What is Better than Warfarin?

English: Ball and stick model of the drug warf...

Ball and stick model of the drug warfarin.

Coumarin-induced skin necrosis: The patient on...

Coumarin-induced skin necrosis: The patient on the left had a deep vein thrombosis, while the patient on the right had rheumatic mitral stenosis with atrial fibrillation. (Photo credit: Wikipedia)

IV bruise

IV bruise (Photo credit: Pak Gwei)

Good long-term anticoagulant medicines are hard to come by. Warfarin remains the mainstay of preventative treatment despite the side-effects and the complexity of use. The key unmet need is for viable alternative long-term oral anticoagulation treatments.

Warfarin is a far from ideal medicine. It reduces the risk of stroke in patients with atrial fibrillation (AF) by about 60%, while anti-platelet therapy is much less effective, but warfarin requires frequent clotting assessment and monitoring.

Low molecular weight heparins and fondaparinux offer predictable anticoagulation, which obviates the need for monitoring, but they need to be administered parenterally, and cannot be used for long-term treatment.

Newer oral agents offer some potential advantages and indications, but they still remain used only as a back-up for patients who don’t comply with warfarin or are intolerant.

Properties of Warfarin

Warfarin is an oral medicine, but shows an unpredictable anticoagulant response, because of genetic variability between patients, dietary vitamin K intake, and the potential for multiple drug-drug interactions, which affect metabolism of the drug.

So warfarin needs to be monitored carefully to ensure it is effective. The dose is frequently adjusted to ensure an adequate therapeutic level.

The introduction of novel oral agents remains hampered by warfarin’s effectiveness in preventing venous thromboembolism and deep vein thrombosis or a pulmonary embolism (PE). These newer agents are used in patients who cannot tolerate, or who do not comply with warfarin medication.

Risks of Clotting

Thrombosis – formation of clots – is the main risk for patients with atrial fibrillation. Venous thromboembolis occurs when the clot migrates to another location, and in this case presents considerable risk of major morbidity and even mortality. If the clot migrates to the lungs – pulmonary venous thromboembolism – it is a potentially life-threatening illness.

Who Needs Anticoagulants?

Anticoagulants are used in both acute and chronic venous thromboembolism, but also for prevention in high-risk patients. Those most at risk have undergone either major surgery or have just had repeat surgery.

Anticoagulants are used to treat arterial thrombosis, mostly in the prevention of ischaemic stroke in patients with atrial fibrillation.

Which Anticoagulant is Best for Which Patient?

For acute venous thromboembolism, the current standard of anticoagulant care is intravenous or subcutaneous unfractionated heparin.

Heparin is an anti-thrombin III inhibitor. It provides effective anticoagulation, but because of the short half life of one hour, infusions have to be continuous or very frequent, and it thus requires continuous hospitalisation.

Unfractionated heparin has a longer half-life of two hours, and infusions can be less frequent. The newer low molecular weight heparins  have an even longer half-life of up to 4h, and are given once daily.

The short half-life of the heparins makes them unsuitable for long-term treatment. They are given until the initial loading dose of warfarin takes effect.

Warfarin is preferred for long-term anticoagulation, as it is an oral treatment and has a longer half-life. However, it has slow onset of action. So bridging therapy with a parenteral agent is required for immediate anticoagulation.

Warfarin Dosing

Warfarin is given in two doses because of the time lag of 4-5 days before it starts to exert its therapeutic effect. If given initially, without additional anticoagulant cover with heparin preparations, it increases the risk of thrombosis.

The first dose is for loading; the second is for maintenance. The maintenance dose needs to be calibrated and depend on the intake of vitamin K1 in the diet.

The dose of warfarin is balanced between giving sufficient to prevent thrombo-embolic events, but ensuring it does not cause bleeding, or increase the risk of bleeding to an unacceptable level.

Deciding on the most appropriate dose of warfarin for a particular patient is complicated by the fact that warfarin interacts with many common medica tions, and even with chemicalspresent in certain foods. These interactions may enhance or reduce the warfarin anticoagulation effect.

In order to optimize the therapeutic effect, without risking dangerous side effects, such as bleeding, close monitoring of the degree of anticoagulation is required through blood testing and International normalised ration (INR) measurements. During the initial stage of treatment, checking of warfarin levels may be required daily; intervals between tests can be lengthened if the patient manages stable therapeutic INR levels on an unchanged warfarin dose.

As well as this, if the patient is taking drugs that are highly protein-bound then the warfarin can be displaced from albumin leading to higher than normal levels of free warfarin, which thus alters the INR. This can further complicate dosing.

The target INR level varies from case to case depending on the clinical indicators, but tends to be 2–3 in most conditions. In particular, a target INR may be 2.5–3.5 (or even 3.0–4.5) in patients with one or more implanted heart valves.

