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The purpose of this study was to compare CsA dose monitoring with trough levels (T0) vs. levels obtained 6 h after the morning dose of CsA (T6), with respect to the incidence of acute rejection and renal dysfunction, and the cumulative dose, as well as the cost of CsA after heart transplantation. Twenty consecutive adult heart transplant patients receiving quadruple sequential immunosuppression were prospectively randomized into CsA monitoring with T0 (Group I) vs. T6 levels (Group II). Oral CsA was started at a dosage of 2 mg/kg/d, 1-4 d after transplantation. The target range for either T0 or T6 was 150 to 250 ng/ml (enzyme multplied immunologic technique), respectively. The CsA dose was increased or decreased by 0.5-1 mg/kg/d if the measured level was outside of the target range. Throughout the follow-up period (Group I, 11±2 months; Group II, 10±3 months), the incidence of acute rejection (ISHLT grade ≥ 2) was 50% in each group. The left ventricular ejection fraction and serum creatinine were similar in both groups at 1 month and at the end of the follow-up. The maximal dose of CsA (mg/kg/d): 3.8±1 vs. 5±0.6 (P=0.002), the minimal dose: 2.2±0.7 vs. 3.4±0.8 (P=0.003), and the current dose: 2.6±0.6 vs. 3.5±1 (P=0.02), were lower in Group II, as well as the cumulative dose of CsA (mg): 61 790±19 754 vs. 88 524±18 082 (P=0.005), and its cost (CDN$): 3 589±1 116 vs. 5 106±1 045 (P=0.005). In conclusion, CsA dose monitoring with T6 was associated with a 30% lower CsA dose and cost compared to T0, with the same effectiveness in the prevention of acute rejection, and similar cardiac and renal function.