VTE Therapy and Prevention

The use of NOACs expanded quickly into treatment and prophylaxis for recurrent VTE and prophylaxis of VTE following hip and knee replacement surgery. The dosing for this indication is different from the dosing for AF. Patients receive an initial loading dose and then a reduced dose for the remainder of treatment (Table 3).8-11 The duration of treatment is based on risk and maybe lifelong in high-risk individuals.8-11,17

Table 3. Dosing for Acute, Recurrent, or Prophylaxis of VTE Following Hip or Knee Replacement Surgery8-11

Apixaban• VTE: 10 mg bid for 7 days, then 5 mg bid
• Prophylaxis for recurrent VTE: 2.5 mg bid
• Prophylaxis of DVT/PE after hip or knee replacement surgery: 2.5 mg bid
Dabigatran• VTE: 150 mg bid for patients with CrCl >30 mL/min after 5 to 10 days of parenteral anticoagulation
• Prophylaxis for recurrent VTE for patients with CrCl >30 mL/min: 150 mg daily
• Prophylaxis of VTE after hip replacement surgery for patients with CrCl >30 mL/min: 110 mg on day 1, then 220 mg once daily
Edoxaban• VTE: 60 mg/d after receiving 5-10 days of parenteral anticoagulation
• Reduce to 30 mg once daily in patients with CrCL 15 to 50 mL/min, who weigh ≤60 kg, or who are taking certain concomitant P-gp inhibitors
• Not indicated for VTE prophylaxis surrounding knee or hip surgery
Rivaroxaban• VTE: 15 mg bid for 21 days, then 20 mg once daily with food
• Prophylaxis for recurrent VTE: 10 mg/d
• VTE prophylaxis after hip replacement surgery: 10 mg for 35 days, or 10 mg for 12 days for knee replacement surgery
CrCL, creatinine clearance; PE, pulmonary embolism; VTE, venous thromboembolism

The MAGELLAN Study assessed the effectiveness and safety of initiating rivaroxaban during hospitalization and prescribed through a posthospital discharge period for VTE prevention in acutely ill medical patients.  In the study, rivaroxaban 10 mg/d for 35 days (±4 days) was compared with enoxaparin 40 mg per day for 10 days (±4 days) followed by placebo.18 The researchers found that rivaroxaban reduced the risk of VTE in patients but was associated with an increase in bleeding risk. 

In a follow-up study, researchers identified 5 key risk factors for major bleeding from the original MAGELLAN analysis that allowed the investigators to exclude specific subpopulations. These risk factors included active cancer at randomization, dual antiplatelet therapy at baseline, a medical history of bronchiectasis/pulmonary cavitation, active gastroduodenal ulcer, or any bleeding in the previous 3 months prior to randomization. With this exclusion of approximately 20% of the entire MAGELLAN study population due to their high-risk factor profile, rivaroxaban demonstrated a favorable benefit-risk profile for in-hospital and extended thromboprophylaxis.19

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Acute Coronary Syndromes and Coronary Artery Disease

Rivaroxaban is indicated to prevent cardiac events in patients who have known CAD.9 The dosing for this indication is much lower for other indications and has been shown to reduce recurrent myocardial infarction (MI) in patients with known CAD.20

Although warfarin has demonstrated benefit in chronic coronary disease for the prevention of events, it also is associated with a greater incidence of significant bleeding and can be challenging to maintain therapeutic blood levels. Vitamin K antagonist use imposes limitations to patients such as dietary and medication restrictions that can lead to noncompliance. 

With factor Xa inhibitors, increasing clinical data supports their use as an essential part of the preventive armament for CAD.  The factor Xa inhibitors have more specific inhibition of coagulation proteins with similar, if not improved, efficacy over warfarin with lower bleeding rates.20 Factor Xa inhibitors are now part of our treatment for secondary prevention for CAD. Clinical trials for stable CAD patients with the ongoing use of DAPT proved inconsistent.  While they are effective in the acute scenario and lifesaving in the initial 1-year postevent prophylaxis, the antiplatelet clopidogrel added to aspirin in stable CAD showed no significant reduction in vascular and ischemic events. Another clinical trial that utilized the antiplatelet ticagrelor with aspirin showed that this combination demonstrated a decrease in major vascular events but had increased major bleeding events.21 

This data then prompted researchers to consider antithrombotic/antiplatelet combinations for ACS and continued therapy in stable coronary disease patients. Two NOACs have shown efficacy in patients with ACS, CAD, and PAD; apixaban and rivaroxaban (Table 4).22-25 At this time, only rivaroxaban has completed phase 3 clinical trial testing and met its primary endpoint.20,26

Table 4. Clinical Trial Data on NOACs for Acute Coronary Syndromes and Coronary Artery Disease22-25

NOACClinical TrialStrategyResultDosing
ApixabanAPPRAISE-222Compared apixaban 5 mg bid to DAPT in those with ACSFound to have no effect after ACS and had increased bleeding5 mg
RivaroxabanACS 2TIMI 51-5223In patients with ACS requiring DAPT, studied reduced dosing of rivaroxabanPositive outcomes with effective reduction in vascular events2.5 mg bid
RivaroxabanCOMPASS24,25Primary outcome: first occurrence of stroke/MI/cardiovascular death Secondary outcomes: reduction in CAD deaths/ischemic CVA/acute limb ischemia/MI/fatal bleedingRivaroxaban and low-dose aspirin demonstrated decreased cardiovascular events by 26%,  CVA by 44%, and overall mortality by 23%2.5 mg bid
ACS, acute coronary syndrome; CAD, coronary artery disease; CVA, cerebrovascular accident; DAPT, dual antiplatelet therapy; MI, myocardial infarction