Inappropriate Underdosing of Direct Oral Anticoagulants in Atrial Fibrillation Patients: Results from the START2-AF Registry.

Background: Direct oral anticoagulants (DOACs) are recommended for stroke prevention in non-valvular atrial fibrillation (NVAF) patients. We aimed to describe the prevalence of inappropriate DOACs dose prescription in the START2-AF Registry, the outcomes according to the appropriateness of the dosage, and the factors associated with inappropriate dose prescription. Methods: Patients' demographics and clinical data were prospectively collected as electronic files in an anonymous form on the website of the START2-Registry; DOACs dosage was determined to be appropriate when prescribed according to the European Heart Rhythm Association Guidelines. Results: We included 5943 NVAF patients on DOACs; 2572 (46.3%) were female patients. The standard dose (SD) was prescribed to 56.9% of patients and the low dose (LD) was prescribed to 43.1% of patients; 38.9% of all NVAF patients received an inappropriate LD DOAC and 0.3% received inappropriate SD. Patients treated with LD DOAC had a significantly higher rate of all bleedings (RR 1.5; 95% CI 1.2-2.0), major bleedings (RR 1.8; 95% CI 1.3-1.7), and mortality (RR 2.8; 95% CI 1.9-4.1) with respect to patients treated with SD DOAC. No difference was found among patients treated with appropriate and inappropriate LD regarding bleeding, thrombotic, and mortality rates. Age, body weight <60 kg, and renal failure were significantly associated with inappropriate LD DOAC prescription. Conclusions: Inappropriate LD DOACs in NVAF patients is not associated with a reduction in bleeding risk, nor with an increased thrombotic risk. Instead, it is associated with higher mortality rate, suggesting that, in clinical practice, underdosing is preferred for patients at particularly high risk for adverse events.

Anticoagulation in Italian patients with venous thromboembolism and thrombophilic alterations: findings from START2 register study.

BACKGROUND: Randomised control trials have assessed the efficacy and safety of direct oral anticoagulants in the prophylaxis and treatment of venous thromboembolism (VTE). Positive but limited results have been reported in patients with inherited thrombophilia. Using an Italian, multicentre, prospective registry of consecutive patients presenting with symptomatic, acute VTE, we aimed to assess which factors are involved in making the choice of the drug that best fits the patient's risk profile in a large real-world setting of VTE patients. MATERIALS AND METHODS: We investigated 4,866 VTE patients who took oral anticoagulants in the period between 2012 and April 2018 to prevent a new thromboembolic episode. RESULTS: The large majority of patients who underwent thrombophilic screening, regardless of the results obtained, were prescribed direct oral anticoagulants rather than conventional anticoagulant therapy (p<0.001). During anticoagulation, bleeding events occurred more frequently in patients on conventional anticoagulant therapy (4.2%) than in those receiving direct oral anticoagulants (1.8%) and an increase in bleeding events was observed in patients who tested positive at the thrombophilic screening. Overall, a higher number of recurrent VTE was observed in patients not screened for thrombophilia (n=36; 1.7%) than in those screened (n=20; 0.7%; adjusted odds ratio: 2.2; 95% confidence interval: 1.2-4.1). DISCUSSION: The present data confirm previous findings from other post-marketing registries and suggest that the choice of oral anticoagulation is strongly driven by patients' characteristics and VTE manifestations. Factors leading to the prescription of thrombophilic screening may identify a patient with a lower risk of VTE recurrence during anticoagulation.

Anticoagulation resumption after intracranial hemorrhage in patients treated with VKA and DOACs.

BACKGROUND: Intracranial hemorrhage (ICH) is associated with severe prognosis and recurrent risk. This impacts on the decision to resume anticoagulation in atrial fibrillation (AF) or venous thromboembolism (VTE) patients. Purpose of our study is to evaluate the incidence rate of recurrent ICH in patients with AF or VTE resuming anticoagulation after a first ICH episode. METHODS: We report data of two cohorts of AF or VTE after a first ICH. The Vitamin K antagonist (VKA) cohort (166 patients) derives from CHIRONE Study, the direct oral anticoagulant (DOAC) cohort (178 patients) derives from START2-Register RESULTS: The clinical characteristics of the two cohort are similar with the exception of more prevalence of history of previous stroke/TIA in DOAC patients with respect to VKA (p = 0.02) and serum creatinine levels>1.5 mg/dL in VKA patients with respect to DOAC(p = 0.0001). The index ICH was spontaneous in 66.4% and in 33.7% among DOAC and VKAs cohort respectively (p = 0.0001). During follow-up, 14 recurrent ICH were recorded; 9 (rate 2.5 × 100 patient-years) in VKA and 5 (rate 1.3 × 100 patient-years) in DOAC (Relative Risk 1.9; 95% CI 0.6-7.4; p = 0.2). The univariate logistic regression analysis showed that patients with recurrent ICH were more frequently males, hypertensive, with a history of previous Stroke/TIA and older than patients without recurrence. VKA patients showed a higher risk of recurrence with respect to DOAC patients (OR 1.9;95% CI 0.7-6.7). CONCLUSIONS: A trend toward fewer ICH recurrences was detected among DOACs patients in comparison to the previously reported rate of patients on warfarin.

