Ruth E Pakyz  3 , Kathleen Palmer  3 , Josh F Peterson  17 , Toni I Pollin  3 , Alison H Quinn  5 , Shawn W Robinson  25 , Jamie Schub  3 , Todd C Skaar  26 , D Max Smith  8 , Vindhya B Sriramoju  22 , Petr Starostik  15 , Tomasz P Stys  27 , James M Stevenson  16 , Nicholas Varunok  22 , Mark R Vesely  25 , Dyson T Wake  8 , Karen E Weck  28 , Kristin W Weitzel  8 , Russell A Wilke  27 , James Willig  12 , Richard Y Zhao  29 , Rolf P Kreutz  26 , George A Stouffer  22 , Philip E Empey  16 , Nita A Limdi  30 , Alan R Shuldiner  3 , Almut G Winterstein  31 , Julie A Johnson  4 ; IGNITE Network
Affiliations
Multicenter Study

Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention

Larisa H Cavallari et al. JACC Cardiovasc Interv. .

Abstract

Objectives: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI).

Background: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI.

Methods: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights.

Results: Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60).

Conclusions: These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.

Keywords: CYP2C19; antiplatelet therapy; cardiovascular events; clopidogrel; percutaneous coronary intervention; pharmacogenomics.

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Figures

FIGURE 1
FIGURE 1. Study Population by CYP2C19 Genotype Group and Antiplatelet Therapy
*Alternative therapy in patients with a LOF allele consisted of prasugrel (n=222), ticagrelor (n=116), or high dose clopidogrel (150 mg/day, n=2; 225 mg/day, n=6). †Alternative therapy in the non-LOF group consisted of prasugrel (n=125) or ticagrelor (n=68). ‡p<0.001 for use of alternative therapy in the non-LOF group compared to the LOF group. APT, antiplatelet therapy; LOF, loss-of-function; PCI, percutaneous coronary intervention
FIGURE 2, CENTRAL ILLUSTRATION
FIGURE 2, CENTRAL ILLUSTRATION. Outcomes with Clinical Implementation of CYP2C19-Guided Antiplatelet Therapy after PCI
Data are shown for patients with a CYP2C19 loss-of-function (LOF) allele treated with clopidogrel (LOF-Clopidogrel), patients with a LOF allele treated with alternative antiplatelet drug therapy (LOF-Alternative), and patients without an LOF allele treated with either clopidogrel or alternative therapy (non-LOF). The unadjusted log-rank p-values for the LOF-Clopidogrel group compared to LOF-Alternative group and for the Non-LOF group compared to the LOF-Alternative group are provided. LOF, loss-of-function; MACE, major adverse cardiovascular events
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