Non-vitamin K antagonist oral anticoagulants offer an alternative to warfarin and heparins for treating atrial fibrillation and venous thromboembolism
The disadvantages of warfarin and heparins have led to the development of a new class of drugs known as non-vitamin K antagonist oral anticoagulants. These new drugs are effective, safe and do not need to be monitored with blood tests.
Citation: Blann A (2015) Benefits of a new class of oral anticoagulant. Nursing Times; 111: 16, 15-17.
Author: Andrew Blann is a consultant at City Hospital, Birmingham, and a senior lecturer in medicine at the University of Birmingham.
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Thrombosis is a common complication in a range of health conditions. Arterial blood clots form in the coronary circulation, causing myocardial infarction, or in the brain, causing strokes. Clots that form in veins - venous thromboembolism (VTE) manifesting as pulmonary embolus (PE) or deep vein thrombosis (DVT) - are a common complication among hospital inpatients and contribute to longer hospital stays, morbidity and mortality (International Society on Thrombosis and Haemostasis Steering Committee for World Thrombosis Day, 2014). In contrast to arterial thrombosis, where drugs such as aspirin can suppress platelet function, VTE treatment targets the coagulation pathway. Although atrial fibrillation (AF), a leading cause of thrombotic stroke and systemic embolism, arises in the arterial circulation, anticoagulation (as opposed to anti-platelet therapy) provides better protection from thrombosis (Lip, 2012).
Until about 10 years ago, vitamin K antagonists (VKAs) - warfarin, heparin and low-molecular-weight heparin (LMWH) - were the standard options for the prevention and/or treatment of venous thrombosis (Blann and Khoo, 2009). Table 1 shows the major indications for the use . Although effective, these traditional anticoagulants have several drawbacks (Table 2, attached), which led to the development of non-vitamin K antagonist oral anticoagulants (NOACs). These drugs are taking over from the traditional anticoagulants in a number of well-defined conditions (Bauer, 2013).
Mode of action of anticoagulants
Unlike the traditional anticoagulants, which act indirectly, NOACs act directly on coagulation molecules. The first drug to market, dabigatran, is a direct thrombin inhibitor, while rixaroxaban and apixaban target coagulation factor Xa. The first immediate advantage of NOACs is that they are so stable that routine blood testing is not required. They also have a considerably shorter half-life than VKAs, enabling rapid change in anticoagulation.
How can NOACs be used?
In the UK, the National Institute for Health and Care Excellence (NICE) licenses all health interventions, including drugs. As regards NOACs, the indications focus on prevention and/or treatment of VTE in the case of orthopaedic surgery; in AF; and in acute DVT (Table 3, attached).
With three drugs all proven to be effective in AF and after orthopaedic surgery, the decision about which to offer must be made on clinical grounds (Rachidi et al, 2013). However, no single drug out-performs any other in all areas of efficacy (protection against thrombosis) and safety (avoidance of haemorrhage). Practitioners must consider renal function as each drug is metabolised and excreted differently, leading to different half-lives. The dose of the drug must be reduced in patients wiht renal impairment. There are also co-medication issues to take into account:
- NOACs should not be used alongside drugs of the ketoconazole family;
- The dose of dabigatran may need to be reduced if verapamil, amiodarone or certain antibiotics are being administered (Heidbuchel et al, 2013);
- Rivaroxban may need to be reduced if certain antibiotics are being taken (the same applies to apixaban and diltiazem).
NOACs and atrial fibrillation
The risk of stroke in AF is not fixed, but depends on the number of key risk factors. This risk can be determined from a patient’s CHA2DS2-VASc score, formed from chronic heart failure (C), hypertension (H), age greater than 65 or 75 years (A), diabetes (D), previous stroke or transient ischaemic attack (S), other cardiovascular disease (Va) and female (Sc) (Lip et al, 2010). With each factor scoring one point (age over 75 and previous stroke score 2), the total gives an estimate of risk of a major event for an individual AF patient - the higher the score, the greater the risk of thrombosis. A score of zero means that oral anticoagulant (OAC) medication of any sort is not warranted, but the higher the score, the greater the need for an OAC.
The major side-effect of any anticoagulant is haemorrhage, and the risk of this can be assessed in the same way, this time using the HAS-BLED score: a sum of hypertension (H), abnormal renal/liver function (A), stroke (S), bleeding history or predisposition (B), labile International Normalised Ratio (L), elderly (E) and drugs/alcohol concomitantly (D). The higher the HAS-BLED score, the greater the risk of haemorrhage (Pisters et al, 2010). By comparing the risk of haemorrhage (as HAS-BLED) with the protection from stroke (as CHA2DS2-VASc) the overall clinical benefit of anticoagulation can be obtained (Heidbuchel et al, 2013).