Very elderly patients with venous thromboembolism on oral anticoagulation with VKAs or DOACs: Results from the prospective multicenter START2-Register Study.

INTRODUCTION: Few data are available on the safety of anticoagulation in very elderly patients treated with Vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) for venous thromboembolism (VTE). METHODS: We carried out a prospective cohort study on VTE patients aged ≥85 years enrolled in the Survey on anticoagulaTed pAtients RegisTer (START2-Register) on treatment with VKAs or DOACs, with the aim to evaluate mortality, bleeding and thrombotic rates (venous and arterial). RESULTS: We enrolled 272 patients, 58.7% on VKA and 41.3% on DOACs. Baseline characteristics were similar between treatment groups, with a higher prevalence of renal failure in VKAs patients and of a history of bleeding and previous stroke/TIA in DOACs patients. During follow-up of 429 patient-years, 15 major and non-major clinically relevant bleedings were recorded (rate 3.5 × 100 pt-yrs), 5 were major bleeds (rate 1.2 × 100 pt-yrs), 1 in a patient on aspirin (rate 4.3 × 100 pt-yrs). Bleeding rate was higher in patients on DOACs (crude HR 4.7; 95%CI 1.5-15.01). Eight thrombotic events were recorded (rate 1.9 × 100 pt-yrs), 3 recurrent VTE and 5 stroke/TIA. Overall, the incidence of thrombotic events was higher in DOACs patients (crude HR 4.5; 95% CI 1.5; 13.3). The rate of recurrent VTE was similar in the two group. Mortality rate was significantly lower in DOACs patients (crude HR 0.30; 95% CI 0.1;0.9). CONCLUSION: A higher bleeding risk was found in very elderly VTE patients on DOACs despite the wide use of low-dosages. Similarly a higher thrombotic risk was found while the incidence of recurrent VTE was low and similar between the groups. Mortality rate were significantly lower in DOACs patients.

Risk of reoperation in bioprosthetic valve patients with indication for long-term anticoagulation. Results from the observational retrospective multicentre PLECTRUM study.

Objective: Several factors should be considered when a prosthetic heart valve, bioprosthetic valve (BV) or mechanical valve is to be implanted: thrombogenicity, life expectancy and the risk of reoperation. Methods: We conducted an observational retrospective multicentre study among Italian Thrombosis Centers on patients with BV on long-term vitamin K antagonist (VKA) treatment to evaluate the risk of reoperation and the rate of bleeding and thrombotic events. Results: We analysed 612 patients (median age 71.8 years) with BV on long-term VKA treatment for the presence of atrial fibrillation (AF) (78.4%) or other indications (21.6%). Thirty-four major bleeding events (rate 1.1×100 patient-years) and 29 thromboembolic events (rate 0.9×100 patient-years) were recorded, and 46 patients (rate 1.5×100 patient-years) underwent reoperation. The rate of reoperation was higher among younger patients: 32.9% in patients <60 years and 3.9% in patients ≥60 years (relative risk (RR) 3.8, 95% CI 2.1 to 7.2; p=0.0001). When patients were analysed according to age <65 or ≥65 years and <75 or ≥70 years, younger patients still were at higher risk for reoperation (RR 3.1, 95% CI 1.7 to 6.0 and 3.7, 95% CI 1.7 to 8.6, respectively). Conclusions: Our findings suggest that the threshold of 65 years for implanting a BV should be carefully evaluated, considering the high risk for reoperation and the high risk of AF occurrence with persisting need for long-term anticoagulation. The high risk for reoperation of young patients implanted with BV and the availability of a safer and easier way to conduct VKA treatment, such as the use of point-of-care devices, should be considered when the type of valve must be chosen.

MYH9 related disease: four novel mutations of the tail domain of myosin-9 correlating with a mild clinical phenotype.

MYH9-related disease (MYH9-RD) is a rare autosomal dominant disorder caused by mutations in MYH9, the gene encoding the heavy chain of non-muscle myosin IIA. All patients present congenital macrothrombocytopenia and inclusion bodies in neutrophils. Some of them can also develop sensorineural deafness, presenile cataract, and/or progressive nephropathy leading to end-stage renal failure. We report four families, each with a novel mutation: two missense mutations, in exons 31 and 32, and two out of frame deletions in exon 40. They were associated with no bleeding diathesis, normal, or only slightly reduced platelet count and no extra-hematological manifestations, confirming that alterations of the tail domain cause a mild form of MYH9-RD with no clinically relevant defects.