Limitations of Coumarin Derivatives in Atrial Fibrillation and the Quest for New Drugs
Warfarin and similar coumarin derivatives (vitamin K antagonists [VKAs]) clearly have the greatest efficacy among the currently available treatments (mostly aspirin) in preventing stroke in atrial fibrillation (AF).1 However, they carry a substantial risk of major bleeding (approximately 1.2% per year) and have a narrow therapeutic window, which necessitates frequent coagulation monitoring to ensure appropriate dosing.2 The marked variability in the dose–response relationship of VKAs often makes it difficult for the patient to remain within the ideal international normalised ratio (INR) range. While absorption of the various coumarin derivatives from the gastrointestinal tract is generally quite good, their pharmacokinetics are influenced by many other factors, including numerous drug interactions, the dietary intake of vitamin K, hepatic dysfunction, changes in the gut flora, patient compliance and alcohol intake. These factors frequently occur, so that even within the controlled setting of a clinical trial it has not been possible for patients to remain within the therapeutic window more than 50% of the time.3 Thus, in addition to careful patient selection required for any anticoagulant to screen out patients who may be at increased risk of haemorrhage,4–7 every patient treated with VKAs needs frequent, assiduous and unpleasant monitoring of the INR to reduce the risk of undertreatment or overtreatment. In addition to the common contraindications to any anticoagulants, such as dementia, elevated creatinine, anaemia with haemoglobin <10g/l, blood pressure >180/100mmHg despite treatment, severe chronic alcoholism, previous intracranial haemorrhage, severe bleeding despite a therapeutic control, predisposition to head trauma and requirements for non-steroidal anti-inflammatory drugs,8–11 used in most trials as criteria to exclude patients from enrolment, there are specific reasons why VKAs are poorly tolerated and actually impractical for many patients with AF. These include the clear deterioration in the patient’s quality of life:12 the patient is tied to the medical system for lifelong anticoagulation monitoring, with restriction of travelling, anxiety, cost and loss of freedom, as well as caution in the use of other drugs and in dietary patterns because of potential interactions of VKAs with drugs and foods.13 Finally, the high inter-patient variability of VKA requirements has recently been linked to genetic factors. Polymorphisms of vitamin K epoxide reductase complex subunit 1 (VKORC1), a major enzyme of the vitamin K cycle responsible for vitamin K reduction, can affect sensitivity to warfarin therapy and be involved in warfarin resistance.14 Genetic variants in cytochrome P450 2C9 (CYP2C9), largely responsible for the metabolism of warfarin, also contribute to such variability.15
In summary, therapy with VKAs is complex, potentially dangerous and unpleasant, and this has resulted in considerable difficulty in convincing physicians and patients to adhere to current practice guidelines, with subsequent undertreatment in a considerable proportion of patients at risk.16 This is an ample justification for the need for safer and more convenient alternatives to coumarin derivatives for stroke prevention.
Dual Antiplatelet Therapy for Atrial Fibrillation
Ticlopidine and clopidogrel are both non-competitive but selective adenosine diphosphate (ADP) receptor antagonists (irreversibly blocking the P2Y12 platelet receptor). Clopidogrel is now the thienopyridine of choice in clinical practice because of its superior safety profile and tolerability.17 Only clopidogrel has shown its effectiveness and safety compared with aspirin in patients with coronary, cerebro-vascular and peripheral arterial disease.18 In combination with aspirin, clopidogrel has demonstrated similar efficacy against thrombotic events, such as ticlopidine plus aspirin, but with less toxicity.19,20 The benefit of double antiplatelet therapy with aspirin plus clopidogrel compared with aspirin alone has been established in a large number of important randomised trials in patients with acute coronary syndromes without ST-segment elevation,21 in patients with non-ST-segment- elevation acute coronary syndrome (NSTE-ACS) undergoing stent-PCI,21 in patients undergoing PCI in general22 and in patients with ST-elevation myocardial infarction,23,24 indicating that long-term (one-month, one-year) clopidogrel therapy following an acute coronary syndrome with or without percutaneous coronary interventions significantly reduces the risk of adverse ischaemic events.
