Blood Thinning Medications: Alternatives to Warfarin

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The Latest in Blood Thinning Medications: Alternatives to Warfarin

Healthylife Pharmacy20 June 2016|3 min read

Blood thinners do not actually "thin" the blood. Instead, they decrease the blood's ability to clot. Decreased clotting keeps fewer harmful blood clots from forming and from blocking blood vessels. There are two main types of what are commonly referred to as "blood thinners." Anticoagulants and Antiplatelets. Anticoagulants, such as warfarin (also called Coumadin or Marevan), work on clotting factors in the body to lengthen the time it takes to form a blood clot. Antiplatelet drugs, such as aspirin, prevent blood cells called platelets from clumping together to form a clot.

Anticoagulants are most effective for conditions involving venous clots. Venous clots result when an excessive amount of fibrin, a protein that causes blood clotting, develops in blood. An anticoagulant dissolves venous clots by disrupting the development of fibrin, thereby it is the best drug choice for conditions such as deep vein thrombosis or pulmonary embolism. In contrast, antiplatelet drugs are not generally suitable for treating venous clots and are most effective for preventing arterial clots.

What Is Warfarin?

Warfarin continues to be the gold standard in terms of oral anticoagulant therapy. Anticoagulants are used to prevent blood clotting. Warfarin acts by antagonising (blocking the effect of) vitamin K which is needed for the synthesis of clotting factors. The most common indications for warfarinisation are:

  • atrial fibrillation (a type of abnormal heart rhythm that predisposes to stroke)
  • deep vein thrombosis (a blood clot in the deep veins of the legs or pelvis)
  • pulmonary embolus (blockage of a main artery of the lung by a blood clot that has migrated from elsewhere in the body through the bloodstream; also called a thromboembolus)
  • prosthetic heart valves (pose a risk of thromboembolism)
  • high-risk myocardial infarction (which poses a risk of thromboembolism)

Pros and Cons of Warfarin?

Warfarin has advantages and disadvantages. Its primary advantages include its clearly established effectiveness and low cost. On the other hand, it is a difficult medication to take on a regular basis. It requires frequent blood test monitoring to maintain proper dosing.

The range for both safety and efficacy is measured using the international normalised ratio (INR), a laboratory measurement of how long it takes blood to form a clot. The INR is influenced by many factors including diet, age, concurrent illness, alcohol, smoking, exercise andother medications being taken. 

Patients must get blood tests monthly or more often and watch their intake of vitamin K, found in foods such as spinach, kale, and chard. Vitamin K is essential for the activation of certain clotting factors (II, VII, IX and X). Too much vitamin K in the blood can lower the INR and lessen the effectiveness of warfarin.

Numerous common medications interact with warfarin and deregulate the INR (e.g. antibiotics, aspirin, paracetamol). INR values over 4.5 increase the risk of major haemorrhage (internal bleeding), and an INR less than 2 increases the risk of blood clotting rendering the medication ineffective. These shortcomings have prompted the development of new types of oral anticoagulants.

Alternatives to Warfarin?

New oral anticoagulant drugs.

Three new oral anticoagulants have become available in recent years thus increasing therapeutic options for patients with appropriate indications.

They include:

  • dabigatran (Pradaxa)
  • rivaroxaban (Xaralto)
  • apixaban (Eliquis)

Unlike warfarin, they work independently of the vitamin K pathway, and there is no equivalent of the INR blood test needed to monitor the effects of these agents on blood clotting.

Dabigatran inhibits coagulation factor IIa (thrombin), and rivaroxaban and apixaban inhibit coagulation factor Xa. If blood levels of these drugs rise too much, there is no specific ''antidote'' as there is with warfarin. If excessive anticoagulation occurs with warfarin, administration of vitamin K effectively reverses the anticoagulant effect. Other drawbacks of the new drugs include their high cost and their lack of long-term safety data. The new agents also have relatively short half-lives such that if a patient misses a dose, the risk of clot formation goes up fairly quickly until the next scheduled dose is taken. 

Dabigatran etexilate, rivaroxaban and apixaban are recommended for the prevention of venous thromboembolism: All are licensed for use in adults after total hip replacement or total knee replacement surgery. The new anticoagulants have been shown to be as effective as warfarin in reducing the risk of stroke and embolisation in patients with atrial fibrillation. All three new drugs are approved for the treatment of atrial fibrillation in patients who do not have heart valve problems or artificial heart valves and have one or more of the following risk factors: 

For dabigatran etexilate:

  • Previous stroke.
  • Previous transient ischaemic attack.
  • Previous systemic embolism.
  • Left ventricular ejection fraction below 40%.
  • Symptomatic heart failure of New York Heart Association (NYHA) class 2 or above.
  • Age 75 years or older.
  • Age 65 years or older with one of the following: diabetes mellitus, coronary artery disease or hypertension.

