During the Great Depression in Wisconsin, a farmer presented at a school of agriculture with a milk can full of blood which would not coagulate. In his truck, he had also brought a dead young cow and some clover hay; he wanted to know what had killed his cow and spoilt his hay. Prof. Karl Paul Link a biochemist, got funding from the Wisconsin Alumni Research Foundation to research sweet clover disease which was known to cause the cattle to bleed to death after ingesting spoilt sweet clover. He identified a substance with anti-clotting properties he named dicoumarol. Although the drug initially found commercial application as a killer of rats and mice in 1941, it was approved in 1954 and among its first recipients was President Dwight Eisenhower, as he recovered from a heart attack in 1955. It has been widely used in heart and vascular medicine ever since (Warfarin is a portmanteau word combining WARF the accronym of Wisconsin Alumni Research Foundation and adin, the ending from word Coumadin) (1,2)
Warfarin's efficacy in preventing embolic events in patients with atrial fibrillation (AF) has been proven and its mechanism understood (3,4). However, apart from patient's risk of bleeding when using it, Warfarin has several shortcomings:
- Unpredictable response: Within each individual, and especially among elderly individuals, Warfarin has an unpredictable response; studies also show that the dose required to achieve appropriate levels of anticoagulation can be smaller with advancing age. One study (5) included 2,305 patients and showed that the dose required for treatment fell by 0.5 mg per decade of life. Another longitudinal study (6) demonstrated a 21% decrease in the required dose for a period of 15 years.
- Age and gender: Garcia et al (7) showed that, in addition to age, gender has an impact on the required dose of Warfarin for anticoagulation, suggesting that the initial target dose for anticoagulation in the elderly may be overstated, particularly in elderly women.
- Interaction with food and drugs: Warfarin interacts with a variety of foods, (such as large amounts of vitamin K containing foods, cranberry juice, avocados, grapefrjuits, antibiotics, drugs affecting the central nervous system, and cardiac medication, alcohol or antibiotics) (8), which means that extra care is needed with the use of the drug.
- Genetic differences: Genetics impact greatly in need of doses to maintain adequate levels of anticoagulation (9).
These factors render difficult the use of Warfarin to prevent embolic events in patients with AF and therefore anticoagulation is often inadequate in regards to what is recommended (next e-journal for comment on recommendations) (10). Many patients at risk do not benefit from much needed anticoagulation, and remain at risk. Thus, researchers have sought other drugs with improved pharmacodynamic and pharmacokinetic characteristics, yet keeping with the efficacy and hopefully increased levels of safety.
I - Studies and Approvals in Atrial Fibrillation and Cardioversion
Based on the coagulation cascade - the sequence of biochemical activities that stop bleeding by forming a clot, two possible targets for the development of new oral anticoagulants were: 1) drugs acting as direct thrombin inhibitors (such as Dabigatran) or 2) activated factor X (such as Rivaroxaban and Apixaban). These drugs have been developed and tested in large clinical trials in patients with AF, to prove its efficacy and safety compared with Warfarin.
- Dabigatran : The Re-Ly study (11) enrolled 18,113 patients, and the effects of Dabigatran were compared with the classical scheme of anticoagulation for patients with AF (define). Two dose regimens were tested - 110mg and 150mg, twice a day, in comparison with Warfarin at doses adjusted according to INR. Anticoagulant therapy more effective than Warfarin in AF patients was identified for the first time. Main outcome reduction (stroke or systemic embolism) was significant using Dabigatran at a dose of 150mg, with same rate of bleeding events. At a dose of 110mg, there was less bleeding, although reduction of embolic events was no greater.
In cardioversion, analysis of 1983 cardioversions performed on 1270 patients showed that the frequencies of stroke and major bleeding within 30 days of cardioversion on doses of Dabigatran were low and comparable to those of warfarin. (12)
- Rivaroxaban: Besides the direct inhibition of thrombin, experts sought to act on the activated factor X of the coagulation cascade, as it is possible to inhibit the activation of large amounts of thrombin - a theoretically most powerful and effective action. With this objective, Rivaroxaban was tested in the double-blind Rocket AF study (13). In it 14,264 non-valvular AF and moderate to high risk of stroke patients were randomised to treatment with Warfarin or Rivaroxaban, 20mg, once daily. Rivaroxaban was proven non-inferior to Warfarin in preventing stroke or systemic embolism, and no statistical differences in the rates of major or clinically relevant bleeding, although intracranial or fatal bleeding occurred less frequently in the group receiving Rivaroxaban.
- Apixaban, another inhibitor of activated factor X had its clinical efficacy assessed by a large multicenter randomized double-blind study: Aristotle (14), randomised 18,201 patients with AF and at least one additional risk factor to receive either Apixaban 5 mg twice daily or Warfarin dose adjusted to maintaining the INR between 2.0 and 3.0. The aim was to assess whether the new drug was not less powerful than Warfarin in terms of efficacy. The pre-specified hierarchical analysis showed that Apixaban was not only non-inferior compared to Warfarin, but really superior, reducing the risk of stroke or systemic embolism by 21% and more secure, with risk of major bleeding 31% lower. Apixaban, also reduced the risk of death from any cause by 11%, compared to Warfarin.
- Dabigatran was approved based Re-Ly results, by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA), (and in Brazil by the Brazilian Sanitary Surveillance Agency (ANVISA) for prevention of stroke and systemic embolism in patients with atrial fibrillation. The indication of the EMA is for non-valvular AF patients with at least one risk factor, namely, previous stroke, transient ischemic attack (TIA) or systemic embolism; LVEF under 40%, symptomatic heart failure, and age = 75 years or age = 65 years with one of the following additional risk factors: diabetes, coronary artery disease or hypertension. In Brazil, as in Europe, approved doses were of 110mg and 150mg twice daily.