The combination of clopidogrel plus aspirin was compared with VKAs in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events – Warfarin (ACTIVE-W) trial25 and with aspirin alone in patients with contraindication to VKAs in the ACTIVE-A trial26 for the prevention of vascular events associated with AF. The ACTIVE-W trial showed that oral anticoagulant therapy with VKAs is a better treatment than clopidogrel plus aspirin in general for patients with AF. This is particularly true in patients previously exposed to oral anticoagulation therapy with VKAs, while for patients naïve to these drugs the benefit of VKA therapy compared with clopidogrel plus aspirin is less well defined.
The recently completed ACTIVE-A trial26 showed that in patients with AF for whom VKA therapy was unsuitable, clopidogrel provided an additional benefit on top of aspirin alone in terms of reduction of major vascular events, especially stroke, with an increased risk of major haemorrhage. Therefore, VKAs remain, with all their drawbacks, the standard of care in patients with AF at medium to high risk of thromboembolic events,13 unless contraindicated.
Classification of Anticoagulants and New Drugs in the Clinical Arena
Warfarin and related coumarinic VKAs exert their anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide), modulating the gamma-carboxylation of glutamate residues (Gla) on the N-terminal regions of vitamin K-dependent proteins, including the coagulation factors FII (prothrombin), FVII, FIX and FX, as well as of the anticoagulant proteins C and S. The gamma-carboxylation of these proteins is required for their activity. Treatment with coumarins results in the hepatic production of partially carboxylated and decarboxylated proteins with reduced coagulant activity.27
New anticoagulants, now produced in large number from pharmaceutical companies, can be classified according to their mechanism of action in the coagulation cascade (see Figure 1) and their way of administration (oral or parenteral; see Table 1).13
The ‘new entries’ in the arena, theoretically suitable for the long-term thromboembolic prophylaxis in AF, fall into three main categories:
- long-lived indirect parenteral (subcutaneous) FXa inhibitors;
- direct oral thrombin inhibitors (DTIs); and
- direct oral FXa inhibitors.
These will be now briefly discussed from a pharmacological standpoint, before addressing their current therapeutic applicatons in AF.
Indirect Parenteral Factor Xa Inhibitors
Factor Xa inhibitors act indirectly or directly. Heparin and low-molecular-weight heparins indirectly inhibit FXa among other targets, including thrombin, potentiating the anticoagulant action of antithrombin (antithrombin III). However, their action is completely non-selective in the case of unfractionated heparin, and only partially selective for low-molecular- weight heparins. New indirect inhibitors, fondaparinux and idraparinux, are synthetic analogues of the unique pentasaccharide sequence that mediates the interaction of heparins with antithrombin.28 Once the pentasaccharide/antithrombin complex binds FXa, the pentasaccharide dissociates from the antithrombin/Xa complex and can be re-utilised to catalyse other similar types of reactions.
Fondaparinux binds antithrombin with high affinity, has excellent bioavailability after subcutaneous injection and has a plasma half-life of 17 hours, permitting once-daily administration.29 There is no antidote. Fondaparinux has been evaluated as being at least as effective and safe as enoxaparin for the prevention and treatment of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery30 and in patients with deep vein thrombosis (DVT),31 and as unfractionated heparin in patients with pulmonary embolism (PE).32 Thus, it is now approved for thromboprophylaxis and in the initial treatment of patients with DVT and PE. Moreover, since in patients with NSTE-ACS fondaparinux has shown an improved efficacy–safety ratio, translating into a significant reduction in long-term mortality and morbidity,33 it has been introduced as a first-line anticoagulant in the latest guidelines of the European Society of Cardiology34 and the American Heart Association/American College of Cardiology for NSTE-ACS.35 However, due to its subcutaneous route of administration and the need for daily dosing, fondaparinux has not been evaluated in the context of chronic anticoagulation such as AF.
Idraparinux is a derivative of fondaparinux. It has 100% bioavailability via the subcutaneous route, is excreted mainly in the urine, has a linear, dose-dependent pharmacokinetic profile, reaches peak concentration in one to three hours and has a plasma half-life of 130 hours, allowing once-weekly administration, thus making it a candidate drug for long-term prophylaxis of thromboembolism in AF. The drug has no significant binding to other blood, plasma or endothelial proteins.36 Idraparinux has been compared with warfarin in patients with AF at high risk of stroke in A Multicenter, Randomized, Open-Label, Assessor Blind, Non-Inferiority Study Comparing the Efficacy and Safety of Once-Weekly Subcutaneous Idraparinux (SR34006) With Adjusted-Dose Oral Vitamin-K Antagonists in the Prevention of Thromboembolic Events in Patients With Atrial Fibrillation (AMADEUS) trial: long-term treatment with idraparinux 2.5mg once weekly was shown to be non-inferior to VKAs in terms of efficacy, but caused significantly more clinically relevant bleeding, especially in the elderly and in patients with impaired renal function.37 However, despite a significantly higher rate of fatal haemorrhage in patients treated with idraparinux, there was no difference between the two treatments in overall mortality. On the one hand, the results of the AMADEUS trial suggested that an idraparinux dose regimen adjusted to patient characteristics, e.g. age and renal clearance, may preserve efficacy without an increased haemorrhagic risk, and on the other hand that a drug with such a long plasma half-life needs an antidote to rapidly neutralise its effect in case of ongoing bleeding or risk of bleeding (need for surgery, invasive procedures, etc.).
