Oral anticoagulation therapy

Warfarin (and related coumarin compounds) inhibits the activity of hepatic vitamin K-2,3 epoxide, which is used to recycle the active form of vitamin K, vitamin K hydroquinone. Without sufficient vitamin K hydroquinone, clotting factors II, VII, IX, and X fail to be carboxylated, leaving them in an inactive state. The onset of warfarin anticoagulation is gradual and related to the elimination half-lives of the already synthesized active forms of these procoagulation factors.

In addition to inhibiting the formation of active factors II, VII, IX, and X, warfarin also inhibits the vitamin K–dependent formation of two coagulation inhibitors, proteins C and S, which may temporarily create a relative procoagulant state until full anticoagulation is achieved.

Warfarin is a racemic mixture of S and R isomers. The S isomer has more inhibitory activity and is metabolized primarily by cytochrome P450 (CYP) 2C9, which is the major source of drug interactions with warfarin. The R isomer is metabolized primarily by CYP3A4 and CYP1A2, resulting in additional drug interactions.

The intensity of anticoagulation with warfarin depends primarily on the indication for anticoagulation. These are given in Table 67.1 .

For most patients with noncardioembolic ischemic stroke, the underlying pathophysiology is similar to that of acute coronary syndromes—that is, arterial atherothrombosis. Therefore, antiplatelet drugs either alone or in combination have been slightly superior to warfarin in comparative trials for stroke prevention. In addition, despite no clinical advantage, the warfarin patients experience much more major and minor bleeding. Thus warfarin has a limited role added to antiplatelet therapy in selected patients with stroke or transient ischemic attack (TIA) (see Table 67.1 ).

If initial treatment with a parenteral anticoagulant and warfarin is chosen for treatment of venous thromboembolism (VTE), warfarin should be initiated on day 1 of treatment. Choice of dose must be individualized based on patient-specific factors (age, concurrent medications, nutrition status, and comorbidities). However, for most patients, 5 mg daily is an adequate starting dose. According to the 2016 AC Forum Guidance document, the initial dose of warfarin should be 5 mg or 10 mg for most patients. Lower doses may be considered for patients with heart failure, those taking interacting drugs that inhibit warfarin metabolism, malnourished patients, those with liver disease, and patients older than 75 years of age. Initial doses higher than 10 mg should be avoided.

The international normalized ratio (INR) should be measured daily starting at day 3 of treatment, and the dose should be adjusted to achieve an INR of at least 2.0 by day 5. Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or fondaparinux should be overlapped with warfarin for a minimum of 4 to 5 days and until the INR is therapeutic (INR more than 2.5 for 1 day or more than 2.0 for two consecutive days). Switching between warfarin and the direct oral anticoagulants (DOACs) is reviewed later in this chapter.

Because of its complex metabolism and relatively narrow therapeutic index, drug interactions involving warfarin are both common and clinically significant. The majority of the interactions occurs at the level of CYP metabolism, although other mechanisms may be possible. Table 67.2 lists some of the more common interactions.

For interactions listed as the causation being probable or highly probable, the strength of the clinical evidence is sufficient to expect a change in INR, requiring either adjusting the warfarin dose up or down by 25% to 50% in anticipation of the resulting change in INR or frequent INR monitoring to determine the dose adjustment necessary.

Foods and supplements may also alter the INR. Foods that increase the INR (enhance warfarin’s effect) include garlic, danshen, chamomile, cannabis, mango, grapefruit juice, and possibly cranberry juice. Foods and supplements that reduce the INR (reduce warfarin’s effect) include high vitamin K–content foods (e.g., green tea), ginseng, St. John’s wort, enteral feeds, and soy milk. Ginger, ginkgo biloba, and fish oil have additive antithrombotic effects and could increase the risk of bleeding.

Concomitant drugs such as nonsteroidal anti-inflammatory agents, aspirin, and serotonin reuptake inhibitors (e.g., fluoxetine and sertraline) also have antiplatelet effects and should be avoided if possible, and if coprescribed, the patient should be monitored more carefully for bleeding.

Warfarin dosing is challenging, in part, because of the varied response and the wide range of doses required to achieve a therapeutic INR in an individual patient. Contributors to this variability are polymorphisms in the CYP 2C9, metabolizing enzyme responsible for the majority of warfarin metabolism and, in the target enzyme for warfarin, vitamin K epoxide reductase. Patients with either or both of these genetic polymorphisms tend to be more sensitive to warfarin and require lower doses. Three large randomized clinical trials have failed to demonstrate the clinical utility of routine pharmacogenomic testing. At present, such testing is neither inexpensive nor readily available. For these reasons, the American College of Chest Physicians (ACCP) and the AC Forum currently recommend against pharmacogenetic testing for most patients initiating warfarin.

Warfarin has been the standard of care for patients with cirrhosis because the INR may be monitored. However, management of warfarin in patients with underlying significant liver disease can be difficult. In addition to elevated baseline INRs, these patients often have low protein stores, thrombocytopenia, and reduced hepatic clearance, making them especially sensitive to effects of warfarin and more likely to have significant bleeding issues. Recommendations include lower warfarin starting doses and more frequent INR and clinical monitoring. Recent data suggest it may be reasonable to use a DOAC for mild to moderate chronic liver disease (along with increased clinical monitoring), especially for treatment of portal vein thrombosis in patients with compensated cirrhosis without thrombocytopenia. Rivaroxaban has been associated with drug-induced liver injury and should be avoided in these patients. Clinicians prescribing anticoagulants in patients with chronic liver disease should be familiar with agent-specific anticoagulation reversal as these patients are at increased risk of bleeding.