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Extracardiac vascular disease and effectiveness of sustained clopidogrel treatment
  1. D Mukherjee1,
  2. E J Topol2,
  3. D J Moliterno1,
  4. D M Brennan2,
  5. K Ziada1,
  6. L Cho3,
  7. S R Steinhubl1,
  8. for the CREDO Investigators
  1. 1Division of Cardiovascular Medicine and the Gill Heart Institute, Lexington, Kentucky, USA
  2. 2Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA
  3. 3Division of Cardiology, Loyola University Medical Center, Chicago, Illinois, USA
  1. Correspondence to:
    Dr Debabrata Mukherjee
    Gill Heart Institute, Division of Cardiovascular Medicine, University of Kentucky, 900 S Limestone Street, 326 Wethington Building, Lexington, Kentucky 40536-0200, USA; Mukherjee{at}uky.edu

Abstract

Objective: To assess the effectiveness of long term treatment with clopidogrel of patients with extracardiac vascular disease (ECVD) (a history of either peripheral arterial disease or cerebrovascular disease).

Design: Subgroup analysis of a prospective randomised clinical trial.

Setting: The CREDO (clopidogrel for the reduction of events during observation) trial was a randomised, double blind, placebo controlled trial conducted at 99 centres in North America from June 1999 through April 2001.

Patients: 2116 patients who were to undergo elective coronary intervention or were deemed at high likelihood of undergoing percutaneous coronary intervention were enrolled in the CREDO trial. The current study sample consisted of 272 patients with ECVD.

Main outcome measure: One year incidence of the composite of death, myocardial infarction, or stroke in the intent to treat population.

Results: Patients with ECVD had a more than twofold greater relative risk reduction with clopidogrel for the primary end point compared with patients without ECVD (47.9%, 95% confidence interval (CI) −4.2% to 73.9%, v 18.2%, 95% CI −10.5 % to 39.5%, respectively).

Conclusions: Longer term clopidogrel treatment provides added protection against thrombotic events throughout the arterial vasculature, not limited to the coronary arteries, and may be especially effective for patients with more diffuse atherosclerosis such as ECVD.

  • CI, confidence interval
  • CREDO, clopidogrel for the reduction of events during observation
  • ECVD, extracardiac vascular disease
  • PCI, percutaneous coronary intervention
  • peripheral arterial disease
  • clopidogrel
  • vascular disease
  • antiplatelet treatment

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Extracardiac vascular disease (ECVD) is associated with an increased risk of in-hospital mortality and other complications after coronary interventions, independently of other co-morbidities and baseline characteristics.1–3 Treatments that may potentially improve clinical outcomes in this high risk cohort warrant further investigation. We analysed the effectiveness of long term treatment with clopidogrel of patients in the CREDO (clopidogrel for the reduction of events during observation) trial with ECVD (a history of either peripheral arterial disease or cerebrovascular disease). The study shows that patients with ECVD derive particular benefit from long term clopidogrel treatment.

METHODS

We hypothesised that patients with ECVD, being at high risk for cardiovascular events, would derive particular benefit from extended clopidogrel regimens. The design and methods of the CREDO trial have been previously described.4 Briefly, 2116 patients with symptomatic coronary artery disease and objective evidence of ischaemia who underwent elective percutaneous coronary intervention (PCI) or had a strong likelihood of undergoing PCI were enrolled from June 1999 to April 2001 from 99 centres in North America. Patients were randomly assigned to a loading dose of clopidogrel (300 mg) or placebo 3–24 hours before PCI. All patients were given clopidogrel 75 mg/day for 28 days after PCI. After this, the clopidogrel group (who were treated with the 300 mg loading dose) continued receiving clopidogrel 75 mg/day from day 29 through 12 months, whereas the control group (who received the placebo loading dose) received placebo for the same duration. All patients also were given aspirin daily. The primary end point of CREDO was a composite of one year death, myocardial infarction, and stroke.4 In this subgroup analysis, patients were categorised as having ECVD if they had a history of either peripheral arterial disease or cerebrovascular disease.