Keeping anticoagulant intensity constant, and within range, is important. For VTE, and to a greater extent for AF, as the INR falls to less than 2, there is a dramatic increase in the risk of an ischaemic stroke. Likewise, there is a dramatic increase in the risk of bleeding with an INR over 4. Even slight changes in the INR range has a direct effect on the efficacy of the medication.

Warfarin for Secondary Prevention

For chronic secondary prevention, currently the only agent in widespread use is warfarin. The optimal duration of preventative treatment is controversial. For those with provoked reversible risk factors, then the recommendation is for 3 months treatment with warfarin at least. But, in most cases, treatment is for between 3 and 6 months, with an extended duration on a case-by-case basis. Warfarin is also effective for the prevention of stroke in AF, and has efficacy in acute myocardial infarction and the secondary prevention of coronary events.

Advantages of Warfarin

The advantages of warfarin are that it can be given orally, and that it only needs to be taken once a day. It is slower acting than the common anticoagulant heparin, but does not have to be given by injection, which is the way heparin is administered. Many patients monitor their own warfarin levels in their homes. Self-testing and monitoring can work well and is more convenient.

Heparin can cause heparin-induced thrombocytopenia or HIT (a dangerous condition in which there is an antibody-mediated decrease in platelet levels). HIT is a pro-thrombotic condition that increases the risk for thrombosis or clot. Up to an estimated 1% of those given UFH for five days will develop HIT.

Warfarin’s long half-life means that it remains effective for several days after treatment has been stopped and this needs to be considered when managing anticoagulant therapy.

Disadvantages of Warfarin

The major limitations of warfarin as a medicine include:

  • It has unpredictable pharmacokinetics.
  • Inter- and intra-individual patient variability in response to warfarin therapy is very high.
  • Genetic variation – patients should be screened for polymorphisms that may indicate that they are at a higher than normal risk of erratic INR control.
  • Drug-drug interactions – some commonly prescribed medications can interfere with warfarin action.
  • Alcohol may interfere with warfarin action and this is particularly a problem in patients who binge drink.
  • Vitamin K containing foods such as leafy green vegetables can interfere with warfarin action. Vitamin K is an indirect anticoagulant and, therefore, interferes by reversing warfarin action.
  • Frequent dose monitoring and adjustment of warfarin are required.
  • Slow-onset and offset of warfarin action makes peri-operative management of patients very challenging.

Interference with Warfarin Action

Some commonly prescribed antibiotics, such as metrionidazole or the macrolides, will greatly increase the effect of warfarin by reducing metabolism in the body.

Thyroid activity influences warfarin action and hypothyroidism decreased thyroid function makes people less responsive to warfarin, while hyperthyroidism boost the anticoagulant effect.

Some gut bacterial flora make vitamin K and this can potentiate the effect of warfarin. Thus anything that interferes with or alters gut microbial flora can influence the impact of warfarin.

Excessive use or abuse of alcohol affects the metabolism of warfarin and can elevate the INR. Patients are warned against excessive alcohol intake while taking warfarin. Binge drinking in particular is dangerous.

Warfarin interacts with many herbs and spices, some used in food – eg ginger and garlic – and others used purely for medicinal purposes – eg ginseng and Gingko biloba. All may increase bleeding and bruising in people taking warfarin; similar effects have been reported with borage oil or fish oils.

St John’s wort – sometimes recommended to help with mild to moderate depression – reduces the effectiveness of a given dose of warfarin. There have been some recent reports of a potential interaction between warfarin and cranberry juice.

Direct thrombin and Factor Xa Inhibitors

Unfractionated heparin or its low molecular weight derivatives enoxaparin  or dalteparin are anticoagulants used to prevent DVT and PE in patients who are at risk. They are ideal for short-term anticoagulant treatment. There is no evidence that UFH or any preparation of LMWH is more effective at preventing mortality than any other.

Low molecular weight heparins and fondaparinux inhibit factor Xa reduced risk of HIT and osteoporosis. the effects of heparin are measured using the partial thromboplastin time aPTT – a measure of the clotting time.

The big disadvantage of heparin is that it cannot be given orally. It has to be given parenterally because it is too large and negatively charged to be absorbed in the gut. Heparin can be given intravenously (iv) or subcutaneously (sc), but not intramuscularly (im), because it can cause haematomas.

Heparin has a short half life of one hour it needs to be given continuous infusion. UFH has a half life of two hours after infusion. LMWH has a half life of 4-5 h.

The use of LMWH has allowed for once daily dosing and it does not require continuous infusion. If long term anticoagulation is used heparin is often only used to commence anticoagulation therapy until the oral anticoagulant warfarin takes effect.

Contraindications to Warfarin

Warfarin is contraindicated in pregnancy as it passes through the placental barrier and may cause foetal bleeding. During pregnancy it may cause abortion, still birth, neonatal death or preterm birth. Warfarin is also teratogenic and can cause birth defects.

