Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patients.

BACKGROUND: Warfarin is commonly prescribed for prophylaxis and treatment of thromboembolism after orthopedic surgery. During warfarin initiation, out-of-range International Normalized Ratio (INR) values and adverse events are common. METHODS: In orthopedic patients beginning warfarin therapy, we developed and prospectively validated pharmacogenetic and clinical dose refinement algorithms to revise the estimated therapeutic dose after 4 days of therapy. RESULTS: The pharmacogenetic algorithm used the cytochrome P450 (CYP) 2C9 genotype, smoking status, peri-operative blood loss, liver disease, INR values and dose history to predict the therapeutic dose. The R(2) was 82% in a derivation cohort (n = 86) and 70% when used prospectively (n = 146). The R(2) of the clinical algorithm that used INR values and dose history to predict the therapeutic dose was 57% in a derivation cohort (n = 178) and 48% in a prospective validation cohort (n = 146). In 1 month of prospective follow-up, the percent time spent in the therapeutic range was 7% higher (95% CI: 2.7-11.7) in the pharmacogenetic cohort. The risk of a laboratory or clinical adverse event was also significantly reduced in the pharmacogenetic cohort (Hazard Ratio 0.54; 95% CI: 0.30-0.97). CONCLUSIONS: Warfarin dose adjustments that incorporate genotype and clinical variables available after four warfarin doses are accurate. In this non-randomized, prospective study, pharmacogenetic dose refinements were associated with more time spent in the therapeutic range and fewer laboratory or clinical adverse events. To facilitate gene-guided warfarin dosing we created a non-profit website, http://www.WarfarinDosing.org.

Five-year results of a randomized, single-center study of tacrolimus vs microemulsion cyclosporine in heart transplant patients.

BACKGROUND: Previous multicenter, randomized trials, lacking standardized post-transplant protocols, have compared tacrolimus (Tac) and cyclosporine (CyA, Sandimmune) and demonstrated similar outcomes with some different adverse effects. The microemulsion form of CyA (mCyA, Neoral) has replaced Sandimmune CyA as the more widely utilized CyA formulation. This is the first 5-year follow-up study of a large, single-center trial (n = 67) under a standardized post-transplant protocol comparing Tac and mCyA. METHODS: Sixty-seven heart transplant patients were randomized to Tac (n = 33) or mCyA (n = 34), both in combination with corticosteroids and azathioprine without cytolytic induction. Five-year end-points included survival, Grade > or = 3A or treated rejection, angiographic cardiac allograft vasculopathy (CAV; any lesion > or = 30% stenosis), renal dysfunction (creatinine > or = 2.0 mg/dl), use of two or more anti-hypertensive medications, percent diabetic and lipid levels. RESULTS: Five-year survival, freedom from Grade > or = 3A or any treated rejection and angiographic CAV, mean cholesterol level and percent diabetic were similar between the two groups. The Tac group had a significantly lower 5-year mean triglyceride level (Tac 97 +/- 34 vs mCyA 175 +/- 103 mg/dl, p = 0.011) and average serum creatinine level (Tac 1.2 +/- 0.5 mg/dl vs mCyA 1.5 +/- 0.4 mg/dl, p = 0.044). There was a trend toward fewer patients requiring two or more anti-hypertensive drugs in the Tac group (Tac 33% vs mCyA 59%, p = 0.065). CONCLUSIONS: Tac and mCyA appear to be comparable with regard to 5-year survival, freedom from rejection and CAV. However, compared with mCyA, Tac appears to reduce the adverse effect profile for hypertriglyceridemia and renal dysfunction and the need for hypertensive medications.

Incidence of acute cellular rejection and non-cellular rejection in cardiac transplantation.

BACKGROUND: Rejection continues to be one of the leading causes of death during the first year after cardiac transplantation. With the advent of more potent immunosuppressive therapies, the incidence of graft rejection has been reported to be decreasing. Yet, this trend has not been well established due to differences in the interpretation of and the protocols for endomyocardial biopsy specimens. Additionally, the incidence of humoral (noncellular) rejection has not been adequately addressed. METHODS: Six thousand one hundred thirty endomyocardial biopsy specimens in 487 cardiac transplant recipients during the first year posttransplantation from 1990 to 2000 were reviewed to assess the incidences of acute cellular and treated noncellular rejection episodes. Cellular rejection was defined as ISHLT grades 3-4; noncellular rejection as a 20% decrease in echo LVEF, cardiac index <2.0, and/or inotropic support associated with ISHLT grades 0-2 necessitating treatment. RESULTS: The incidence of noncellular rejection has remained relatively unchanged at approximately 20% (P=nonsignificant for all years); in contrast, there has been a significant decrease (P <.001) in the incidence of cellular rejection from 54% to 5%. CONCLUSION: The incidence of noncellular rejection in cardiac transplant recipients has remained unchanged through the 1990s despite improved immunosuppressive therapies, which have significantly decreased the incidence of acute cellular rejection. There appears to be a need for newer immunosuppressive agents to effectively treat noncellular rejection. Clinical trials using allograft rejection as a major endpoint will need to increase the enrollment of patients to achieve adequate power to demonstrate differences between study groups.