- Email: [email protected]
Cytochrome P450 2C19 polymorphism and clopidogrel after MI
Correspondence
www.thelancet.com Vol 373 April 4, 2009
We declare that we have no conflict of interest.
Henry Kitchener, *Ann Marie Swart, Wendi Qian, Mahesh Parmar [email protected] University of Manchester, Manchester, UK (HK); and MRC Clinical Trials Unit, London NW1 2DA, UK (AMS, WQ, MP) 1
2
3
ASTEC Writing Committee on behalf of ASTEC study group. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet 2009; 373: 125–36. Panici PB, Basile S, Maneschi F, et al. Systematic pelvic lymphadenectomy vs no lymphadenectomy in early-stage endometrial carcinoma: randomised clinical trial. J Natl Cancer Inst 2008; 100: 1707–16. ASTEC/EN.5 writing committee on behalf of the ASTEC/EN.5 study group. Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled results, systematic review and meta-analysis. Lancet 2009; 373: 137–46.
Cytochrome P450 2C19 polymorphism and clopidogrel after MI Jean-Philippe Collet and colleagues (Jan 24, p 309)1 show that young patients with a previous myocardial infarction who are carriers of the CYP2C19*2 allele have a significantly worse long-term outcome than those without this allele. Previous studies have shown that patients carrying this polymorphism have reduced platelet inhibition when exposed to clopidogrel.2 Collet and colleagues correctly point out that strategies to overcome this lack of platelet inhibition, such as using higher doses of clopidogrel, are worthy of investigation. The patient group without the CYP2C19*2 allele still had an event rate of 2·89 per 100 patient-years for death, non-fatal myocardial infarction, or urgent revascularisation during follow-up. It would be interesting to know whether platelet function in patients who had further cardiovascular events in this group was inhibited sufficiently by clopidogrel. Although these patients might not be genetically predisposed to a lack
of platelet inhibition, other factors such as a lack of patients’ adherence to clopidogrel therapy could affect it. Spertus and colleagues3 showed that more than 13% of patients had discontinued use of clopidogrel within 30 days of having a myocardial infarction. Jackevicius and colleagues4 showed that a change in the healthcare system in Canada from prior authorisation to limited-use prescription of clopidogrel improved both uptake of clopidogrel therapy and clinical outcomes in patients after myocardial infarction. Although the trend in medicine is towards targeting therapy tailored to an individual’s genetic profile, the importance of the need for improvement in the delivery of health care and of patients’ adherence to therapy should not be underestimated. We declare that we have no conflict of interest.
Sanjeev Bhattacharyya, *Roby Rakhit [email protected] Department of Cardiology, Royal Free Hospital, Pond Street, London NW3 2QG, UK 1
2
3
4
Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009; 373: 309–17. Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19681>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare metal stents. J Am Coll Cardiol 2008; 51: 1925–34. Spertus JA, Kettelkamp R, Vance C, et al. Prevalence, predictors and outcomes of premature discontinuation of thienopyridine therapy after drug eluting stent placement; results from the PREMIER registry. Circulation 2006; 113: 2803–09. Jackevicius CA, Tu JV, Demers V, et al. Cardiovascular outcomes after a change in prescription policy for clopidogrel. N Engl J Med 2008; 359: 1802–10.
Corbis
nor necessary because it is now clear that external-beam radiation therapy has no effect on overall survival.3 Aoun Hakmi, Frédéric Amant and colleagues, and Stefano Uccella and colleagues suggest that we should not have included women whose risk of nodal metastases is low. It is possible that for these women the effect of lymphadenectomy might be smaller, but an analysis of treatment effect by risk group did not provide evidence of this. The power to detect a treatment effect in the “high-risk” early-stage subgroup (80 deaths in 507 patients) is obviously lower than the overall power, but is similar to that in the Panici study2 (53 deaths in 514 women), which also showed no evidence of benefit. Hakmi and Amant and colleagues ask about the number of nodes removed. Observational studies linking node counts to outcome are subject to bias from factors unrelated to therapeutic potential and cannot lead to reliable conclusions of treatment effect. The median number of nodes removed was used to group centres to look for an effect associated with removing more nodes: none was found. An unbiased analysis of whether removing more nodes might lead to benefit on an individual patient basis is not possible. Uccella and colleagues and Amant and colleagues argue that residual unresected para-aortic disease is a reason that no benefit was seen. We do not regard metastatic disease involving para-aortic nodes as being surgically curable, and with no evidence of benefit from two randomised trials, it does not seem logical to suggest that an even more extensive operation (with more postoperative morbidity) should be done. Lymphadenectomy was introduced as part of International Federation of Gynecology and Obstetrics staging without evidence of benefit, and it is now incumbent on those who argue for its continuation to provide this evidence. Surgical oncology merits as robust an evidence base as is expected of non-surgical cancer treatment.
Jean-Philippe Collet and co-workers1 disclose that the genetic variant CYP2C19*2 is a major determinant of prognosis in young patients on clopidogrel treatment after myocardial infarction. We think that the results should be interpreted with caution. 1171
www.thelancet.com Vol 373 April 4, 2009
We declare that we have no conflict of interest.
