0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Review |

Reduced-Function CYP2C19 Genotype and Risk of Adverse Clinical Outcomes Among Patients Treated With Clopidogrel Predominantly for PCI: A Meta-analysis

Jessica L. Mega, MD, MPH; Tabassome Simon, MD, PhD; Jean-Philippe Collet, MD, PhD; Jeffrey L. Anderson, MD; Elliott M. Antman, MD; Kevin Bliden, BS; Christopher P. Cannon, MD; Nicolas Danchin, MD, PhD; Betti Giusti, PhD; Paul Gurbel, MD; Benjamin D. Horne, PhD; Jean-Sebastian Hulot, MD, PhD; Adnan Kastrati, MD; Gilles Montalescot, MD, PhD; Franz-Josef Neumann, MD; Lei Shen, PhD; Dirk Sibbing, MD; P. Gabriel Steg, MD; Dietmar Trenk, PhD; Stephen D. Wiviott, MD; Marc S. Sabatine, MD, MPH
JAMA. 2010;304(16):1821-1830. doi:10.1001/jama.2010.1543.
Text Size: A A A
Published online

Content Clopidogrel, one of the most commonly prescribed medications, is a prodrug requiring CYP450 biotransformation. Data suggest its pharmacologic effect varies based on CYP2C19 genotype, but there is uncertainty regarding the clinical risk imparted by specific genotypes.

Objective To define the risk of major adverse cardiovascular outcomes among carriers of 1 (≈ 26% prevalence in whites) and carriers of 2 (≈ 2% prevalence in whites) reduced-function CYP2C19 genetic variants in patients treated with clopidogrel.

Data Sources and Study Selection A literature search was conducted (January 2000-August 2010) in MEDLINE, Cochrane Database of Systematic Reviews, and EMBASE. Genetic studies were included in which clopidogrel was initiated in predominantly invasively managed patients in a manner consistent with the current guideline recommendations and in which clinical outcomes were ascertained.

Data Extraction Investigators from 9 studies evaluating CYP2C19 genotype and clinical outcomes in patients treated with clopidogrel contributed the relevant hazard ratios (HRs) and 95% confidence intervals (CIs) for specific cardiovascular outcomes by genotype.

Results Among 9685 patients (91.3% who underwent percutaneous coronary intervention and 54.5% who had an acute coronary syndrome), 863 experienced the composite end point of cardiovascular death, myocardial infarction, or stroke; and 84 patients had stent thrombosis among the 5894 evaluated for such. Overall, 71.5% were noncarriers, 26.3% had 1 reduced-function CYP2C19 allele, and 2.2% had 2 reduced-function CYP2C19 alleles. A significantly increased risk of the composite end point was evident in both carriers of 1 (HR, 1.55; 95% CI, 1.11-2.17; P = .01) and 2 (HR, 1.76; 95% CI, 1.24-2.50; P = .002) reduced-function CYP2C19 alleles, as compared with noncarriers. Similarly, there was a significantly increased risk of stent thrombosis in both carriers of 1 (HR, 2.67; 95% CI, 1.69-4.22; P < .0001) and 2 (HR, 3.97; 95% CI, 1.75-9.02; P = .001) CYP2C19 reduced-function alleles, as compared with noncarriers.

Conclusion Among patients treated with clopidogrel for percutaneous coronary intervention, carriage of even 1 reduced-function CYP2C19 allele appears to be associated with a significantly increased risk of major adverse cardiovascular events, particularly stent thrombosis.

Figures in this Article

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal
• Rent this article ?

Figures

Place holder to copy figure label and caption
Figure 1. Study Selection Flow Diagram
Graphic Jump Location
Place holder to copy figure label and caption
Figure 2. Cardiovascular Death, Myocardial Infarction, or Ischemic Stroke by CYP2C19 Genotype
Graphic Jump Location

Among patients treated with clopidogrel, hazard ratios (HRs) are reported for cardiovascular death, myocardial infarction, or ischemic stroke among carriers of 1 or 2 (panel A), 1 (panel B), or 2 (panel C) reduced-function CYP2C19 alleles vs noncarriers. Size of data markers reflects the statistical weight of the study in the meta-analysis. Data marker for the overall category indicates the 95% confidence interval (CI) for the overall HR. The number of events and of individuals at risk for events is presented for each study. Panel C, Studies with no adverse cardiovascular events among carriers of 2 reduced-function CYP2C19 alleles were excluded from analysis.

Place holder to copy figure label and caption
Figure 3. Stent Thrombosis by CYP2C19 Genotype
Graphic Jump Location

Among patients treated with clopidogrel, hazard ratios (HRs) are reported for stent thrombosis among carriers of 1 or 2 (panel A), 1 (panel B), or 2 (panel C) reduced-function CYP2C19 alleles vs noncarriers. Size of data markers reflects the statistical weight of the study in the meta-analysis. Data marker for the overall category indicates the 95% confidence interval (CI) for the overall HR. Number of events and of individuals at risk for events is presented for each study. Panel C, Studies that had no stent thrombosis events among carriers of 2 reduced-function CYP2C19 alleles were excluded from analysis.

Place holder to copy figure label and caption
Figure 4. Timing of Events for Cardiovascular Death, Myocardial Infarction, or Ischemic Stroke and Stent Thrombosis
Graphic Jump Location

Among patients treated with clopidogrel, hazard ratios (HRs) are reported for cardiovascular death, myocardial infarction, or ischemic stroke and for stent thrombosis among carriers of 1 or 2 reduced-function CYP2C19 alleles vs noncarriers. Data markers indicate HRs and CIs across the different time points. Nine studies contributed to the end point of cardiovascular death, myocardial infarction, or stroke from 0 to 30 days, and 6 studies from 31 days to end of follow-up. Analogously, 6 studies contributed to the end point of stent thrombosis from 0 to 30 days, and 3 studies from 31 days to end of follow-up. Number of events and of individuals at risk for events is presented for each study. In the analysis, a patient could have had a nonfatal event during 0 to 30 days and a subsequent event after day 30.

Tables

References

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

4,824 Views
359 Citations

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal
• Rent this article ?

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles
Jobs
JAMAevidence.com

Users' Guides to the Medical Literature
Was the Individual Trial or Meta-Analysis Large Enough? Just Check the Confidence Intervals

Users' Guides to the Medical Literature

×
brightcove.createExperiences();