Warfarin and Adverse Drug Events

US Pharm. 2008;33(2):22-25.

Warfarin, the oral anticoagulant most frequently used to control and prevent thromboembolic disorders, is increasingly common among seniors.^1,2 The debate continues, however, regarding the risks associated with therapy, even though its use has been extensively studied in the geriatric population.³ In fact, the black box warnings for warfarin therapy include age over 65 years as a specific risk factor for bleeding. While seniors derive the greatest benefit from anticoagulant therapy, the elderly demonstrate an enhanced responsiveness to warfarin, and pharmacists need to provide monitoring that is delivered with greater vigilance in this population. ^1,4

In the U.S., approximately two million individuals use warfarin as maintenance therapy in the treatment of atrial fibrillation or to prevent blood clotting after a heart attack, stroke, fracture, or surgery.⁵ Warfarin sodium (Coumadin), introduced into the American marketplace in 1954, continues to rank highly among prescription medications dispensed--over 30 million in 2006.^6-8 From patient to patient, dosages vary widely, with a tenfold difference in strength between the least potent and most potent tablet. Even for an individual patient, the dosage is often adjusted to accommodate a response due to interactions with other medications, nutritional supplements, herbal products, food, and alcohol, resulting in time-intensive management for both health care provider and patient alike. Arriving at the specific dose that avoids hemorrhagic complications while at the same time achieving sufficient suppression of thrombosis requires a thorough understanding of the drug's unique pharmacology.

Anticoagulation clinics have been operating for over three decades to manage patients receiving warfarin with its complex doseñresponse relationship; however, safe and effective use remains a challenge due to the multifaceted potential for altered response to therapy (TABLE 1).^2,6,9 This difficulty underscores the need for all pharmacists involved in the care of the warfarin patient to closely monitor therapy--from the anticoagulation pharmacist, to the dispensing pharmacist, to the consultant pharmacist, to the hospital pharmacist--across all health care settings so that the continuum of care does not falter. This notion of comprehensive monitoring and the significance of the pharmacist's involvement in the outcome of the warfarin patient is represented in the following tenet of pharmacotherapy: "Careful observation of a patient's response to treatment is necessary to confirm efficacy, prevent, detect, or manage adverse effects, assess compliance, and determine the need for dosage adjustment or discontinuation of drug therapy."¹⁰

Emergency Department Visits
A recent large study looking at emergency department (ED) visits for the adverse events among persons 65 years or older found that, aside from the small percentage (3.6%) of visits for adverse drug events (ADEs) associated with medications considered to be always potentially inappropriate in the elderly (i.e., according to the Beers criteria), approximately one-third of all visits were for adverse events associated with warfarin (17.3%), insulin (13.0%), and digoxin (3.2%).^11,12 The researchers reported that, considering frequency of prescribing, the risk of ED visits from warfarin, insulin, and digoxin is 35 times greater than the risk of visits from Beers criteria medications.¹² The researchers suggested that performance measures and interventions targeting warfarin, insulin, and digoxin use could prevent more ED visits for adverse events.¹²†

Key Issues and Adverse Events
Seniors may be more prone to excessive anticoagulation secondary to comorbidities, nutritional deficiencies, and multiple drug interactions.¹ Bleeding is the most common complication of warfarin therapy, contributing to medication-related ED visits, morbidity, mortality, and increased health care expenditures. The increased risk of falls in this population is also a factor related to bleeding.¹ Pharmacists should note that warfarin is contraindicated in a patient who has a history of falls or is a significant fall risk.¹³

Bleeding: The primary adverse effect from warfarin is bleeding.¹ The most powerful risk factor for bleeding is intensity of anticoagulation (e.g., international normalized ratio [INR] > 4.0); others include age greater than 65; initiation of therapy (first few weeks), comorbidities (cerebrovascular disease, renal failure, malignancy); a history of gastrointestinal bleeding; concurrent antiplatelet drug or NSAID use; recent surgery, trauma, or fall; heavy alcohol use; and unstable anticoagulation response.¹ Patients with two or three risk factors have a considerably higher incidence of warfarin-associated bleeding compared with those with one or none.¹⁴ Changes in dosage should be made more cautiously in the geriatric patient. ¹ Reference 13 provides thorough charts for INR ranges (based on indication) and the management of elevated INR (with no significant bleeding, serious bleeding, or life-threatening bleeding), an extensive list of warfarin drug interactions (including CYP-450 information), and specific geriatric dosing and administration issues.¹³

The reader is reminded of the importance of postmarketing surveillance with newer drugs; its significance was illustrated by the drug celecoxib, which showed no interactions in phase 2 studies but was subsequently suspected of potentiating the effect of warfarin in several case reports.¹⁵ Furthermore, the clinician should not overlook the potential interactions with less well-regulated herbal medicines. Due to these considerations, the INR should be measured more frequently when virtually any drug or herbal medicine is added to or withdrawn from the medication regimen of a warfarin patient.¹⁴ Additionally, it is considered a generally good practice to monitor response with additional INR determinations in the period immediately following discharge from the hospital.¹⁶

