Comparative non-persistence in the first year of treatment with oral anticoagulants in patients with atrial fibrillation: A French comprehensive nationwide study.

BACKGROUND: Direct oral anticoagulants (DOACs) were developed as an alternative to vitamin K antagonists (VKAs) and are commonly used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Unlike VKAs, DOACs do not require Internal Normalized Ratio (INR) monitoring, but regular intake is as important for effective anticoagulation. OBJECTIVES: This study examined treatment persistence among patients receiving oral anticoagulants (OACs) for NVAF. METHODS: Within the French healthcare claims database (SNDS), we assessed and compared the rates of non-persistence (≥ 30-day treatment gap) among patients with NVAF initiating an OAC between January 2014 and December 2016. The time-to-event of non-persistence was computed and plotted using a cumulative incidence function accounting for the competing risk of mortality. After adjusting on confounding factors, the risk for non-persistence was compared between apixaban and each other OACs using a Cox proportional hazard model, or Fine and Gray models. RESULTS: In a cohort of 321,501 OAC-naive patients with NVAF, the cumulative incidence of non-persistence at 12 months considering competing risk was 44.3%, 31.0%, 41.3% and 46.8% for VKAs, apixaban, rivaroxaban and dabigatran, respectively. Median therapy duration before non-persistence ranged between 70 and 121 days. Non-persistence was lower with apixaban compared with VKAs (HR=0.63, 95%CI=[0.62-0.64]), rivaroxaban (HR=0.71, 95%CI=[0.70-0.73]), and dabigatran (HR=0.60, 95%CI=[0.59-0.62]). CONCLUSIONS: In this nationwide observational study, non-persistence rates of oral anticoagulant treatment were high in patients treated for NVAF. Apixaban-treated patients seem to experience lowest discontinuation rates 12 months after treatment initiation compared to patients treated with any other OAC.

Extended Anticoagulant Treatment with Full- or Reduced-Dose Apixaban in Patients with Cancer-Associated Venous Thromboembolism: Rationale and Design of the API-CAT Study.

Cancer-associated thrombosis (CT) is associated with a high risk of recurrent venous thromboembolic (VTE) events that require extended anticoagulation in patients with active cancer, putting them at risk of bleeding. The aim of the API-CAT study (NCT03692065) is to assess whether a reduced-dose regimen of apixaban (2.5 mg twice daily [bid]) is noninferior to a full-dose regimen of apixaban (5 mg bid) for the prevention of recurrent VTE in patients with active cancer who have completed ≥6 months of anticoagulant therapy for a documented index event of proximal deep-vein thrombosis and/or pulmonary embolism. API-CAT is an international, randomized, parallel-group, double-blind, noninferiority trial with blinded adjudication of outcome events. Consecutive patients are randomized to receive apixaban 2.5 or 5 mg bid for 12 months. The primary efficacy outcome is a composite of recurrent symptomatic or incidental VTE during the treatment period. The principal safety endpoint is clinically relevant bleeding, defined as a composite of major bleeding or nonmajor clinically relevant bleeding. Assuming a 12-month incidence of the primary outcome of 4% with apixaban and an upper limit of the two-sided 95% confidence interval of the hazard ratio <2.0, 1,722 patients will be randomized, assuming an up to 10% loss in total patient-years (ß = 80%; α one-sided = 0.025). This trial has the potential to demonstrate that a regimen of extended treatment for patients with CT beyond an initial 6 months, with a reduced apixaban dose, has an acceptable risk of recurrent VTE recurrence and decreases the risk of bleeding.

Comparative Safety and Effectiveness of Oral Anticoagulants in Nonvalvular Atrial Fibrillation: The NAXOS Study.

