C. Richard Conti, MD, MACC

Introduction

Naccarelli et al. review the field of stroke prevention in atrial fibrillation and emphasizes the point that a large number of patients are not anticoagulated [1].In numerous trials, NOACS have been shown to be better than Warfarin in reducing intra cranial hemorrhage and hemorrhagic stroke in patients with non-valve atrial fibrilation [2]. But it is important to point out that the absolute risk reduction is small.As far as I can tell, no trial has compared NOACS to placebo. Whereas warfarin has been compared to placebo and has been shown to be markedly effective as an anticoagulant to prevent stroke.

Food, Drug and Renal Interactions

There are a lot of drug and food interactions with warfarin and fewer with the NOACS. Any food containing vitamin K will ameliorate the anticoagulant effect of warfarin, which can be measured by the international normalized ratio (INR) level. Apparently verapamil and amiodarone will enhance the levels of NOACS which at this time cannot be measured.

Chronic Kidney disease (CKD) impairs the excretion of NOACS and therefore the dose of NOAC in patients requiring anticoagulation who have chronic kidney disease must be decreased and based on the creatinine clearance [3].

Anticoagulation and Compliance Issues

One of the issues that is not usually mentioned relating to the use of NOACS is the fact that patients who fail to comply with the recommended dosing e.g. miss a day, may get un-anticoagulated rather rapidly and as a result may develop thrombosis.This is in contrast to patients receiving warfarin which takes several days to be eliminated from the patient’s system after stopping the drug.

Current Recommendations for NOAC Use

Current indications for direct thrombin inhibitors and direct factor Xa inhibitors (NOACS) include prevention and treatment of venous thromboembolism (VTE) and treatment of non-valvar atrial fibrillation (AF). NOACS are not indicated in any other serious condition in which thrombosis may occur.e.g. patients with valvar heart disease or who have a mechanical valve replacement.

Patient and Physician Annoyance

Patients and physicians seem to be annoyed by the fact that the anti-coagulant effect of warfarin needs to be measured frequently, particularly if the INR is not stable. Why this is the case is not entirely clear to me since measurement of effective anticoagulation seems like the right thing to do.

Concerns About Randomized Clinical Trials

I am very much in favor of randomized clinical trials but to be honest, I like them paired with registry data.Therefore I feel compelled to point out that clinical trials have shown that compared with warfarin the NOACS reduce mortality in the population enrolled in the clinical trials [4]. I have no argument with that fact. Unfortunately, patients enrolled in clinical trials may not be the same as the typical patient that is rejected from enrollment in a clinical trial but may be included in registry data. e.g. elderly patients,patients with a history of stroke, renal dysfunction,pregnant women, children, and those with valvar heart disease. Many (maybe not all) of these latter patients can be given warfarin for anticoagulation.

Level of Anticoagulation

With NOACS, clinicians are only able to make an educated guess regarding the level of anticoagulation in the individual patient.

Registry Data from Sweden Regarding NOAC Dosing

In a recent publication Steinberg and colleagues [5]evaluated 5738 patients treated with NOACS in a registry study. They were interested to find out whether patients were under-dosed or overdosed according to US labeling. It turns out that all patients who were given off label doses of NOACS were older, more likely female, less likely to be treated by an electrophysiologist, and had higher CHA2DS2-VASc scores and higher bleeding scores when compared to patients given recommended doses of NOACS according to US labeling. Over-dosing was associated with increased all-cause mortality. Under-dosing was associated with increased cardio-vascular hospitalization.The investigators concluded that approximately one in eight US patients in the community received NOAC doses that are inconsistent with US labeling and that either underdosing or overdosing were associated with increased risk for adverse events.

My Advice to Physicians Regarding Anticoagulation

NOACS are significantly more expensive than Coumadin and therefore Warfarin will be used more commonly throughout the world than any other anticoagulant agent.

If warfarin is easily managed and patients are satisfied taking the drug, there is no need to switch to a NOAC.

Although I believe that patients with severe CKD should not be anticoagulated with a NOAC, it can be done if dose adjustments are made relating to the creatinine clearance and there is close follow-up monitoring of creatinine clearance [3].

I still like being able to measure the status of anticoagulation in the individual patient. e.g. with INR in patients receiving warfarin.

Those who treat patients with NOACS should make sure that they (the physician) and their patients know the appropriate dose of the NOAC as recommended by the manufacturer.

It seems to me that NOACS are used in patients,principally for patient and physician convenience.i.e. no need for measuring INR. Knowledgeable patients i.e. those who look things up on Google,know that warfarin is used as rat poison and they do not like that fact. I suspect that if NOACS are given in high doses, rats would also die of poisoning.

Finally, if NOACS are so good, why are they not used for indications other than non-valvar atrial fibrillation. e.g. valve prostheses anticoagulation. I suspect the answer it that the dose of the drug cannot be quantified.

REFERENCES

1. Naccarelli GV, Caputo G,Abendroth T, Faber S, Sendra-Ferrer M et al. Stroke prevention in atrial fibrillation: current strategies and recommendations. CVIA 2016;1:157–64.

2. Camm AJ. New oral anticoagulants for non-valvar atrial fibrillation;harder to handle than expected. Eur Heart J 2014;35:1825–6.

3. Lau YC, Proietti M, Guiducci E,Blann AD, Lip GY. Atrial fibrillation and thromboembolism in patients with chronic kidney disease. J Am Coll Cardiol 2016;68:1452–64.

4. Hanley CM, Kowey PR. Are the novel anticoagulants better than warfarin for patients with atrial fibrillation? J Thorac Dis 2015;7:165–71.

5. Steinberg BA, Shrader P, Thomas L, Ansell J, Fonarow GC, Gersh BJ, et al. Off-label dosing of nonvitamin K antagonist oral anticoagulants and adverse outcomes:The Orbit-AF ll registry. JACC 2016;65:2597–604.