For rivaroxaban and apixaban:

  • Congestive heart failure.
  • Hypertension.
  • Age 75 years or older.
  • Diabetes mellitus.
  • Prior stroke or transient ischaemic attack.

Availability and cost

Dabigatran, apixaban and rivaroxaban are all subsidised by the Australian Pharmaceutical Benefits Scheme (PBS) for preventing stroke in people with atrial fibrillation, for preventing blood clots after hip and knee replacement surgery, and for preventing blood clots recurring in people who have had a prior deep vein thrombosis or pulmonary embolism. Rivaroxaban is also PBS subsidised for treating deep vein thrombosis and pulmonary embolus. If the patient does not qualify for PBS subsidy, the medication is still available at full cost. This can be as much as $100 per month. No direct head-to-head comparison of the three new anticoagulant drugs has yet been performed.

What Are Antiplatelet Agents?

Platelet function

A thrombus (blood clot) is a life-saving process when it occurs in the presence of haemorrhage, and a life-threatening process when it occurs at any other time.

Platelets play a key role in the formation of thrombosis. In the normal process, when haemorrhage occurs as the result of trauma or surgery, platelets commence the process of clot formation in an attempt to seal the wound to reduce bleeding.

Platelets, the smallest of the three major types of blood cells, play a primary role in clot formation in diseases such as coronary thrombosis, stroke, deep vein thrombosis, and transient ischemic attack.

Antiplatelet Drugs

"Antiplatelet drugs" is a generic term, describing agents which decrease platelet aggregation and inhibit thrombus formation.

There are four classes of antiplatelet drugs: the thienopyridines, COX-1 inhibitors, phosphodiesterase inhibitors, and GPIIb/IIIa antagonists. 

Aspirin

Aspirin has been the drug of choice for over half a century for the primary and secondary prevention of thrombotic events. Aspirin is recommended in patients with angina, previous heart attack or stroke (i.e. secondary prevention), but it is not clear whether patients who have not previously experienced angina, heart attack or stroke benefit from aspirin (i.e. primary prevention). If rapid and complete platelet inhibition is required (e.g. if a patient is having a heart attack), the first dose of aspirin should be 160 to 325 mg. For long-term prevention of cardiovascular disease in Australia, the recommended dose of aspirin is 100mg once daily. Some guidelines recommend only low-dose aspirin (75 to 100 mg) for long-term prevention, based on evidence that higher doses cause more gastrointestinal bleeding but do not provide additional protection against heart attack and stroke.

Dipyridamole

Dipyridamole (Persantin) is indicated as an adjunct to warfarin in the prevention of postoperative thromboembolic complications of cardiac valve replacement. The American College of Chest Physicians guidelines also recommends the combination of aspirin and ER (extended release) dipyridamole over aspirin alone. This recommendation comes as a result of two published trials, ESPS-2 and ESPRIT.

Thienopyridines

The thienopyridines (ticlopidine, clopidogrel, and prasugrel) are all used before and after percutaneous coronary intervention (PCI) procedures to prevent stent thrombosis. Percutaneous coronary intervention (commonly known as coronary angioplasty or simply angioplasty) involves the use of a balloon catheter to dilate a narrowed artery. A stent is often placed at the site of blockage to maintain patency of the artery. Currently, the drug of choice is clopidogrel, which is indicated for medical management of acute coronary syndrome in addition to prevention of stent thrombosis.

Acute coronary syndrome refers to any group of clinical symptoms compatible with acute myocardial ischemia and includes: 

  • unstable angina
  • non-ST-segment elevation myocardial infarction (NSTEMI)
  • ST-segment elevation myocardial infarction (STEMI)

Ticlopidine, the earlier generation thienopyridine, has fallen out of favour for prevention of stroke and stent thrombosis as a result of haematologic reactions, including neutropenia, agranulocytosis, thrombotic thrombocytopenia purpura, and aplastic anemia. In acute coronary syndrome patients undergoing PCI, recent evidence has suggested that clopidogrel may be less clinically efficacious than pragugrel. Prasugrel yields greater inhibition of platelet aggregation. Initially, clopidogrel was shown to be more efficacious than aspirin as a single drug in reducing ischemic risk in stable patients with atherosclerosis. Additional trials have shown a significant reduction in the number of both short and long-term ischemic events when clopidogrel and aspirin are used together in acute coronary syndrome patients (see section below on dual antiplatelet therapy). 

