Thromboembolism after treatment with 4-factor prothrombin complex concentrate or plasma for warfarin-related bleeding.

Limited data exist in large, representative populations about whether the risk of thromboembolic events varies after receiving four-factor human prothrombin complex concentrate (4F-PCC) versus treatment with human plasma for urgent reversal of oral vitamin K antagonist therapy. We conducted a multicenter observational study to compare the 45-day risk of thromboembolic events in adults with warfarin-associated major bleeding after treatment with 4F-PCC (Kcentra®) or plasma. Hospitalized patients in two large integrated healthcare delivery systems who received 4F-PCC or plasma for reversal of warfarin due to major bleeding from January 1, 2008 to March 31, 2020 were identified and were matched 1:1 on potential confounders and a high-dimensional propensity score. Arterial and venous thromboembolic events were identified up to 45 days after receiving 4F-PCC or plasma from electronic health records and adjudicated by physician review. Among 1119 patients receiving 4F-PCC and a matched historical cohort of 1119 patients receiving plasma without a recent history of thromboembolism, mean (SD) age was 76.7 (10.5) years, 45.6% were women, and 9.4% Black, 14.6% Asian/Pacific Islander, and 15.7% Hispanic. The 45-day risk of thromboembolic events was 3.4% in those receiving 4F-PCC and 4.1% in those receiving plasma (P = 0.26; adjusted hazard ratio 0.76; 95% confidence interval 0.49-1.16). The adjusted risk of all-cause death at 45 days post-treatment was lower in those receiving 4F-PCC compared with plasma. Among a large, ethnically diverse cohort of adults treated for reversal of warfarin-associated bleeding, receipt of 4F-PCC was not associated with an excess risk of thromboembolic events at 45 days compared with plasma therapy.

Classification and characteristics of on-label and off-label apixaban use in Denmark and Sweden.

PURPOSE: To estimate the proportion of apixaban users who received the drug for on-label indications and characterise the patients using apixaban for on-label and off-label indications. METHODS: We report results from two independently conducted studies in Denmark and Sweden, with 19,709 Danish and 17,592 Swedish patients, who received at least one outpatient dispensing of apixaban as identified through nationwide prescription registries. Indications, inferred from inpatient and hospital diagnoses recorded at the initial apixaban dispensing, were classified as on-label, off-label, or unclassified according to the Summary of Product Characteristics. All diagnoses were retrieved using inpatient or outpatient hospital diagnoses at the first outpatient dispensing during the study period. RESULTS: Men comprised 52% of the users in both Denmark and Sweden. The median age was 76 years (interquartile range [IQR]: 68-83 years) among Danish patients and 74 years (IQR: 67-82 years) among Swedish patients. An on-label indication could be assigned to 82.6% (95% confidence interval [CI]: 82.1%-83.1%) of the Danish patients and 86.4% (95% CI: 85.9%-86.9%) of the Swedish patients. The main on-label indication for apixaban was non-valvular atrial fibrillation (NVAF), which accounted for 76.1% of the indications in Denmark and 69.1% of the indications in Sweden. Off-label indications were assigned to 10.8% (95% CI: 10.3-11.2) of the Danish patients (main indication possible mechanical heart valve) and 7.7% (95% CI: 7.3-8.1) of the Swedish patients (main indication off-label atrial fibrillation). CONCLUSION: The majority of apixaban initiators in Denmark and Sweden received apixaban for an on-label indication, primarily for NVAF.

Use of depot medroxyprogesterone acetate contraception and incidence of bone fracture.

OBJECTIVE: Depot medroxyprogesterone acetate (DMPA) reversibly reduces bone mineral density. To estimate the extent to which DMPA might increase fracture risk, we undertook a retrospective cohort study of fractures in DMPA users and users of non-DMPA contraceptives, using the General Practice Research Database. METHODS: Eligible women were aged younger than 50 years at the qualifying first contraceptive prescription. The DMPA users were classified by DMPA exposure (cumulative and time of last dose) based on prescription records. All incident fractures were included; fracture incidence and risk factors before starting contraceptive use (DMPA or other) also were estimated. RESULTS: We identified 11,822 fractures in 312,395 women during 1,722,356 person-years of follow-up. Before contraceptive use started, DMPA users had higher fracture risk than nonusers (incidence rate ratio 1.28, 95% confidence interval [CI] 1.07-1.53). After DMPA started, crude fracture incidence was 9.1 per 1,000 person-years for DMPA users and 7.3 for nonusers (crude incidence rate ratio 1.23, 95% CI 1.16-1.30). Fracture risk in DMPA users did not increase after starting DMPA (incidence rate ratio after or before 1.08, 95% CI 0.92-1.26). There was little confounding by age or other factors that could be measured. Fracture incidence was 9.4 per 1,000 person-years in low-exposure DMPA users, and 7.8 per 1,000 in high-exposure DMPA users. The DMPA users had higher fracture risk than nonusers at the start of contraceptive use, with no discernible induction period. CONCLUSION: Although DMPA users experienced more fractures than nonusers, this association may be the result of confounding by a pre-existing higher risk for fractures in women who chose DMPA for contraception.

The epidemiology and clinical correlates of HIV-1 co-receptor tropism in non-subtype B infections from India, Uganda and South Africa.

BACKGROUND: The introduction of C-C chemokine receptor type-5 (CCR5) antagonists as antiretroviral therapy has led to the need to study HIV co-receptor tropism in different HIV-1 subtypes and geographical locations. This study was undertaken to evaluate HIV-1 co-receptor tropism in the developing world where non-B subtypes predominate, in order to assess the therapeutic and prophylactic potential of CCR5 antagonists in these regions. METHODS: HIV-1-infected patients were recruited into this prospective, cross-sectional, epidemiologic study from HIV clinics in South Africa, Uganda and India. Patients were infected with subtypes C (South Africa, India) or A or D (Uganda). HIV-1 subtype and co-receptor tropism were determined and analyzed with disease characteristics, including viral load and CD4(+) and CD8(+) T cell counts. RESULTS: CCR5-tropic (R5) HIV-1 was detected in 96% of treatment-naïve (TN) and treatment-experienced (TE) patients in India, 71% of TE South African patients, and 86% (subtype A/A1) and 71% (subtype D) of TN and TE Ugandan patients. Dual/mixed-tropic HIV-1 was found in 4% of Indian, 25% of South African and 13% (subtype A/A1) and 29% (subtype D) of Ugandan patients. Prior antiretroviral treatment was associated with decreased R5 tropism; however, this decrease was less in subtype C from India (TE: 94%, TN: 97%) than in subtypes A (TE: 59%; TN: 91%) and D (TE: 30%; TN: 79%). R5 virus infection in all three subtypes correlated with higher CD4(+) count. CONCLUSIONS: R5 HIV-1 was predominant in TN individuals with HIV-1 subtypes C, A, and D and TE individuals with subtypes C and A. Higher CD4(+) count correlated with R5 prevalence, while treatment experience was associated with increased non-R5 infection in all subtypes.