BACKGROUND AND PURPOSE: The effects of direct oral anticoagulants in nonvalvular atrial fibrillation should be assessed in actual conditions of use. France has near-universal healthcare coverage with a unified healthcare information system, allowing large population-based analyses. NAXOS (Evaluation of Apixaban in Stroke and Systemic Embolism Prevention in Patients With Nonvalvular Atrial Fibrillation) aimed to compare the safety, effectiveness, and mortality of apixaban with vitamin K antagonists (VKAs), rivaroxaban, and dabigatran, in oral anticoagulant-naive patients with nonvalvular atrial fibrillation. METHODS: This was an observational study using French National Health System claims data and including all adults with nonvalvular atrial fibrillation who initiated oral anticoagulant between 2014 and 2016. Outcomes of interest were major bleeding events leading to hospitalization (safety), stroke and systemic thromboembolic events (effectiveness), and all-cause mortality. Four approaches were used for comparative analyses: matching on propensity score (PS; 1:n); as a sensitivity analysis, matching on high-dimensional PS; adjustment on PS; and adjustment on known confounders. For each outcome, cumulative incidence rates accounting for competing risks of death were estimated. RESULTS: Overall, 321 501 patients were analyzed, of whom 35.0%, 27.2%, 31.1%, and 6.6% initiated VKAs, apixaban, rivaroxaban, and dabigatran, respectively. Apixaban was associated with a lower PS-matched risk of major bleeding compared with VKAs (hazard ratio [HR], 0.43 [95% CI, 0.40-0.46]) and rivaroxaban (HR, 0.67 [95% CI, 0.63-0.72]), but not dabigatran (HR, 0.93 [95% CI, 0.81-1.08]). Apixaban was associated with a lower risk of stroke and systemic thromboembolic event compared with VKAs (HR, 0.60 [95% CI, 0.56-0.65]), but not rivaroxaban (HR, 1.05 [95% CI, 0.97-1.15]) or dabigatran (HR, 0.93 [95% CI, 0.78-1.11]). All-cause mortality was lower with apixaban than with VKAs, but not lower than with rivaroxaban or dabigatran. CONCLUSIONS: Apixaban was associated with superior safety, effectiveness, and lower mortality than VKAs; with superior safety than rivaroxaban and similar safety to dabigatran; and with similar effectiveness when compared with rivaroxaban or dabigatran. These observational data suggest potentially important differences in outcomes between direct oral anticoagulants, which should be explored in randomized trials.

Life-Threatening Hypercalcemia Revealing Diffuse and Isolated Acute Sarcoid-Like Myositis: A New Entity? (A Case-Series).

Up to 50% patients with sarcoidosis display extra-pulmonary disease. However, initial and isolated (ie, without lung disease) acute muscular involvement associated with pseudo-malignant hypercalcemia is very uncommon. We report on 3 cases of life-threatening hypercalcemia revealing florid and isolated acute sarcoid-like myositis.All patients complained of fatigue, progressive general muscle weakness, and weight loss. Laboratory tests showed a severe life-threatening hypercalcemia (>3.4 mmol/L). Hypercalcemia was associated with increased serum level of 1,25-(OH)2 vitamin D and complicated with acute renal failure. One patient displayed acute pancreatitis due to hypercalcemia.In all cases, PET-scan, performed for malignancy screening, incidentally revealed an intense, diffuse, and isolated muscular fluorodeoxyglucose (FDG) uptake consistent with diffuse non-necrotizing giant cells granulomatous myositis demonstrated by muscle biopsy. Of note, creatine phosphokinase blood level was normal in all cases. No patients displayed the usual thoracic features of sarcoidosis.All patients were treated with high dose steroids and achieved rapid, complete, and sustained remission. A review of English and French publications in Medline revealed 5 similar published cases.Steroid-sensitive acute sarcoid-like myositis causing high calcitriol levels and life-threatening hypercalcemia should be recognized as a separate entity.

Efficacy and safety of three ophthalmic inserts for topical anaesthesia of the cornea. An exploratory comparative dose-ranging, double-blind, randomized trial in healthy volunteers.