The latest European guidelines on atrial fibrillation (15) state that in cases where the use of anticoagulants is indicated - AF lasting more than 48 hours for an unknown duration -, elective cardioversion can be performed safely with Dabigatran provided 3 weeks of therapeutic anticoagulation pre-cardioversion is continued for a minimum of 4 weeks after the procedure. However, the authors point out that the correct usage of the medication is crucial for peri-cardioversion anticoagulation period since, unlike Warfarin (for which anticoagulation is possible to monitor by IRN), there is no way to verify whether the treatment is being properly followed.
- Rivaroxaban also was approved for stroke prevention in non-valvular AF by FDA and EMA and ANVISA, at 20mg once daily (15 mg for patients with renal insufficiency).
- Apixaban has just recently gained regulatory approval by the EMA, FDA (not yet by ANVISA), and was included in the European guidelines for the management of patients with AF (15)
Rivaroxaban or Apixaban: Data on Rivaroxaban or Apixaban in cardioversion is not yet available.
II - New drugs: common features and controversies
Direct comparison among the new anticoagulants is not easy to carry out since despite their similarities, these large studies have distinctive designs, and evaluated patients with clinically significant differences. Still, it is possible to establish certain common features in these new drugs.
- Hemorrhagic stroke: The new drugs have demonstrated in above-stated studies non-inferiority in comparison with Warfarin, more safety- consistently reducing the cases of hemorrhagic stroke (12-14).
- Onset: The effect of novel anticoagulants occurs within a few hours after the first dose. Advantages are the following 1) in view of a surgical procedure allows for rapid anticoagulation reversal, however cannot be omitted (forgotten), since patients would be without protection of the anticoagulant effect 2) in the perioperative setting, low molecular weight heparin as a bridge for most interventions becomes unnecessary 3) after surgery, its use can be restarted immediately after obtaining effective hemostasis.
- Fixed dose: The fixed facilitates prescription. In this item, Dabigatran has a characteristic which differs from the others, since the two doses available allow a choice between an anticoagulant effect most marked with bleeding similar to Warfarin (which was demonstrated at a dose of 150mg twice daily) or the same anticoagulant efficacy with less bleeding (achieved with a dose of 110mg twice daily).
- Drug-drug/Drug-food interaction: The little interaction between the new anticoagulants and other medications or foods is undoubtedly one of the most significant differences in regards to Warfarin, since this feature makes Warfarin use very complex and potentially risky.
- INR monitoring: One can wonder whether, withouth the monitoriing, patient is really anticoagulated? There is some controversy over whether not needing to monitor is in in fact an advantage or not. While with the new drugs, the patient does not need frequent tests to assess coagulation status - avoiding patient discomfort, loss of time and money spent, loosing the need for regular INR checks may cause anxiety over whether in fact, the patient is anticoagulated or not. Nevertheless, it appears that most people view this convenience as a significant advantage.
- Cost: While the current cost of the medicines will hinder its use on a large scale, (mainly in countries such as Brazil) one needs to put in the balance the costs related to the use of Warfarin, which are waste of time and money and lost work days due to frequent INR monitoring or treatment and complications related to its use. Cost-effectiveness in favor of new treatments have been published (16, 17).
- Adherence in the very elderly: There are still concerns about the applicability of the data of new anticoagulants for the very elderly. This population, which also has restrictions on the use of Warfarin, usually has multiple comorbidities, using several different drugs, and has difficulty issues regarding adherence to treatments.
- Renal failure: Patients with severe renal insufficiency were excluded from the trials because Dabigatran has a significant renal excretion rate, which may limit its use in patients in this situation. Also, monitoring the progress of renal function of patients is recommended, since changes over time may be significant. However, one should not forget that the use of Warfarin in these conditions is also often very difficult.
- Coronary event or PCI: In the absence of robust data in AF patients who have an acute coronary event or requiring percutaneous coronary intervention with stent implantation, physicians should guide through recommendations based on expert consensus on the management of such patients (18). Thus, usually a period of triple therapy is required (anticoagulant associated with aspirin and clopidogrel) followed by combining an antiplatelet isolated and, after a year, in stable patients appears to be safe to administer only the anticoagulant. Our readers can refer to this previous edition of the e-journal for more on this topic.
- Antidote: Whereas the antidote to Warfarin is straight-forward (vitamin K) that of these new drugs can be cited as a sobering fact. However, let it be reminded that the action of Warfarin is not immediate, and the risk of bleeding and management of bleeding during its use is non-negligible. Nevertheless, the new treatments are being researched for more adequate control to avoid situations that can become catastrophic.
- Efficacy vs. Efficiency: Behavior of new anticoagulants in the "real world" is not yet full known: will they behave as documented in clinical trials. Only time will tell, but in fact they have already come to facilitate the use of anticoagulants in patients with non-valvular AF at risk for embolic events.
Warfarin's shortcomings regard variations in individual responses and interactions with certain foods and drugs. In atrial fibrillation, the Rely, Rocket-AF and Aristotle studies have proven the efficacy of Dabigatran, Rivaroxaban and Apixaban which have now all been approved for use in stroke prevention and Dabigatran in cardioversion. Rapid onset, a fixed doe, with no need for INR counterbalance the added cost.