Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy.

CONTEXT: Clopidogrel therapy improves cardiovascular outcomes in patients with acute coronary syndromes and following percutaneous coronary intervention by inhibiting adenosine diphosphate (ADP)-dependent platelet activation. However, nonresponsiveness is widely recognized and is related to recurrent ischemic events. OBJECTIVE: To identify gene variants that influence clopidogrel response. DESIGN, SETTING, AND PARTICIPANTS: In the Pharmacogenomics of Antiplatelet Intervention (PAPI) Study (2006-2008), we administered clopidogrel for 7 days to 429 healthy Amish persons and measured response by ex vivo platelet aggregometry. A genome-wide association study was performed followed by genotyping the loss-of-function cytochrome P450 (CYP) 2C19*2 variant (rs4244285). Findings in the PAPI Study were extended by examining the relation of CYP2C19*2 genotype to platelet function and cardiovascular outcomes in an independent sample of 227 patients undergoing percutaneous coronary intervention. MAIN OUTCOME MEASURE: ADP-stimulated platelet aggregation in response to clopidogrel treatment and cardiovascular events. RESULTS: Platelet response to clopidogrel was highly heritable (h(2) = 0.73; P < .001). Thirteen single-nucleotide polymorphisms on chromosome 10q24 within the CYP2C18-CYP2C19-CYP2C9-CYP2C8 cluster were associated with diminished clopidogrel response, with a high degree of statistical significance (P = 1.5 x 10(-13) for rs12777823, additive model). The rs12777823 polymorphism was in strong linkage disequilibrium with the CYP2C19*2 variant, and was associated with diminished clopidogrel response, accounting for 12% of the variation in platelet aggregation to ADP (P = 4.3 x 10(-11)). The relation between CYP2C19*2 genotype and platelet aggregation was replicated in clopidogrel-treated patients undergoing coronary intervention (P = .02). Furthermore, patients with the CYP2C19*2 variant were more likely (20.9% vs 10.0%) to have a cardiovascular ischemic event or death during 1 year of follow-up (hazard ratio, 2.42; 95% confidence interval, 1.18-4.99; P = .02). CONCLUSION: CYP2C19*2 genotype was associated with diminished platelet response to clopidogrel treatment and poorer cardiovascular outcomes.

The inpatient consultation approach to osteoporosis treatment in patients with a fracture. Is automatic consultation needed?

BACKGROUND: Osteoporosis has been described as a "silent epidemic." We describe an osteoporosis consultation program to facilitate the evaluation and treatment of inpatients with fragility fractures. METHODS: The inpatient orthopaedic team voluntarily requested an osteoporosis consultation on all patients with a fragility fracture. The osteoporosis consultant evaluated patients for secondary causes and started treatment with calcium, vitamin D, and bisphosphonates unless contraindicated. From November 2001 to December 2003, fifty-three osteoporosis consultations were performed. A retrospective review of the charts of all patients with a hip fracture treated during this twenty-six-month period revealed that only 47% were actually seen by the osteoporosis consultants, creating an unintentional "nonintervention" cohort of thirty-one patients with a hip fracture. Treatment for osteoporosis was assessed by a review of the inpatient charts and by a telephone interview after discharge. RESULTS: The study group consisted of eighty-four patients, which included fifty-three in the intervention cohort (twenty-eight hip and twenty-five other fractures) and thirty-one in the nonintervention cohort (all patients with a hip fracture). In the intervention cohort, most patients were vitamin-D deficient. Calcium and vitamin-D treatment was recommended for all fifty-three patients, and bisphosphonates were recommended for forty-one of the fifty-three patients in the intervention cohort. In the nonintervention cohort, two patients received calcium and vitamin D and one received a bisphosphonate; the difference between the cohorts was significant (p < 0.0001). In the intervention cohort, twenty-seven of the thirty-four patients who were available for a telephone interview after discharge (at a mean of eighteen months) remained on calcium and vitamin D; twenty-two of the thirty-four patients remained on bisphosphonates. In the nonintervention cohort, only one of the twelve patients who were available for follow-up (at a mean of thirty-nine months) was receiving calcium and vitamin D and none were on bisphosphonate treatment. CONCLUSIONS: This consultation program cannot be considered an outright success since only half of all patients with a hip fracture actually received a consultation. However, osteoporosis consultation, when provided, facilitated the recognition of secondary causes and the generic treatment of osteoporosis, and inpatients started on treatment generally continued the medication after discharge. The results of this study strongly support the need for a mechanism of automatic osteoporosis consultation for inpatients with a fragility fracture and suggest that, if consultation is reliably obtained, this approach can be effective in improving patient care. LEVEL OF EVIDENCE: Therapeutic Level III.

Do Bcl-2 and survivin help distinguish benign from malignant B-cell lymphoid aggregates in bone marrow biopsies?

Bcl-2 and survivin are cellular proteins that are known to be inhibitors of apoptosis and are commonly found in malignant tissues, including lymphomas. In previous studies, it has been shown that staining for bcl-2 can help distinguish between benign and malignant lymphoid aggregates in bone marrow biopsies. To determine whether staining for survivin expression in lymphoid aggregates can aid investigators in making this clinically important distinction, we stained bone marrow biopsies from 10 patients with benign lymphoid aggregates, and 15 malignant ones derived from B cells (six mantle cell, four follicular cells, two diffuse large cell, two small lymphocytic cell, and one marginal zone lymphoma) with antibodies to CD3, CD20, bcl-2, and survivin by an indirect immunoperoxidase technique. Whereas staining for bcl-2 was significantly stronger in the malignant lymphoid aggregates (P=0.001), both the control and malignant cases were almost uniformly negative for survivin expression. Only three cases (two mantle cell and one small lymphocytic lymphoma) showed very faint expression of survivin. Although bcl-2 and survivin both act to inhibit apoptosis, their expressions do not parallel each other. Survivin is not significantly expressed in either benign or malignant bone marrow aggregates, and therefore measuring its expression does not help distinguish benign from malignant B-cell bone marrow lymphoid aggregates.