Statistical analysis

Baseline characteristics were compared by χ2 and Fisher’s exact tests for discrete variables and Wilcoxon rank sum tests for continuous variables. Kaplan-Meier estimates and log rank tests were used to compare one year events between patients with ECVD treated with and those treated without long term clopidogrel. Hazard ratios and 95% confidence intervals (CIs) were generated from Cox proportional hazards models. Relative risk reductions with corresponding 95% CIs were calculated for patients with and without ECVD treated with long term clopidogrel. Lastly, risk adjusted hazard ratios were calculated for the composite events of death, myocardial infarction, stroke, and urgent revascularisation. A probability value of p < 0.05 was considered significant. Data were analysed with SAS 8.2 (SAS Institute, Cary, North Carolina, USA).

RESULTS

The study sample consisted of 272 patients with ECVD, 132 of whom received clopidogrel. Baseline demographic characteristics were similar in the patients with ECVD treated with and in those without clopidogrel (table 1), except that the clopidogrel group tended to be older.

Table 1

 Baseline characteristics of patients with a history of extracardiac vascular disease (ECVD) in the CREDO trial stratified by clopidogrel use

The main CREDO trial observed an overall relative risk reduction of 26.9% (95% CI 3.9% to 44.4%) in the one year primary composite end point (death, myocardial infarction, and stroke) with clopidogrel compared with placebo (8.6% v 11.8%, p  =  0.02). Patients with ECVD had a more than twofold greater relative risk reduction with clopidogrel for the primary end point compared with patients who did not have ECVD (47.9%, 95% CI −4.2% to 73.9%, v 18.2 %, 95% CI −10.5 % to 39.5 %, respectively) as fig 1 shows. Overall event rates were significantly lower with long term clopidogrel treatment among patients with ECVD considering all possible composite ischaemic outcomes (table 2, fig 2).

Table 2

 Clinical outcomes of patients with ECVD at one year assessed by the Kaplan-Meier method

Figure 1

 Bar graph showing relative risk reductions with clopidogrel treatment of patients with and without extracardiac vascular disease (ECVD). Patients with ECVD had higher relative risk reduction with sustained clopidogrel treatment. MI, myocardial infarction; TVR, target vessel revascularisation.

Figure 2

 Kaplan-Meier curves showing significantly lower incidence of the composite of death, MI, stroke, and urgent TVR in patients with ECVD treated with clopidogrel.

A Cox proportional hazards analysis adjusted for age, diabetes, and history of prior myocardial infarction showed that clopidogrel treatment was associated with a substantially lower risk of death, myocardial infarction, stroke, and urgent target vessel revascularisation (odds ratio 0.49, 95% CI 0.25 to 0.99, p  =  0.04) (table 3).

Table 3

 Multivariate risk adjusted* hazard ratios (HR) of adverse clinical outcomes in patients with ECVD treated with clopidogrel

DISCUSSION

Clopidogrel pretreatment and long term treatment after PCI has been shown to reduce short term (30 day) and long term (eight months to one year) adverse cardiovascular outcomes.4,5 Clopidogrel treatment also improves clinical outcomes among patients undergoing peripheral vascular interventions.6 Our post hoc analysis of the CREDO trial suggests that long term clopidogrel treatment particularly benefits patients with ECVD. Peripheral arterial disease is a marker of systemic atherosclerosis and the presence of ECVD may conceivably be an indicator of more advanced, active, or aggressive vascular disease.6,7 Longer term treatment appears to provide added protection against thrombotic events throughout the arterial vasculature, not limited to the coronary arteries, and may be especially effective for patients with ECVD.

Our study has inherent limitations given the post hoc analyses, thus precluding definitive conclusions. Because the ECVD group was not selected randomly, potential selection bias may exist. However, clopidogrel treatment was randomly assigned and blinded, so any bias should be balanced between the clopidogrel and control groups. Moreover, we used a risk adjusted Cox proportional hazards model to account for differences in baseline demographic co-morbidities, and long term treatment with clopidogrel remained a significant independent predictor of lower one year death, myocardial infarction, stroke, and urgent target vessel revascularisation.

REFERENCES

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Footnotes

  • Published Online First 21 April 2005

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