Warfarin is usually avoided in the first trimester, and LMWH is used instead. With heparin, there is still the risk of maternal hemorrhage and other complications is still increased, but they do not cross the placental barrier and therefore do not cause birth defects.

Warfarin administration in the second and third trimesters is much less commonly associated with birth defects, and when they do occur, are considerably different from fetal warfarin syndrome.

Adverse Effects of Warfarin

The most common side-effect of warfarin treatment is bleeding. Risk of major bleeding is slight, but it is more dangerous if the INR is frequently out of range. The symptoms are usuall bad bruising or bleeding from nose, gums or in the urine or stool.

The risk of bleeding is increased when warfarin is used with antiplatelets such as aspirin, NSAIDS or clopidrogel. Also there may be increased risk in the elderly or in those who are hemodialysis.

In patients with protein C deficiency, there is an increased risk of warfarin necrosis, a rare but serious complication that can cause massive thrombosis, skin necrosis and gangrene of the limbs.

There is some evidence that in some women on warfarin BMD is reduced and thus there is an increased risk of an osteoporotic vertebral or rib fracture.

Purple toe syndrome is another rare complication with cholesterol deposited into the blood vessels in the feet. It characterised by discolouration of the foot and can be painful.

Warfarin Versus Antiplatelets

Warfarin treatment, if the INR is maintained within the therapeutic range, is more effective than antiplatelet treatment for stroke prevention in AF patients.

Adding an antiplatelet, such as low dose aspirin, for patients who are already taking warfarin may further reduce the risk of systemic embolism but can increase the risk of bleeding, including major bleeds.

Rationale for New Oral Anticoagulants

Long-term warfarin offers challenges from a logistics point of view but also challenges in terms of efficacy. In patients with AF there is very poor uptake rates of 30-40% and many who should be on anticoagulant therapy are not. Therefore, a clear care gap exists and this is where novel compounds fit. The ideal anticoagulant agents should have the following characteristics:

  • An oral compound as it is much more convenient.
  • Once a day fixed doses. Does not have to be dose adjusted as with warfarin.
  • Rapid onset and offset of action and thus is convenient for interruption for procedures or surgery.
  • Predictable pharmacokinetics.
  • Low propensity for food and drug interactions.
  • Wide therapeutic window.

Newer Oral Agents

The development of the newer agents has focused on the coagulation cascade and the aim has been to be to develop more direct and targeted inhibitors than the heparin antithrombin II inhibitors.

The big challenge to developing new compounds is that warfarin is such an effective medicine. Warfarin works between 2-3 and reduces the risk of VTE by 80-90% and risk in AF by 66-70%. When trying to evaluate a novel anticoagulant, as warfarin already has such usefulness, the need is to find out if it is comparable and equivalent to the established medicine, which is warfarin itself.

Warfarin works extraordinarily well. We know the danger of major bleeding and there is not the decades of experience with other novel anticoagulants. There is the concern that if something enters into clinical practice that is easy to prescribe and does not require monitoring that it might increase the bleeding risk.

Performing clinical trials of the newer oral anticoagulant therapies remains fraught with difficulty. It is very difficult to perform head to head trials against warfarin to show superiority, and most are designed to show non-inferiority.

The newer agents have been shown to be non-inferior but these studies have the disadvantage that if a patient is doing well on warfarin. There is not sufficient evidence to consider taking a patient off warfarin, and putting them on an alternative oral agent.

The clear ideal therapeutic targets in the cascade are Xa and thrombin (IIa). Thrombin inhibition has the advantage that it is further up the cascade, but there are other possibly beneficial effects of thrombin that are lost with inhibition. Xa inhibition is more selective for the clotting cascade.

Oral direct thrombin inhibitors include ximelagatran and dabigatran. Ximelagatrin was shown to be non-inferior to warfarin, but there it was shown that patients who took it had liver toxicity problems so development was discontinued.

Dabigtran does not cause liver damage and has recently been shown to be more effective than warfarin for thromboprophylaxis in AF, but the rate of myocardial infarction might be higher.

Idraparinux, a subcutaneous Xa inhibitor, with a long half life has the disadvantage of no antidote. The development of the biotinylated antidote version has been discontinued.

Indication for Newer Agents

These new anticoagulants are generally used for poor warfarin candidate patients who can’t tolerate or don’t take warfarin, for patients with active cancer where quality of life is very important and daily injections are difficult, and in patients with a mechanical bio-prosthetic valve.

Cost factors may be a deciding factor in using newer agents. It is also important that these medications currently don’t have antidotes. This raises the thorny issue of how to monitor and manage acute bleeding. Currently, the option is to wait until anticoagulants are eliminated and their half-life is thus a crucial factor.

Warfarin Still Wins

Warfarin has an awful lot of complications. It has enormous limitations. But it is still considered the mainstay treatment for long-term anticoagulation.

Promising novel anticoagulants are coming into established clinical practice. Most of the indication will be in the prevention of VTE. Cost will limit their use.



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