BACKGROUND: Cataract surgery requires prolonged anaesthesia, concomitant with permanent hydration and lubrication of the cornea, in order to provide a clear view of the operation area. AIMS: The primary objective of the study was to assess several formulae of a soluble ophthalmic insert: TOPICSERT [bupivacaine (Bupi) + hyaluronic acid (HA) or sodium hyaluronate] in terms of complete and long-lasting anaesthesia of the cornea. The hydration properties of HA were not assessed in this study. METHODS: In a prospective double-blind, cross-over, randomized study, with latin-square allocation of treatments, 16 healthy volunteers received a single dose of each formula (A, 1 mg Bupi and 0.1 mg HA; B, 0.5 mg Bupi and 0.1 mg HA; C, 1 mg Bupi and 0 mg HA, and D acting as a placebo) via the ocular route with 1 week of wash-out between each period. Corneal anaesthesia was measured using a Cochet-Bonnet esthesiometer. RESULTS: There was a statistically significant difference between treatments with regard to the main criterion (complete anaesthesia lasting at least 20 min) when general association statistics were used (Mantel-Haenzel test, P < 0.0001): 68.75% (n = 11) of subjects receiving treatment A, 37.5% (n = 6) receiving treatment B, and 87.5% (n = 14) on treatment C reached complete and satisfactory anaesthesia, while this was not achieved in any of the subjects receiving placebo. Ninety-five percent confidence intervals of the difference between treatments were as follows: treatment A vs. B (-0.03, 0.66), treatment A vs. C (-0.47, 0.10), treatment B vs. C (-0.84, - 0.16). Only the difference between B and C was statistically significant (adjusted probability by the method of Bonferroni, P < 0.001). When complete anaesthesia was reached, mean (+/-SD) duration of anaesthesia was as follows: 20.7 (+/-6.5), 15.3 (+/-11.4) and 24.7 (+/-7.6) min for treatments A, B, C, respectively. CONCLUSIONS: Bupivacaine 1 mg seems to be the efficient and safe dose. The value of hyaluronic acid as a corneal hydration agent and used in association with bupivacaine will be the subject of further studies.

Effects of the addition of high-dose vitamin C to polyethylene glycol solution for colonic cleansing: A pilot study in healthy volunteers.

BACKGROUND: Polyethylene glycol (PEG) solutions, with or without osmotic agents, are used to empty the large intestine before procedures such as colonoscopy or colonic surgery. Data concerning the effectiveness of vitamin C as an ingredient in colonic preparations are scant. OBJECTIVE: The aim of this article was to assess the effectiveness, acceptability, and tolerability of 6 preparations of a standard PEG electrolyte solution containing different doses of PEG, vitamin C (as an osmotic agent), and sodium sulfate in colonic cleansing. METHODS: This double-blind, randomized, 2-period crossover study was conducted at the Lariboisière Hospital, Paris, France. Healthy adult volunteers were randomly assigned to receive 2 of 6 colonic cleansing preparations, each containing different doses of PEG (100 or 125 g/L), vitamin C (0, 5, or 10 g/L, in the form of sodium ascorbate, ascorbic acid, or a mixture of both), and sodium sulfate (5 or 7.5 g/L), diluted in water to a volume of 2 L. Study drug administration was separated by a washout period of 7 to 15 days, after which the volunteers received an alternate preparation. Stools were collected for 10 hours after the start of solution ingestion. The primary efficacy end point was stool volume. Secondary end points included acceptability of taste, assessed using a 100-mm visual analog scale (VAS) (0 = excellent to 100 = execrable), taste criteria (saltiness, acidity, and sweetness, assessed on a 4-point Likert-type scale [0 = very pleasant to 3 = intolerable]) and tolerability (clinical effects [changes in body weight, blood pressure, heart rate, and nausea and vomiting] and biologic effects [changes in serum electrolytes, creatinine, hematocrit, and ascorbic acid]). RESULTS: Thirty volunteers (15 men, 15 women; mean [SD] age, 29.8 [8.2] years [range, 20-45 years]) were enrolled and completed the study. Mean (SD) stool volume obtained with preparations containing 10 g/L of vitamin C did not differ significantly from the volume obtained without vitamin C (2.54 [0.54] L vs 1.93 [0.62] L; 95% CI, -0.13 to 1.47). Mean (SD) VAS scores for acceptability of taste ranged from 54.4 (25.0) (preparation E) to 74.4 (20.1) (preparation C) (P = 0.03 preparation E vs all other preparations). The only significant difference in taste criteria was in acidity, with preparation A being the least acidic according to patients' ratings on the VAS (1.4 [0.7] vs 1.8 [0.4] [mean of the other 5 preparations combined]; P = 0.04 preparation A vs all other preparations). Mild dehydration occurred in 6 subjects (1 for each preparation). No clinical or biological adverse effects were found. CONCLUSIONS: In this study of 6 colonic cleansing preparations in healthy volunteers, the use of high-dose vitamin C as an osmotic agent in addition to PEG did not significantly increase stool output. All 6 preparations were well tolerated.