A 70-year old woman with hypertension, diabetes, nonischemic stroke, moderate renal insufficiency (creatinine clearance [CrCl] 45 mL/min), heart failure, and nonvalvular atrial fibrillation (AF) on warfarin is admitted because of a very supratherapeutic INR. She reports labile INR values despite strict adherence to her medication regimen. Her cancer screening tests had previously been unremarkable. She inquires about the risks and benefits of switching to a novel oral anticoagulant (NOAC) as advertised on television. Should you consider it while she is still in the hospital?
Brief overview of the issue
Lifelong anticoagulation therapy is common among patients with AF or recurrent venous thromboembolism (VTE). Until the advent of NOACs, a great majority of patients were prescribed warfarin, the oral vitamin K antagonist that requires regular blood tests for monitoring of the INR. In contrast to warfarin, NOACs are direct-acting agents (hence also known as “direct oral anticoagulants” or DOACs) that are selective for one specific coagulation factor, either thrombin (e.g., dabigatran) or factor Xa (e.g., rivaroxaban, apixaban, and edoxaban, all with an “X” in their names).
NOACS have been studied and approved by the Food and Drug Administration for nonvalvular AF, i.e., patients without rheumatic mitral stenosis, mechanical or bioprosthetic heart valve, or prior mitral valve repair. Compared to warfarin, NOACS have fewer drug or food interactions, have more predictable pharmacokinetics, and may be associated with reduced risk of major bleeding depending on the agent. The latter is a particularly attractive feature of NOAC therapy, especially when its use is considered among older patients at risk of intracranial hemorrhage (ICH), such as those with previous strokes, ICH, or reduced renal function. Unfortunately, data on the efficacy and safety of the use of NOACs in certain patient populations (e.g., those with severe renal insufficiency, active malignancy, the elderly, patients with suboptimal medication adherence) are generally lacking.
Overview of the data
There are no randomized controlled trials (RCTs) addressing the clinical benefits of switching from warfarin to NOAC therapy. However, based on a number of RCTs comparing warfarin to individual NOACs and their related meta-analyses, the following conclusions may be made about their attributes:
1. Noninferiority to warfarin in reducing the risk of ischemic stroke in AF.
2. Association with a lower rate of major bleeds (statistically significant or trend) and a lower rate of ICH and hemorrhagic strokes compared to warfarin.
3. Association with a higher rate of gastrointestinal bleeding compared to warfarin (except for apixaban, low-dose dabigatran, and edoxaban1).
4. Association with a decreased rate of all stroke and thromboembolism events compared to warfarin.
5. Association with a slightly decreased all-cause mortality in AF compared to warfarin in many studies,2-8 but not all.1,9
6. Noninferiority to warfarin in all-cause mortality in patients with VTE and for its secondary prevention.1,4
NOACS should be used with caution or avoided altogether in patients with severe liver disease or renal insufficiency (see Table 1).
Potential advantages and disadvantages of NOAC therapy are listed in Table 2.
It should be emphasized that in patients with cancer or hypercoagulable state, no clear efficacy or safety data are currently available for the use of NOACs.
The 2016 CHEST guideline on antithrombotic therapy for VTE recommends NOACs over warfarin.10 The 2012 European Society of Cardiology AF guidelines also recommend NOACs over warfarin.11 However, the 2014 American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines on AF state that it is not necessary to change to a NOAC when patients are “stable, easily controlled, and satisfied with warfarin therapy.”12
Data from a relatively small, short-term study examining the safety of switching patients from warfarin to a NOAC suggest that although bleeding events are relatively common (12%) following such a switch, major bleeding and cardiac or cerebrovascular events are rare.10