Direct Oral Anticoagulants for the Prevention and Acute Treatment of Cancer-Associated Thrombosis.

Cancer is a major risk factor for venous thromboembolism (VTE), and cancer-associated thrombosis (CAT) constitutes approximately 15-25% of all VTE cases. For decades, the standard treatment for CAT used to be daily subcutaneous low molecular weight heparin (LMWH). Data on the safety and efficacy of the direct oral anticoagulants (DOACs) in this population emerged only in recent years and specific DOACs were included into recent guidelines recommendations. In this narrative review of the literature, we reported the results of the phase III randomized controlled trials that evaluated the DOACs for the prevention and the acute treatment of CAT. For the acute phase treatment, the anti-Xa inhibitors (apixaban, edoxaban, rivaroxaban) showed better efficacy than LMWH in preventing VTE recurrence; however, rivaroxaban and edoxaban were also associated with an increased risk of bleeding events. For primary prevention of CAT in ambulatory cancer patients starting chemotherapy, apixaban and rivaroxaban showed better efficacy than placebo but a trend towards higher bleeding rates. Recent guidelines suggest the DOACs for the treatment of CAT in selected cancer patients (eg, low bleeding risk, no luminal gastrointestinal or genitourinary malignancies, no interfering medications). The DOACs are also suggested for primary thromboprophylaxis in selected ambulatory cancer patients at high risk of VTE (eg, Khorana score ≥2 prior to starting new chemotherapy, low bleeding risk, no interfering medications).

Rivaroxaban for the treatment of noncirrhotic splanchnic vein thrombosis: an interventional prospective cohort study.

Heparins and vitamin K antagonists are the mainstay of treatment of splanchnic vein thrombosis (SVT). Rivaroxaban is a potential alternative, but data to support its use are limited. We aimed to evaluate the safety and efficacy of rivaroxaban for the treatment of acute SVT. In an international, single-arm clinical trial, adult patients with a first episode of noncirrhotic, symptomatic, objectively diagnosed SVT received rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg daily for an intended duration of 3 months. Patients with Budd-Chiari syndrome and those receiving full-dose anticoagulation for >7 days prior to enrollment were excluded. Primary outcome was major bleeding; secondary outcomes included death, recurrent SVT, and complete vein recanalization within 3 months. Patients were followed for a total of 6 months. A total of 103 patients were enrolled; 100 were eligible for the analysis. Mean age was 54.4 years; 64% were men. SVT risk factors included abdominal inflammation/infection (28%), solid cancer (9%), myeloproliferative neoplasms (9%), and hormonal therapy (9%); 43% of cases were unprovoked. JAK2 V617F mutation was detected in 26% of 50 tested patients. At 3 months, 2 patients (2.1%; 95% confidence interval, 0.6-7.2) had major bleeding events (both gastrointestinal). One (1.0%) patient died due to a non-SVT-related cause, 2 had recurrent SVT (2.1%). Complete recanalization was documented in 47.3% of patients. One additional major bleeding event and 1 recurrent SVT occurred at 6 months. Rivaroxaban appears as a potential alternative to standard anticoagulation for the treatment of SVT in non-cirrhotic patients. This trial was registered at www.clinicaltrials.gov as #NCT02627053 and at eudract.ema.europa.eu as #2014-005162-29-36.

Which is the optimal antihypertensive combination in different diseases, a renin- angiotensin-aldosterone system inhibitor with a diuretic or with a calcium channel blocker?