Biotinylated idraparinux (biotaparinux) is a biotinylated derivative of idraparinux with the same pharmacodynamic and pharmacokinetic properties as the parent molecule. Recently, it has been developed to offer the advantage of rapid neutralisation by an antidote through the injection of avidin, exploiting the extremely high-affinity avidin– biotin binding.38
Direct Oral Thrombin Inhibitors
The oral DTIs evaluated so far in phase III studies, ximelagatran and dabigatran etexilate, are synthetic low-molecular-weight peptidomimetics that bind directly and reversibly to the catalytic site of the thrombin molecule.39,40 They are administered orally as prodrugs, which are rapidly metabolised to the active compound: ximelagatran is converted to melagatran in several organs, including the liver, lungs, intestines and kidneys, whereas dabigatran etexilate is rapidly and completely converted to dabigatran primarily by serum esterase-catalysed hydrolysis. Pharmacokinetic data for dabigatran etexilate in healthy volunteers show peak plasma levels within two to three hours after oral administration41,42 and a half-life in healthy subjects of three to four hours for melagatran and around 12–14 hours in patients for dabigatran.43 Both are eliminated primarily by the kidney. Therefore, plasma concentrations are increased for both compounds in patients with impaired renal function. However, the therapeutic window is fairly wide, and these compounds have therefore been tested in fixed doses (ximelagatran 24 or 36mg twice a day [BID]; dabigatran etexilate 110 and 150mg BID), in patients with a glomerular filtration rate >30ml/minute.39,44
Ximelagatran showed greater efficacy than warfarin and equivalent efficacy to enoxaparin, without increased bleeding incidence, for venous thromboprophylaxis in high-risk orthopaedic patients,45 for which indications it had been licensed in Europe in 2004. In the acute treatment of VTE, ximelagatran had been shown to be an effective and safe alternative to standard therapy.45 In acute coronary syndromes, ximelagatran appeared to reduce all-cause mortality, non-fatal myocardial infarction and severe recurrent ischaemia.46
For prevention of thromboembolic events in AF, ximelagatran was associated with a 16% relative risk reduction in the composite outcome of all strokes (ischaemic or haemorrhagic), systemic embolic events, major bleeding and death.47–49 However, in the long term use ximelagatran was associated with transient elevations of liver-function tests (alanine amino transferase [ALAT]) (three times above upper normal limits) in around 8% of patients, the majority of cases occurring between one and six months after the start of treatment. This also led to protocol-mandated cessation of treatment in some patients.50 At the beginning of 2006, the company producing ximalagatran decided to withdraw it from the market and terminate its development. The withdrawal was triggered by new patient safety data with an adverse event report of serious liver injury in a clinical trial.
Phase III trials has been reported with dabigatran in hip/knee-replacement surgery. In the Thromboembolism Prevention After Knee Surgery (RE-MODEL) trial, dabigatran etexilate was at least as effective as and had a similar safety profile to enoxaparin for prevention of VTE after total knee-replacement surgery.51 In A Phase III Randomised, Parallel Group, Double-blind, Active Controlled Study to Investigate the Efficacy and Safety of Orally Administered 220 mg Dabigatran Etexilate Capsules (110 mg Administered on the Day of Surgery Followed by 220 mg Once Daily) Compared to Subcutaneous 40 mg Enoxaparin Once Daily for 28–35 Days, in Prevention of Venous Thromboembolism in Patients With Primary Elective Total Hip Arthroplasty Surgery (RE-NOVATE II) trial, oral dabigatran etexilate was as effective as enoxaparin in reducing the risk of VTE after total hip replacement, with a similar safety profile.52 No significant differences were observed in the incidences of liver enzyme elevation. Therefore, on March 2008 the European Medicines Agency (EMEA) approved the use of dabigatran for the prevention of venous thromboembolic events after total hip replacement and total knee replacement surgery.