Having decided that the patient requires anticoagulation medication, the next question is whether this should be warfarin or an NOAC. Another scoring system has been developed to help predict the likelihood of achieving good anticoagulation with warfarin in a newly diagnosed non-anticoagulated patient with AF. In this model female sex (S), age less than 60 years (A), medical history of chronic disease (Me), treatment with certain drugs (T), use of tobacco within the last two years (T, 2 points), and non-Caucasian race (R, 2 points) are put together to give the SAMe-TT2R2 score (Apostolakis et al, 2013). If a patient’s SAMe-TT2R2 score is 0 or 1, then warfarin is recommended. For those with SAMe-TT2R2 score >2, an NOAC is recommended.
NOACs and orthopaedic surgery
Unfortunately, there is no assessment score for surgery, but as in AF, NOACs have been shown to be at least as effective, and in some cases superior to low molecular weight heparin (LMWH), the latter sometimes combined with warfarin. The position regarding which NOAC to choose in preventing VTE after orthopaedic surgery is less well explored, but the same general principles (renal function, age, risk) apply as with AF.
NOACs and acute VTE
The third aspect of the relative value of NOACs in prevention and treatment of VTE after an acute VTE or PE (generally in a medical setting) is relatively unexplored as only rivaroxaban has NICE approval (NICE, 2012; EINSTEIN investigators, 2010).
Implications for practice
NOACs will be encountered in a small number of well-defined situations: in AF, after orthopaedic surgery, and after acute DVT or PE (Cowell, 2014). Once an NOAC has been started, the patient will continue to be monitored as with any drug. The role of co-medications and renal function has already been emphasised. Other factors possibly leading to the need to reduce NOAC levels include the use of anti-platelet drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), chemotherapy, a history of or active gastrointestinal bleeding, recent surgery on a critical organ (the brain, the eye) and thrombocytopenia. Practitioners will be aware of factors leading to increased plasma levels of the NOAC, such as increasing age (e.g. >75-80 years) and weight <60kg (Heidbuchel et al, 2013).
Risks of haemorrhage
Excessive and therefore inappropriate use of any kind of anticoagulant may impair the coagulation pathway so that an ineffective thrombus is formed (if at all) and haemorrhage may occur. Monitoring of signs and symptoms of over-anticoagulation, such as bruising and bleeding, is needed, exactly as if the patient was on warfarin. However, the extent of haemorrhage is variable and may not always be treatable. Such haemorrhage may be classified clinically, and the practitioners must make a clinical decision as to the severity (Cushman et al, 2014). The clinical picture will guide action, which is likely to include:
- Determination of recent dosing regimen (time and dose).
- Withholding the NOAC as long as is appropriate and treating symptomatically.
- If haemorrhage is mild, treatment may be little more than temporary drug withdrawal, and fluid replacement to maintain diuresis and blood volume.
- Modest bleeding may be treated locally (for example, compression, tight bandaging of wounds). Oxygenation, fluid and red blood cell replacement, platelet infusions, fresh frozen plasma (as plasma expander, not to maintain haemostasis), tranexamic acid, and desmopressin may need to be considered. There may be endoscopic or surgical intervention to find and treat the source of bleeding.
- If bleeding severely, all the above and consider Factor Xa-inhibitors, concentrates of coagulation factors II, IX and X, charcoal and dialysis.
Some practitioners are concerned that there are as yet no antidotes to NOACs (although they are being developed), and therefore they should be used with caution. However, the alternative to NOACs, warfarin, can actually cause more haemorrhage. NOACs’ short half-life means that an adverse effect soon washes out by simply withholding the drug. If haemorrhage does occur, the treatment is exactly the same as in the use of warfarin.
NOACs are at least as effective in providing protection from thrombosis as their condition-specific comparator (VKA or LMWH), but also have better safety profiles. However, NOACs are not perfect: a trial using dabigatran to treat patients with a mechanical heart valve caused more thrombosis and haemorrhage than warfarin (Eikelboom et al, 2013). It has also been suggested that NOACs may need to be dose-adjusted on a patient-by-patient basis, just as is required for warfarin (Moore et al, 2014).
NOACs are currently more expensive than warfarin. However, since they do not need a routine blood test, the NHS is relieved of the burden of expensive anticoagulant clinics.
With increasing confidence in the use of these agents, it is likely that their use will extend to other conditions where VKAs and/or LMWHs are only partially effective, are inconvenient, and/or are contraindicated, such as in acute coronary syndromes. With further drugs in development, oral anticoagulation will continue to be an important and rapidly developing area for at least the coming five or 10 years.
- The new class of non-vitamin K antagonist oral anticoagulants are as effective as, and may be safer, than traditional anticoagulants for treating AF and VTE
- NOACs do not need to be injected and do not require multiple routine blood tests
- Individual NOACs behave differently and have different half-lives
- As with any anticoagulant there is risk of haemorrhage, so patients need to be monitored
- Practitioners must check for interaction with other medications and consider the patient’s renal function
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