Successful treatment of hypertension often requires the association of drugs from different classes. Combination therapy takes advantage of complementary mechanisms of action, in order to reach target blood pressure (BP) earlier and to minimize the side effects of medications. In the last decade, several randomized trials have demonstrated the efficacy of combining a renin-angiotensin-aldosterone system (RAAS) inhibitor with a calcium channel blocker (CCB) or with a diuretic in different populations. The ACCOMPLISH trial was the only large clinical trial that directly compared the two combination strategies. In hypertensive individuals at high cardiovascular risk, benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing the primary composite endpoint of cardiovascular events plus death from cardiovascular causes. Small randomized trials have evaluated the two combination therapies in surrogate endpoints, such as microalbuminuria, with contrasting results. Current European and American guidelines recommend combination therapy as first-line when BP is at least 20/10 mmHg above treatment goals. However, the choice of the best combination therapy is still debated: the National Institute for Health and Clinical Excellence guidelines recommend a RAAS inhibitor plus a CCB, while the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines underline the pivotal role of thiazide diuretics. The combination of a RAAS inhibitor with a CCB demonstrated the best efficacy in reducing cardiovascular endpoint. However, the combination of a RAAS inhibitor with a diuretic has shown beneficial results in particular subgroup of patients, such as patients with heart failure or with African American origin. This review will focus on the rationale and current evidences about combination therapy in the management of arterial hypertension.

Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature.

BACKGROUND: Novel oral anticoagulants (NOACs) have been proposed as alternatives to vitamin K antagonists for the prevention of stroke and systemic embolism in patients with atrial fibrillation. Individually, NOACs were at least noninferior to vitamin K antagonists, but a clear superiority in overall and vascular mortality was not consistently proven. METHODS AND RESULTS: We performed a meta-analysis of phase II and phase III randomized, controlled trials comparing NOACs with vitamin K antagonists in patients with atrial fibrillation. The MEDLINE and EMBASE databases, supplemented with conference abstract books and www.clinicaltrials.gov, were searched up to the first week of July 2012 with no language restriction. Two reviewers performed independent article review and study quality assessment. Data on overall and cardiovascular mortality, stroke or systemic embolism, ischemic stroke, major and intracranial bleeding, and myocardial infarction were collected. NOACs were pooled to perform a comparison with vitamin K antagonists, calculating pooled relative risks (RRs) and associated 95% confidence intervals (CIs). We retrieved 12 studies (3 administering dabigatran, 4 administering rivaroxaban, 2 administering apixaban, and 3 administering edoxaban) enrolling a total of 54 875 patients. NOACs significantly reduced total mortality (5.61% versus 6.02%; RR, 0.89; 95% CI, 0.83-0.96), cardiovascular mortality (3.45% versus 3.65%; RR, 0.89; 95% CI, 0.82-0.98), and stroke/systemic embolism (2.40% versus 3.13%; RR, 0.77; 95% CI, 0.70-0.86). There was a trend toward reduced major bleeding (RR, 0.86; 95% CI, 0.72-1.02) with a significant reduction of intracranial hemorrhage (RR, 0.46; 95% CI, 0.39-0.56). No difference in myocardial infarction was observed. CONCLUSIONS: NOACs are associated with an overall clinical benefit compared with vitamin K antagonists. Additional research is required to confirm these findings outside the context of randomized trials.

A new era for anticoagulation in atrial fibrillation. Which anticoagulant should we choose for long­term prevention of thromboembolic complications in patients with atrial fibrillation?

For more than 60 years, vitamin K antagonists have been the only available oral anticoagulants for the prevention of stroke and systemic embolism in atrial fibrillation (AF). Several new molecules, with a favorable pharmacokinetic profile and avoiding routine monitoring, have been recently developed, opening a new era in anticoagulation. The oral direct thrombin inhibitor, dabigatran, and the oral activated factor X inhibitors, rivaroxaban and apixaban, are the novel oral anticoagulants with data from large randomized clinical trials showing that these drugs are noninferior to warfarin in the prevention of stroke and thromboembolic complications of AF, with the advantage of less hemorrhagic stroke and intracranial bleeding. While these trial data are extremely encouraging, several practical issues (e.g., lack of specific antidote, safety of long-term treatment or cost-effectiveness in "real-life" clinical practice) still need to be elucidated.