Reversal of Warfarin-Associated Major Hemorrhage: Activated Prothrombin Complex Concentrate versus 4-Factor Prothrombin Complex Concentrate.

BACKGROUND: Warfarin-associated major hemorrhage is frequently treated with prothrombin complex concentrates to correct international normalized ratio (INR). OBJECTIVE: This article aims to investigate the efficacy of activated prothrombin complex concentrate (aPCC) versus 4-factor prothrombin complex concentrate (4PCC) for vitamin K antagonist reversal in patients with warfarin-associated major hemorrhage. MATERIALS AND METHODS: This was a multicenter, retrospective cohort study. Patients included were age ≥ 18 years with pretreatment INR of > 1.5. Exclusion criteria were patients treated for urgent procedures without hemorrhage, treated but not taking warfarin, unavailable INR values, and pregnant patients. Patients were stratified into two groups: aPCC or 4PCC. The primary outcome was achievement of INR ≤ 1.5 at the posttreatment INR sampling. Secondary outcomes focused on thrombotic events and mortality. RESULTS: Of 342 patients, 237 patients received aPCC and 105 patients received 4PCC. After 1:1 propensity score matching, 86 patients remained in each group. In the matched cohort, the proportion of patients who achieved target INR ≤ 1.5 was greater with 4PCC (aPCC = 61 [70.9%] vs. 4PCC = 76 [88.4%]; 95% confidence interval [CI] -29.2% to -5.7%) and groups had comparable in-hospital thrombotic events and mortality. In the unmatched cohort, achievement of target INR ≤ 1.5 was greater with 4PCC (aPCC = 151 [63.7%] vs. 4PCC = 92 [87.6%]; 95% CI -32.7% to -15.1%). CONCLUSION: In the treatment of warfarin-associated major hemorrhage, 4PCC compared with aPCC was associated with greater achievement of INR ≤ 1.5 with comparable thrombotic events and mortality. Further controlled studies are needed to confirm these findings and determine the optimal dosing strategy that maximizes efficacy and safety.

Treatment with the atypical antipsychotic, olanzapine, prevents the expression of amphetamine-induced place conditioning in the rat.

Place conditioning (PC) experiments were conducted as a means to further elaborate the treatment potential of the atypical antipsychotic, olanzapine (OLZ), for stimulant abuse. The resulting preference/aversion provides an indirect measure of the incentive salience (i.e., euphoria/dysphoria) produced by a drug. Male Sprague-Dawley rats (n=48) were conditioned in two unique environments (i.e., vertical vs. horizontal stripped walls, large vs. small grid flooring) using injections (1.0 mg/kg ip) of either amphetamine (AMPH) or saline (SAL). On average, animals displayed a significant preference for the AMPH-paired location after 2.5 weeks of conditioning (five pairings each of AMPH and SAL). Once the preference was established, animals were pretreated (60 min) with a single dose of OLZ (0.0, 0.56, 1.0 or 1.5 mg/kg sc) given on the test (AMPH-free) day. For the following week's test, animals were injected with SAL (1.0 mg/kg ip) in an attempt to recapture the side preference exhibited before OLZ treatment. OLZ treatment prevented the expression of the AMPH-conditioned preference and reduced locomotor activity. Inhibition of preference resulted from the highest dose of OLZ (1.5 mg/kg), while the inhibition of locomotor activity occurred across all three doses. Additionally, while the effects on preference were no longer apparent by the SAL test the following week (reversible), the activity was still depressed during the SAL tests in animals that had experienced the highest dose of OLZ (1.5 mg/kg). Control experiments, in which OLZ was used as the conditioning drug, suggest that OLZ itself possesses no aversive effects in the PC paradigm, and may even produce a preference for the drug-paired chamber. Because the AMPH preference is dependent on dopamine (DA) release in the nucleus accumbens (NAcc), these experiments suggest that OLZ pretreatment interferes with the rewarding, as well as the subjective effects of AMPH.