Two recent studies suggest that NOACs promise better prophylaxis when compared to heparin standard use. On the other hand, the risk of bleeding is higher among NOACs. At a state-of-the-art symposium at GTH in Vienna, Prof. Dr. Anne Angelillo-Scherrer, University Clinic of Hematology and Central Hematology Laboratory Bern, presented which patients might be eligible for NOACs.
The hematologist conducting this research used three practical cases. A 55-year-old man with metastatic lung cancer undergoing chemotherapy and with no renal or hepatic dysfunction. The plates were placed at 120G/l, normal PT, aPTT, fibrinogen 4.5 g/L. He had been recently diagnosed with proximal venous thrombosis in his right leg. A 25-year-old woman with Acute Lymphoblastic Leukemia (ALL) and Deep Vein Thrombosis (DVT) in her left leg. Complete Blood Count (CBC) readings were: Hb 80 g/L, leukocytes 41 G/L (75% blisters), platelets 55 G/L. No kidney and no liver dysfunction. Finally, the last case pertained a 45-year-old man with stage IIIB gastric cancer undergoing chemotherapy. His CBC stood at Hb 120 g/L, 100 G/L platelets, creatinine clearance 30 mL/min, diagnosed with pulmonary embolism. Which substance is suitable for initial and long-term anticoagulation in these patients?
Cancer is a strong risk factor for Venous ThromboEmbolism (VTE), as Chen's work in Archives of Internal Medicine, 2006 shows. Two years after diagnosis, the risk of VTE in pancreatic cancer is greatly increased. Bleeding complications occurred in 10% of patients with solid tumors and to an even higher extent in patients with malignant hematological diseases.
The guidelines for the treatment of cancer-associated VTE recommend low molecular weight heparin for initial therapy and maintenance therapy, including the extended maintenance phase.
However, a network meta-analysis (Posch et al., Thrombosis Research, 2015) shows that small molecule heparin and Novel Oral Anticoagulants (NOACs, also known as directly acting oral anticoagulants or DOACs) are comparable in the prevention of recurrent VTEs and also in the risk for major bleedings.
Several studies compare NOACs and small molecule heparin for VTE prevention in cancer patients. HOKUSAI VTE Cancer (Raskob et al. NEJM, 2018) and SELECT-D (Young et al. ASH Meeting 2017) are completed, CARAVAGGIO (apixaban vs. low molecular weight heparin) and CANVAS (NOACs vs. low molecular weight heparin with and without warfarin) are still ongoing.
SELECT-D compares rivaroxaban with dalteparin (n=406) in cancer patients. The majority of the subjects suffer from colorectal, lung and breast cancer. The rate of recurrent VTEs is 11% for dalteparin and 4% for rivaroxaban. However, rivaroxaban increases the number of bleedings: Major bleedings are 11 vs.6, with a clinically relevant bleeding ratio of 25 to 6.
HOKUSAI VTE Cancer tests low molecular weight heparin ≥ 5 days followed by edoxaban 60 mg daily against Dalteparin (200 U/d) for 1 month, then 150 U/d on 522 patients. Study duration is 12 months. It was found that Edoxaban is not inferior to Dalteparin: 12.8% vs. 13.5%, HR: 0.97. The rate of recurrent VTEs was numerically lower under Edoxaban than under Dalteparin: 7.9% vs. However, the rate of major bleedings under edoxaban was significantly increased: 6.9% vs. 4.0%, mainly gastrointestinal bleeding.
Prof. Dr. Angelillo-Scherrer would treat patient 1 with edoxaban, provided the patient is aware of and agrees with the increased risk of bleeding. Patient 2 could undergo NOAC because there are no liver and kidney restrictions. The vascular physician recommended halving the dose of low-molecular-weight heparin. Due to gastrointestinal (GI) bleeding and the Glomerular Filtration Rate (GFR) rate, NOAC is out of the question in these patients. Anticoagulation with low molecular weight heparin would be safest, but it would be wrong to give only half a dose for these cases. Prof. Dr. Angelillo-Scherrer proposed that there should be a careful evaluation of the following:
Prof. Dr. Thomas Gary from the Angiology Department of the University Hospital Graz presented reversal strategies for NOACs. At present, three strategies have been developed so far:
Idarucizumab is a monoclonal human Fab fragment that binds dabigatran with an affinity 350 times higher than thrombin. It is given as 2 iv bolus of 2.5 g, each given within 5 to 10 minutes.
In the REVERSE AD study, 8/503 patients received more than 5g idarucizumab, thrombotic events occurred in 4.8%, and three patients died from a stroke, according to vascular reports.
Andexanet was developed as an antagonist for the elimination of Factor Xa inhibitors. It is a factor X fragment that carries a binding site for inhibitors and thus represents a competitive substrate for the anticoagulant. Higher doses are required to reverse rivaroxaban or edoxaban than for apixaban.
The dose for apixaban reversal stands at 400mg bolus followed by an infusion of 4mg/min over two hours while the dose for rivaroxaban reversal stands at 800mg bolus followed by an infusion of 8mg/min over two hours.
The inorganic synthetic molecule Ciraparantag is a kind of all-purpose weapon. It eliminates the effects of direct Factor Xa inhibitors and Factor II (thrombin) inhibitors as well as unfractionated heparin and low molecular weight heparins. However, a broad-spectrum antidote is ineffective against vitamin K antagonists. A single dose of Ciraparantag (100-300mg) for 10 to 30 min reverses the anticoagulative effect of Edoxaban within 10 min.
There is currently a gap in the reversal of Factor Xa inhibitors (Andexanet is still under evaluation and Ciraparantag is still under development). To fill this gap, a Prothrombin Complex Concentrate (PCC) is usually administered. FEIBA, on the other hand, is only recommended as an exit strategy if a bleeding stop cannot be achieved by administering PCC.
Prof. Dr. Gary recommended the following procedures for managing bleeding:
It was indicated that FEIBA (50 IU/kg) or recombinant FActor VLLa (90 µg/kg) were found to stop bleeding.
State-of-the-Art: Critical aspects in the use of DOACs, Thursday, February 22, 2018, GTH Vienna
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