The oral direct thrombin inhibitor AZD0837 is a prodrug that is metabolised to the active thrombin inhibitor via an intermediate form. Based on encouraging results from the first phase IIa study, development of AZD0837 is continuing, with the decision to develop this product through an extended-release formulation for prophylaxis of thromboembolic events.
Direct Oral Factor Xa Inhibitors
After the results with the parenteral fondaparinux, proving the concept of the antithrombotic effect due to FXa inhibition, a number of oral FXa inhibitors have entered clinical development. These agents, having a molecular weight of approximately 500Da, are direct inhibitors of FXa, as they do not require a plasma co-factor for their action, and are selective for FXa, as their Ki is at least 5,000 times lower than that for any other serine protease. The direct inhibitors of FXa are inhibitors of the catalytic site of this important coagulation factor. It has been shown that the direct inhibitors of FXa can inhibit FXa both in the fluid phase and in the context of the prothrombinase complex. The clinical relevance of this biochemical feature is unclear.
Clinical data are currently available for at least five oral inhibitors of FXa: razaxaban,53 rivaroxaban (BAY 59-7939),54,55 apixaban (BMS-562247-01),56 LY 5157117,57 YM 15058 and edoxaban (DU-176b).59 In general, these agents have shown a reasonably large therapeutic window. Doses of rivaroxaban between 10 and 30mg once a day,54,55 apixaban 2.5–10mg twice a day56 and edoxaban 15–60mg once a day60 have been proved to be as effective as LMWHs in the prevention of DVT after major orthopaedic surgery without being associated with excessive bleeding in phase II trials. Doses of edoxaban between 30 and 60mg once a day have been also compared with warfarin (INR 2-3) in patients with AF,a showing similar and lower bleeding rate, respectively, in phase II trials.61 Rivaroxaban has also successfully completed some phase III trials in DVT prophylaxis,62 and it is now approved in Europe for the indication of VTE prevention in patients undergoing major orthopaedic surgery. Phase III trials with apixaban and edoxaban are ongoing.
Recently Completed and Ongoing Clinical Trials in Atrial Fibrillation
The results obtained from the first studies with these new anticoagulants suggested that several of those not requiring coagulation monitoring have the potential to replace VKAs for prevention of stroke and systemic embolism in AF. The main characteristics of recently completed or ongoing clinical trials with new anticoagulants in patients with AF are comparatively reported in Table 2.
Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) is a randomised, parallel-group, open-label, active-controlled, non-inferiority trial comparing two doses of dabigatran etexilate, 150 and 110mg BID, with VKAs in patients with non-valvular AF with additional risk factors for stroke, for the prevention of stroke and systemic embolism. This trial has been recently completed and published (see below).63
Rivaroxaban Once daily oral direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) is a randomised, double-blind, double-dummy, parallel-group, active-controlled study testing the hypothesis that the direct oral FXa inhibitor rivaroxaban is non-inferior to warfarin in the prevention of the composite end-point of stroke and systemic embolism in subjects with non-valvular AF. The principal safety objective of the study was to demonstrate that rivaroxaban is superior to dose-adjusted warfarin, as assessed by the composite of major and non-major clinically relevant bleeding events.
Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE) is a randomised, double-blind, double-dummy, parallel-arm study testing the hypothesis that apixaban is non-inferior to warfarin in the combined end-point of stroke (ischaemic or haemorrhagic) and systemic embolism in subjects with AF and at least one additional risk factor for stroke.
A Phase III Study of Apixaban in Patients With Atrial Fibrillation (AVERROES) is a randomised, double-blind, double-dummy, parallelarm study assessing whether apixaban is superior to aspirin for preventing the composite outcome of stroke or systemic embolism in patients with AF and at least one additional risk factor for stroke who have failed or are unsuitable for vitamin K antagonist therapy.