Henry Kitchener, *Ann Marie Swart, Wendi Qian, Mahesh Parmar [email protected] University of Manchester, Manchester, UK (HK); and MRC Clinical Trials Unit, London NW1 2DA, UK (AMS, WQ, MP) 1
2
3
ASTEC Writing Committee on behalf of ASTEC study group. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet 2009; 373: 125–36. Panici PB, Basile S, Maneschi F, et al. Systematic pelvic lymphadenectomy vs no lymphadenectomy in early-stage endometrial carcinoma: randomised clinical trial. J Natl Cancer Inst 2008; 100: 1707–16. ASTEC/EN.5 writing committee on behalf of the ASTEC/EN.5 study group. Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled results, systematic review and meta-analysis. Lancet 2009; 373: 137–46.
Cytochrome P450 2C19 polymorphism and clopidogrel after MI Jean-Philippe Collet and colleagues (Jan 24, p 309)1 show that young patients with a previous myocardial infarction who are carriers of the CYP2C19*2 allele have a significantly worse long-term outcome than those without this allele. Previous studies have shown that patients carrying this polymorphism have reduced platelet inhibition when exposed to clopidogrel.2 Collet and colleagues correctly point out that strategies to overcome this lack of platelet inhibition, such as using higher doses of clopidogrel, are worthy of investigation. The patient group without the CYP2C19*2 allele still had an event rate of 2·89 per 100 patient-years for death, non-fatal myocardial infarction, or urgent revascularisation during follow-up. It would be interesting to know whether platelet function in patients who had further cardiovascular events in this group was inhibited sufficiently by clopidogrel. Although these patients might not be genetically predisposed to a lack
of platelet inhibition, other factors such as a lack of patients’ adherence to clopidogrel therapy could affect it. Spertus and colleagues3 showed that more than 13% of patients had discontinued use of clopidogrel within 30 days of having a myocardial infarction. Jackevicius and colleagues4 showed that a change in the healthcare system in Canada from prior authorisation to limited-use prescription of clopidogrel improved both uptake of clopidogrel therapy and clinical outcomes in patients after myocardial infarction. Although the trend in medicine is towards targeting therapy tailored to an individual’s genetic profile, the importance of the need for improvement in the delivery of health care and of patients’ adherence to therapy should not be underestimated. We declare that we have no conflict of interest.
Sanjeev Bhattacharyya, *Roby Rakhit [email protected] Department of Cardiology, Royal Free Hospital, Pond Street, London NW3 2QG, UK 1
2
3
4
Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009; 373: 309–17. Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19681>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare metal stents. J Am Coll Cardiol 2008; 51: 1925–34. Spertus JA, Kettelkamp R, Vance C, et al. Prevalence, predictors and outcomes of premature discontinuation of thienopyridine therapy after drug eluting stent placement; results from the PREMIER registry. Circulation 2006; 113: 2803–09. Jackevicius CA, Tu JV, Demers V, et al. Cardiovascular outcomes after a change in prescription policy for clopidogrel. N Engl J Med 2008; 359: 1802–10.
Corbis
nor necessary because it is now clear that external-beam radiation therapy has no effect on overall survival.3 Aoun Hakmi, Frédéric Amant and colleagues, and Stefano Uccella and colleagues suggest that we should not have included women whose risk of nodal metastases is low. It is possible that for these women the effect of lymphadenectomy might be smaller, but an analysis of treatment effect by risk group did not provide evidence of this. The power to detect a treatment effect in the “high-risk” early-stage subgroup (80 deaths in 507 patients) is obviously lower than the overall power, but is similar to that in the Panici study2 (53 deaths in 514 women), which also showed no evidence of benefit. Hakmi and Amant and colleagues ask about the number of nodes removed. Observational studies linking node counts to outcome are subject to bias from factors unrelated to therapeutic potential and cannot lead to reliable conclusions of treatment effect. The median number of nodes removed was used to group centres to look for an effect associated with removing more nodes: none was found. An unbiased analysis of whether removing more nodes might lead to benefit on an individual patient basis is not possible. Uccella and colleagues and Amant and colleagues argue that residual unresected para-aortic disease is a reason that no benefit was seen. We do not regard metastatic disease involving para-aortic nodes as being surgically curable, and with no evidence of benefit from two randomised trials, it does not seem logical to suggest that an even more extensive operation (with more postoperative morbidity) should be done. Lymphadenectomy was introduced as part of International Federation of Gynecology and Obstetrics staging without evidence of benefit, and it is now incumbent on those who argue for its continuation to provide this evidence. Surgical oncology merits as robust an evidence base as is expected of non-surgical cancer treatment.
Jean-Philippe Collet and co-workers1 disclose that the genetic variant CYP2C19*2 is a major determinant of prognosis in young patients on clopidogrel treatment after myocardial infarction. We think that the results should be interpreted with caution. 1171