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Children with cyanotic congenital heart disease derived no benefit from prophylactic clopidogrel (Plavix) for shunt thrombosis, a large, randomized trial showed.
The composite endpoint of death plus three types of clinical events occurred in 19.1% of clopidogrel-treated patients and 20.5% of the placebo group. Separate analyses of each component of the endpoint also showed no significant differences between treatment groups.
Subgroup analysis failed to identify any patients who benefited more or less from clopidogrel, as reported in the June 20 issue of the New England Journal of Medicine.
"We found no benefit of clopidogrel, as compared with placebo, in reducing the rate of death for any cause or shunt-related morbidity, particularly shunt thrombosis, among infants with congenital heart disease palliated with a systemic-to-pulmonary-artery shunt," David L. Wessel, MD, of Children's National Medical Center in Washington, and co-authors concluded.
Placement of a systemic-to-pulmonary-artery shunt for palliation increases the risk of shunt thrombosis and death among infants with congenital heart disease. Prophylactic anti-thrombotic therapy had not been evaluated in a randomized trial, but data from a prospective registry showed a significant reduction in the risk of death and shunt thrombosis among infants treated with aspirin, the authors noted.
As an approved medication for adults, clopidogrel use has spread into pediatric populations, absent sound evidence of efficacy. Retrospective, single-center reviews have suggested clopidogrel is safe and effective in infants.
Wessel and collaborators at 134 sites in Europe, Asia, North America, South America, and Africa prospectively evaluated the safety and efficacy of prophylactic clopidogrel in a randomized trial involving children with congenital heart disease. Eligible patients were 92 days or younger at randomization and had received a palliative systemic-to-pulmonary-artery shunt. Patients with active bleeding or with an increased risk of bleeding were excluded.
Patients were randomized to weight-based clopidogrel or matching placebo and were followed by telephone or clinic visits at weeks 4, 12, 24, and 36. A final visit occurred on a patient's first birthday, the common study end date, or first occurrence of a qualifying event for termination: shunt thrombosis, elective surgery to correct the congenital heart defect, or death.
The primary endpoint was the composite of death, heart transplantation, shunt thrombosis requiring intervention, or a cardiac procedure performed before 120 days of age because of thrombotic event. The final analysis included 906 patients, 88% of whom were receiving aspirin in addition to the study drug.
The trial had a median duration of follow-up of 5.8 months. Administration of study drug was stopped temporarily (for median of 8 days) in 53.6% of patients, and study drug was permanently discontinued in significantly more patients in the clopidogrel group (24.0% versus 18.2%, P=0.03). Median time to permanent discontinuation was 96 days, and reasons for discontinuation did not differ significantly between groups.
A primary-endpoint event occurred in 89 patients in the clopidogrel group and 90 patients in the placebo group. The combination of death and heart transplantation occurred slightly less often in the clopidogrel group (11.8% versus 13.9%, NS); death accounted for all but one of the events. Causes of death did not differ significantly between groups, nor did the remaining components of the composite endpoint.
A post-hoc analysis showed that patients receiving concomitant aspirin had a significantly lower rate of the composite endpoint when treated with clopidogrel (18.6% versus 28.2%, P=0.009).
Adverse events occurred more often with clopidogrel than with placebo, whether assessed in all randomized patients (76.1% versus 71.1%, P=0.09) or per protocol (73.9% versus 66.9%, P=0.04). Bleeding occurred in 18.8% of clopidogrel patients and 20.2% of the placebo group and severe bleeding in 4.1% and 3.4%, respectively, neither of which achieved statistical significance.
The study was supported by sanofi-aventis and Bristol-Myers Squibb.
Wessel disclosed a relationship with sanofi-aventis. One or more co-authors disclosed relationships with AGA, Actelion, Pfizer, sanofi-aventis, Daiichi Sankyo, Bristol-Myers Squibb, and Merck. Investigators included current or former employees of sanofi-aventis and Bristol-Myers Squibb.
Charles Bankhead
Staff Writer
Working from Houston, home to one of the world's largest medical complexes, Charles Bankhead has more than 20 years of experience as a medical writer and editor. His career began as a science and medical writer at an academic medical center. He later spent almost a decade as a writer and editor for Medical World News, one of the leading medical trade magazines of its era. His byline has appeared in medical publications that have included Cardio, Cosmetic Surgery Times, Dermatology Times, Diagnostic Imaging, Family Practice, Journal of the National Cancer Institute, Medscape, Oncology News International, Oncology Times, Ophthalmology Times, Patient Care, Renal and Urology News, The Medical Post, Urology Times, and the International Medical News Group newspapers. He has a BA in journalism and MA in mass communications, both from Texas Tech University.
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