Evaluation of Weekly Subcutaneous Biotinylated Idraparinux Versus Oral Adjusted-dose Warfarin to Prevent Stroke and Systemic Thromboembolic Events in Patients With Atrial Fibrillation (BOREALIS-AF) is a randomised, double-blind, assessor-blind, non-inferiority trial with biotinylated idraparinux. The primary study objective is to evaluate whether once-weekly subcutaneous injection of biotinylated idraparinux is at least as effective as warfarin in the prevention of stroke or systemic embolic events in patients with AF at high risk of stroke. Based on the data from the AMADEUS trial, a modified dosing regimen incorporating age and baseline renal function has been devised with the objective of reducing the risk of excess bleeding while preserving the efficacy outcome.
The Global Study to Assess the Safety and Effectiveness of DU-176b vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation (ENGAGE AF-TIMI 48) is a randomised, double-blind, double-dummy, parallel-group, multicentre study for the evaluation of the efficacy and safety of two doses of edoxaban (DU-176b), 60mg daily (with dosage adjustment to 30mg daily for moderate renal impairment or low bodyweight) and 30mg daily (with dosage adjustment to 15mg daily for moderate renal impairment or low bodyweight), versus warfarin in subjects with AF and congestive heart failure, hypertension >160mmHg (or treated hypertension), age >75 years, diabetes and prior stroke or transient ischaemic attack (TIA) (CHADS2) risk score ≥2. The composite primary endpoint is stroke and systemic embolism, and the study hypothesis is that at least one dosage regimen of edoxaban will be non-inferior to warfarin in reducing the end-point.
Results of RE-LY and Its Implications
The RE-LY study is a randomised trial designed to blind-compare two fixed doses of dabigatran etexilate, 110 and 150mg BID, with open-label warfarin in patients with AF and increased risk of stroke. The primary efficacy outcome was stroke and systemic embolism and the primary safety outcome was major haemorrhage. Secondary outcomes were stroke, systemic embolism and death. Other outcomes were myocardial infarction, PE transient ischaemic attack and hospitalisation.
The results of this trial have recently been published.63 Both doses of dabigatran etexilate were non-inferior to warfarin in terms of the primary efficacy outcome of stroke or systemic embolism. Moreover, dabigatran etexilate 150mg was superior to warfarin for the prevention of stroke or systemic embolism, and dabigatran etexilate 110mg was superior to warfarin for the prevention of major bleeding. Unlike ximelagatran, dabigatran etexilate did not shown hepatotoxicity. The rate of myocardial infarction was higher with both doses of dabigatran etexilate than with warfarin: this might be due to a better protection against coronary ischaemic events by warfarin, although patients treated with ximelagatran, another direct thrombin inhibitor, had a similar rate of myocardial infarction to warfarin in the Stroke Prevention Using the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Nonvalvular Atrial Fibrillation (SPORTIF) studies.47,48 There were more gastrointestinal bleeding events with dabigatran etexilate 150mg, despite the overall lower rate of bleeding at other sites. However, as the most dangerous complication of warfarin therapy is intracranial haemorrhage, especially haemorrhagic stroke, the advantage of dabigatran etexilate is a lower rate of this complication (occurring at less than one-third the rate seen with warfarin), without lesser efficacy against ischaemic stroke.
The implications of these results are very important. Dabigatran etexilate is the first oral anticoagulant satisfying the criteria of an alternative drug to VKAs for the prevention of thromboembolic events in patients with AF: the drug has a wide therapeutic window, can be administered in fixed doses with no need for monitoring and no interaction with food and other drugs, is easily managed, has equivalent efficacy in the prevention of thromboembolic events compared with warfarin if used at 110mg doses twice daily, has superior efficacy if used at 150mg doses twice daily, is safer than warfarin if used at 110mg doses twice daily and is as safe as warfarin if used at 150mg doses twice daily. An important factor is the choice of the right dose, which could be potentially tailored considering the risk characteristics of a specific patient, particularly the haemorrhagic risk and the thromboembolic risk. The higher risk of myocardial infarction related to dabigatran use compared with warfarin remains to be explained and defined.
The past 20 years have led to a considerable improvement in the antithrombotic prophylaxis of AF through a proper stratification of the thromboembolic risk, the establishment of the proper ranges of anticoagulation with VKAs and the demonstration of its superiority compared with treatment with both aspirin alone and aspirin plus clopidogrel combination. We are now witnessing a therapeutic revolution that shows the possibility of overcoming VKA therapy with more tolerable and manageable drugs. The cardiologist needs to be aware of the pharmacology literature being accrued with these new drugs. This is not just in the realm of future therapeutic possibilities, but a reality that will become available for the practising physician as soon as dabigatran etexilate (Pradaxa®) is licensed.