For secondary prevention of major cardiovascular events in indicated patients, clopidogrel and aspirin combined are considered the medications of choice. Ticagrelor is indicated for the prevention of thrombotic events (for example, stroke or heart attack) in patients with acute coronary syndrome or myocardial infarction with ST elevation. The drug is combined with aspirin unless the latter is contraindicated. 

Treatment of acute coronary syndromes with ticagrelor as compared with clopidogrel significantly reduces the rate of death. The advantages of new antiplatelet medications, such as clopidogrel and prasugrel, over older medications, such as dipyridamole and ticlopidine, are less frequent dosages each day and fewer side effects. This is important in terms of patient compliance; however, the newer medications are costlier.

Warfarin Versus Aspirin

Warfarin has been shown in multiple trials to be superior to aspirin for patients with atrial fibrillation, and is clearly indicated in patients with stroke caused by atrial fibrillation if there are no contraindications to therapy. Recent trials, however, have failed to show a significant benefit for warfarin over aspirin for ischemic stroke not associated with atrial fibrillation. 

The Warfarin Aspirin Recurrent Stroke Study (WARSS) was a superiority trial that compared aspirin to warfarin for secondary stroke prevention in 2,206 patients with recent noncardioembolic stroke - that is a clot that occludes a brain vessel but did not come from the heart.

 Stroke rates as well as major haemorrhage rates were non-significantly higher in the warfarin arm. 

The American College of Cardiology has recommended antiplatelet agents over oral anticoagulation for most patients with noncardioembolic stroke.

Risk of Bleeding

All anticoagulants and antiplatelet drugs pose a significant risk of bleeding.

Aspirin

The incidence of major haemorrhage with aspirin alone is approximately 1.5% per year. The incidence of gastrointestinal bleeding, the most common type of major bleed among patients receiving aspirin therapy, is positively correlated with dose. This is a main reason why low-dose aspirin is currently preferred to high-dose for secondary prevention of stroke.

Antiplatelet agents

The risks of haemorrhage with antiplatelet agents are generally similar to those of aspirin. Major hemorrhage with clopidogrel in the CAPRIE trial (1.4%) was similar to that in the aspirin arm (1.6%). Similarly, extended release dipyridamole plus aspirin resulted in rates of bleeding of any type similar to those of aspirin monotherapy (8.7% vs 8.2%). Ticlopidine was found to have a lower rate of major haemorrhage (0.5%) than aspirin (1.4%), and the rates of minor bleeding were similar between the two groups (9% vs 10%). Clopidogrel in the CAPRIE trial (1.4%) was similar to that in the aspirin arm (1.6%).

Are There Benefits in Combining Anticoagulants and Antiplatelet Drugs?

Warfarin plus aspirin use for patients with Mechanical Heart Valves: 

Overall, there does not appear to be compelling evidence that combined warfarin-aspirin therapy is more effective than warfarin alone for the prevention of cardiovascular and thromboembolic events but there is consistent evidence that warfarin-aspirin therapy increases serious bleeding. The exception to this conclusion is patients with mechanical heart valves who, despite an increased risk for serious bleeding with combination therapy, derive a net therapeutic benefit with warfarin-aspirin because the reduction in thromboembolic events outweighs the increase in the risk for serious bleeding. Patients with prosthetic heart valves should not take Pradaxa, Xarelto, or Eliquis nor should patients with atrial fibrillation that is caused by a heart valve problem. Although these patients have not been studied in clinical trials with rivaroxaban or apixaban, a study involving dabigitran, patients with mechanical heart valves had higher rates of clot formation.

Dual or triple antiplatelet therapy

Acute coronary syndrome

Dual antiplatelet regimens are a mainstay in the management of acute coronary syndrome and typically consist of aspirin combined with a thienopyridine (eg, clopidogrel, prasugrel, ticagrelor) or a glycoprotein IIb/IIIa inhibitor (eg, abciximab, eptifibatide, tirofiban) before and during percutaneous coronary intervention (PCI). Following PCI, aspirin is combined with a thienopyridine to prevent restenosis.

Percutaneous coronary intervention with stent placement

In patients who have undergone percutaneous coronary intervention with stent implantation, dual antiplatelet therapy with aspirin and a thienopyridine—ie, clopidogrel (Plavix) or ticlopidine (Ticlid)—is superior to aspirin or warfarin alone in reducing the risk of stent thrombosis and major adverse cardiovascular events such as myocardial infarction or urgent revascularization.If patients have an indication for long-term anticoagulation, triple therapy with aspirin, warfarin, and clopidogrel or ticlopidine may be considered in order to reduce the likelihood of stent thrombosis. 

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