by Professor Dr Harris Ngow Abdullah
Mr Chu is a 61 year-old former executive of MAS, visited your clinic to follow up on his multiple chronic conditions. He was accompanied by his daughter, who seemed to be unusually angry. She read some materials on the internet related to the treatment of Mr Chu. She was upset that the father was taking “rat poison” for his abnormal irregular heart beat for the past few years when better blood thinner were available. She wanted to know your opinion on the latest NOACs.
How Common is This in Clinical Practice
Atrial fibrillation or irregular heart beat is quite common in clinical practice. It is the most common cardiac arrhythmias in clinical practice. The prevalence is increasing in elderly patients and patients hospitalized for other medical conditions. The incidence is about 3.5% in men older than 50 years to 9% in general population older than 70 years. (1)
There are three kinds of treatments in atrial fibrillation, namely medical therapies, surgical treatments and catheter ablation. Medical therapies include anti-arrhythmic drugs and anticoagulation.
What are Oral anticoagulants?
Anticoagulant is an effective treatment in preventing primary and secondary thromboembolic complication from atrial fibrillation. Warfarin was approved by the FDA in 1954 and remained the only option for long term anticoagulation therapy.(2) In 2010, Dabigatran, a direct thrombin inhibitor was approved by the FDA followed by other factor Xa inhibitors like Rivaroxaban and Apixaban. This newer class of therapy is referred to as an oral non-vitamin K dependent antagonist anticoagulants or novel oral anticoagulants. (NOACs)
Though warfarin is effective, it has a narrow therapeutic index that may result in serious bleeding complications. Warfarin was first used as a rodenticide and at that time it was thought to be too powerful for use as medication for humans.(2) Warfarin has many known interactions with food and drugs, including traditional herbal or allopathic medicines. Warfarin toxicity is reversed by administering vitamin K. Clinically, the international normalised ratio (INR) is used to monitor the therapeutic effectiveness of warfarin as well as the bleeding risk. Overall, a good target INR for most clinical indications is between 2.0-3.0.(2） Nevertheless, this range should be individualised according to the patient’s bleeding risk and thrombotic risks.
For non-valvular atrial fibrillation, NOACs are new alternatives to warfarin. They have been shown to be superior to warfarin in clinical trials in preventing thromboembolic events resulting in stroke. In addition, NOACs have been shown to have lower bleeding complications such as haemorrhagic stroke or intracranial bleeding. Besides, they also showed favourable outcomes for other bleeding risks such as gastrointestinal bleeding compared to warfarin.(3) Other clinical indications for NOACs include deep venous thrombosis, pulmonary embolism and post-surgery thromboembolic events.
Who Should Be On NOACs
The following groups of patient may benefit from NOACs and they should be assessed for suitability of NOACs by a cardiologist:
- Patients who have poor venous access.
- Patients who have difficulty receiving regular INR monitoring.
- Patients who are on drugs treatment that interact with warfarin for example long term NSAIDs, anti-epileptics or long term anti-tuberculous or antibiotics.
- Patients whose INR cannot be easily stabilised to achieve target INR (> 65% in therapeutic range over 3 months duration) due to drugs or dietary interaction.
At this juncture, NOACs are not approved for use in patients with prosthetic heart valve or those with moderate or severe mitral stenosis.
No antidote is available for factor Xa inhibitors but idarucizumab( Praxiband) was approved recently by FDA for dabigatran related life-threatening or uncontrolled bleeding.(4) Though for non-emergency bleeding, proper hydration and haemodialysis can be used for over-coagulation.
Prior to starting NOACs, a baseline renal profile and liver function test should be obtained. Blood count is also important to assess the bleeding complications. NOACS are not advisable in patients with severe renal impairment (GFR< 30ml/min/m2).(5) Patients who are already on NOACs with stable anticoagulation may encounter bleeding complications when their renal functions deteriorate suddenly. Rivaroxaban is metabolised in the liver therefore it is not suitable in patient with moderate or severe liver impairment. Anticoagulation effect is assessed by prothrombin time (PT) and activated partial thromboplastin time (aPTT). In patient with dabigatran, the aPTT is more prolonged compare to PT in the absent of other confounding factors like heparin use or low molecular weight heparin (LMWH). Conversely, in patients taking Apixaban or Rivaroxaban, PT will be more prolonged compare to aPTT in the absent of liver impairment or warfarin usage.(6)
Importantly, NOACs have less drug-drug interaction than warfarin. Nevertheless, patient who is concurrently taking drugs metabolized by P-glycoprotein or CYP3A4 enzymes may result in over coagulation. Such drugs include ketoconazole, verapamil, amiodarone, anti-retrovirus protease inhibitors, clarithromycin and anti-tuberculous rifampicin. Patient should be caution of bleeding complications prior to prescribing NOACS.
Decision on NOACs
Active discussion should be performed with patients and their family members before switching to NOACs. Points discuss should include NOACs’ clinical performance as compare to warfarin. NOACs generally are more expensive than long term warfarin; the long term financial implication shall be discussed before switching. An estimate of the monthly expenses may help patient to decide on their affordability. At the same time, patient should be advised on drug compliance as some NOACS have short half-life.
An obvious advantage of switching to NOACS is the ease of monitoring for the anticoagulation effect. Patient may no longer need to regularly come to clinic for blood taking in contrary to long-term warfarin therapy. This may translate into monetary and times saving for patients who need extra help i.e. bedbound or wheel chair bound patients. The option must be discussed with the patient as well as the next-of-kin.
Decision to Switch
Once decision is made to switch to NOACs from warfarin therapy in non-valvular atrial fibrillation, the switch can be done by stopping warfarin. When the INR falls below 2.0, at which time patient can be started on NOAC. Treatment should be individualised and monitor for bleeding complications.
Ms Chu was very impressed with your explanation and information on newer anticoagulation. Mr Chu politely reproached his daughter for being rude. He, meanwhile, decided to continue with the warfarin therapy for his irregular heartbeat. He was concerned on the long term financial implication of this medication.
NOACs are new alternative to long term warfarin therapy in non-valvular atrial fibrillation. NOACs do not require frequent blood investigations and titration as in warfarin therapy. NOACS with twice daily dosing may have a higher risk of pro-thrombotic state when the drug is missed due to their shorter half-life. Recently, an antidote is available for dabigatran but not the factor Xa inhibitors. Finally, NOACs have greater financial implication compare to warfarin as they are significantly more costly though they have better clinical efficacy.
1. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial ﬁbrillation: the Framingham study. New England Journal of Medicine 1982; 306:1018–22.
2. Pirmohamed M. Warfarin: almost 60 years old and still causing problems. Br J Clin Pharmacol 2006; 62: 509-11.
3. Ruff CT, Giugliano RP, Braunwald E et al.Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383: 955-62.
4. US Food and Drug Administration. FDA approves Praxiband, the first reversal agent for the anticoagulant Pradaxa.
Accessed December 20, 2015.
5.Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label ,parallel group, single-center study. Clin Phamacokinet 2010; 49:259-68.
6. Favaloro EJ, Bonar R, Butler J, Marsden K. Laboratory testing for the new oral anticoagulants: a review of current practice. Pathology 2013; 45:435-7.