Absence of clinically relevant pharmacokinetic interaction between ribavirin and tenofovir in healthy subjects

This was a 36-day, open-label, fixed-sequence, multiple-dose drug interaction study in 23 healthy subjects to evaluate the effects of multiple doses of tenofovir disoproxil fumarate on the single-dose pharmacokinetics of ribavirin. Subjects received a 600-mg once-daily oral dose of ribavirin on days 1 and 22 and 300-mg once-daily oral doses of tenofovir disoproxil fumarate on days 17 through 24. Pharmacokinetic sampling was performed on days 1 through 4 and 22 through 25. Pharmacokinetics of ribavirin was not altered by its coadministration with tenofovir disoproxil fumarate as the point estimates (day 22 [test treatment]/day 1 [reference treatment]), and the 90% confidence interval for maximum observed concentration (0.95; 88.7-101) and area under the plasma concentration-time curve up to time of last measurable concentration (1.12; 106-117) were within the equivalence bounds of 80% to 125%. Tenofovir pharmacokinetics after ribavirin coadministration was similar to that observed in previous studies. These results indicate that coadministration of tenofovir disoproxil fumarate and ribavirin does not result in substantial changes to their individual pharmacokinetic profiles.     

Heparin sensitivity test for patients requiring cardiopulmonary bypass

Anticoagulation for the open heart surgery patient undergoing cardiopulmonary bypass (CPB) is achieved with the use of heparin. The industry standard of activated clotting time (ACT) was used to measure the effect of heparin. The commonly acceptable target time of anticoagulation adequacy is 480 seconds or greater. Some patients, however, exhibit resistance to standard dosing of heparin and do not reach target anticoagulation time (480 seconds). Antithrombin III deficiency has been previously cited as the cause of heparin resistance. Early detection of heparin resistance (HR) may avoid both the delayed start of CPB and inadequate anticoagulation, if emergency bypass is required. An anticoagulation sensitivity test (AST) was developed by adding 12 units of porcine mucosa heparin to the ACT tube (International Technidyne, celite type). Before anticoagulation, 4 mL of blood was drawn from the patient arterial line. Following the manufacturer's instructions, 2 mL of blood was added to each tube (ACT-baseline and ACT-AST). Three minutes after anticoagulation with 4 mg heparin/kg body weight, a second sample (ACT-CPB) was taken to determine anticoagulation adequacy. The ACT times of each sample were recorded for 300 procedures occurring during 2004 and were retrospectively reviewed. Heparin resistance occurred in approximately 20% of the patients (n = 61). In 54 patients, heparin resistance was predicted by the ACT-AST. This was determined by the presence of an ACT-AST time and an ACT-CPB that were both < 480 seconds. The positive predictive value was 90%, with a false positive rate of 3%. Heparin resistance occurs in patients undergoing CPB. We describe a simple and reliable test to avoid the delays of assessing anticoagulation for CPB (90% positive predictive value). Depending on program guidelines, patients can be given additional heparin or antithrombin III derivatives to aid in anticoagulation. An additional ACT must be performed and reach target times before CPB initiation. Testing of patient blood before the time of incision for sensitivity to heparin is a way to avoid a delay that can be critical in the care of the patient. Commercial tests are available, but efficacy data are limited, and they lead to added inventory expense. This method of titrating a diluted heparin additive, mixed with patient blood in a familiar ACT test, has proven to be an inexpensive and reliable test to predict patient's sensitivity to heparin.     

Mortality incidence of patients with non-obstructive coronary artery disease diagnosed by computed tomography angiography

It was previously reported that event-free survival rates of symptomatic patients with coronary artery disease (CAD) diagnosed by computed tomographic angiography decreased incrementally from normal coronary arteries to obstructive CAD. The aim of this study was to investigate the clinical outcomes of symptomatic patients with nonobstructive CAD with luminal stenoses of 1% to 49% on the basis of coronary plaque morphology in an outpatient setting. Among 3,499 consecutive symptomatic subjects who underwent computed tomographic angiography, 1,102 subjects with nonobstructive CAD (mean age 59 ± 14 years, 69.9% men) were prospectively followed for a mean of 78 ± 12 months. Coronary plaques were defined as noncalcified, mixed, and calcified per patient. Multivariate Cox proportional-hazards models were developed to predict all-cause mortality. The death rate of patients with nonobstructive CAD was 3.1% (34 deaths). The death rate increased incrementally from calcified plaque (1.4%) to mixed plaque (3.3%) to noncalcified plaque (9.6%), as well as from single- to triple-vessel disease (p <0.001). In subjects with mixed or calcified plaques, the death rate increased with the severity of coronary artery calcium from 1 to 9 to ≥ 400. The risk-adjusted hazard ratios of all-cause mortality in patients with nonobstructive CAD were 3.2 (95% confidence interval 1.3 to 8.0, p = 0.001) for mixed plaques and 7.4 (95% confidence interval 2.7 to 20.1, p = 0.0001) for noncalcified plaques compared with calcified plaques. The areas under the receiver-operating characteristic curve to predict all-cause mortality were 0.75 for mixed and 0.86 for noncalcified coronary lesions. In conclusion, this study demonstrates that the presence of noncalcified and mixed coronary plaques provided incremental value in predicting all-cause mortality in symptomatic subjects with nonobstructive CAD independent of age, gender, and conventional risk factors.     

Mortality in individuals without known coronary artery disease but with discordance between the Framingham risk score and coronary artery calcium

A risk-management approach based on the Framingham risk score (FRS), although useful in preventing future coronary artery disease (CAD) events, is unable to identify a considerable portion of patients with CAD who need aggressive medical management. Coronary artery calcium (CAC), an anatomic marker of atherosclerosis, correlates well with presence and extent of CAD. This study investigated mortality risk associated with CAC score and FRS in subjects classified as "low risk" versus "high risk" based on FRS. In total 730 veterans without known CAD (61 ± 10 years old, 12.8% women) underwent measurement of their FRS and CAC. Subjects were classified as "discordant low risk" (DLR) if their FRS was <10% and CAC score was ≥ 100 (n = 108, 14.8%) or "discordant high risk" (DHR) if their FRS was ≥ 20% and CAC score was 0 (n = 104, 14.2%). Survival analysis was used to compare mortality rates associated with FRS and CAC in DLR versus DHR subjects. Mortality rate during the mean 48-month follow-up was 7.3% (n = 53) including 18.5% (n = 20) in the DLR group and 7.7% (n = 8) in the DHR group, respectively. Adjusted relative risks of mortality were 5.46 (95% confidence interval [CI] 2.44 to 12.20, p = 0.0001) in subjects with CAC score ≥ 100 compared to CAC score 0 and 1.35 (95% CI 1.01 to 4.32, p = 0.04) in subjects with FRS ≥ 20% compared to FRS <10%. Adjusted relative risk of mortality was 3.6 (95% CI 1.57 to 8.34, p = 0.003) for DLR compared to DHR. Areas under the receiver operator curve to predict mortality were 0.72 for FRS, 0.82 for CAC score, and 0.92 for the combination. In conclusion, the prognostic value of CAC to predict future mortality is superior to the FRS. Addition of CAC score to FRS significantly improves the identification and prognostication of patients without known CAD.