Combination Aspirin and Warfarin Therapy: Following an acute coronary syndrome (i.e., clot formation subsequent to plaque rupture), anticoagulation with warfarin is considered in addition to aspirin in selected patients (e.g., left ventricular thrombus; extensive ventricular wall motion abnormalities on cardiac echocardiogram; history of thromboembolic disease or chronic atrial fibrillation).¹⁷ Patients receiving combination warfarin and aspirin therapy are at increased risk for minor and major bleeding.^18† With regard to adherence, individuals on this combination therapy have been shown to be two to three times more likely to discontinue their treatment. ¹⁸ Even though warfarin in combination with aspirin is superior to aspirin monotherapy, it is not currently recommended as a preferred regimen in practice guidelines by any professional association in patients other than those mentioned earlier.¹⁸

Nonhemorrhagic Adverse Effects: The most important side effect of warfarin, other than hemorrhage, is skin necrosis. While uncommon, its appearance is sudden in onset, is causedby extensive thrombosis of venules and capillaries within subcutaneousfat, and is recognized by patchy skin necrosis observed on the third to eighth day of therapy initiation.¹⁴ While the complete pathogenesis of this complication is uncertain and reports link warfarin-induced skin necrosis and protein C deficiency and, less commonly, protein S deficiency, this condition also occurs in patients without these issues.¹⁴ Since warfarin is considered contraindicated in these individuals and long-term treatment with heparin is inconvenient and associated with osteoporosis, warfarin should be discontinued immediately, vitamin K should be administered, and full-dose unfractionated heparin or low-molecular-weight heparin therapy should be initiated.¹ †Warfarin should be restarted with extreme caution, if at all, in patients with a history of skin necrosis.¹

Medication Errors: A medication error is certainly one of many circumstances that can potentially alter a desired therapeutic outcome of drug therapy (TABLE 1). In general, prescribing errors are common, and the elderly are especially at risk. ⁹ A drug error most commonly results from a patient's confusion about how to take medication.⁹ Dosing instructions should therefore be completely explained. Convenient, safe packaging with clear labeling should be provided, proper storage requirements discussed, and expiration date noted. Nonchildproof packaging should be supplied to a senior to avoid difficulty in opening, as long as children are not likely to have access to the product. ⁹ Furthermore, pharmacists are encouraged to maintain a complete problem list and obtain information regarding all medications that are being prescribed by all involved health care providers; OTCs, nutritional supplements, and herbal therapies should also be included.

Nutritional Factors: Changes in the usual intake of vitamin K may cause variable anticoagulation effects of warfarin.¹⁹ The dietary requirement for vitamin K is about 100 mcg daily, and while deficiency of vitamin K from inadequate diet is extremely rare, a patient with a borderline intake may become deficient in an acute situation where food is withheld or appetite is diminished and antibiotic therapy is required.²⁰ Exquisite sensitivity to warfarin, not uncommon in the elderly, disappears when the dietary intake is supplemented with 80 to 150 mcg of vitamin K daily.²⁰ With appropriate and steady supplementation, the dietary intake of vitamin K becomes a minor consideration in the overall equation, with sensitivity to warfarin returning to normal.²⁰

Reference 1 provides a thorough listing of potential warfarin interactions with herbal and nutritional products and a table noting the vitamin K content of selected foods.¹

Pharmacogenetics: Pharmacogenetics refers to variations in medication response secondary to genetic makeup. It has been predicted that future personalization of warfarin dosing using technology to determine genetic information can save over one billion health care dollars annually in the U.S.^21,22 Along these lines, in August of 2007, the FDA announced a new label for warfarin that for the first time discussed the genetic factors related to therapy. Under the "Precautions" heading in the package insert, it states, "Numerous factors, alone or in combination including changes in diet, medications, botanicals, and genetic variations in the CYP2C9 and VKORC1 enzymes may influence the response of the patient to warfarin."²³ About 10 percent of the difference in patients' responses to warfarin is attributed to variations in a gene encoding the CYP2C9 enzyme that metabolizes warfarin. ^22,24 The recently identified gene, vitamin K epoxide reductase, or VKORC1, is a key component in the clotting process and the primary target of warfarin.^22,25

Conclusion

Comprehensive monitoring, one of the principles of pharmacotherapy, is especially important as part of the pharmaceutical care plan for the warfarin patient. By understanding potential warfarin adverse events, including pharmacogenetic issues and sources and manifestations of medication errors, the pharmacist may be better equipped to identify, resolve, and prevent them. Awareness of key issues related to warfarin therapy can provide for a more tailored medication regimen. There continues to be confirmation regarding the notion that, among seniors, strategies to decrease ADEs in general should include a focus on warfarin.

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