What are the causes of an elevated International Normalized Ratio (INR)?

From the Guidelines

For an elevated INR, the most effective approach to prevent bleeding complications is to stop taking anticoagulant medication immediately and contact a healthcare provider, with oral vitamin K (1-2.5mg) being the preferred treatment for INR values between 5 and 9, as recommended by the European Heart Journal in 2012 1. When managing an elevated INR, it is crucial to consider the risk of bleeding, which increases considerably when the INR exceeds 4.5 and increases exponentially above an INR of 6.0 1. The management of an elevated INR depends on the target INR, the actual INR, and the half-life of the vitamin K antagonist used. Some key points to consider in the management of elevated INR include:

• For minor elevations (INR 3-5) without bleeding, reducing the dose or holding 1-2 doses of anticoagulant medication may be sufficient 1.
• For higher elevations (INR >5) or if bleeding is present, oral vitamin K (1-2.5mg) or, in severe cases (INR >9 or active bleeding), intravenous vitamin K and possibly fresh frozen plasma may be necessary 1.
• The oral route is preferred over the intravenous route for vitamin K administration due to the risk of anaphylaxis associated with intravenous administration 1.
• Immediate reversal of anticoagulation is required only for severe bleeding, defined as not amenable to local control, threatening life or important organ function, causing haemodynamic instability, or requiring an emergency surgical procedure or transfusion 1.
• Intravenous prothrombin complex concentrate has a short half-life and should be combined with oral vitamin K, whatever the INR, and is preferred over fresh frozen plasma when available 1. Regular INR monitoring is essential when taking warfarin, with a target range typically between 2-3 for most conditions, and common causes of elevated INR include medication interactions, dietary changes, alcohol consumption, liver disease, and missed doses 1.

From the FDA Drug Label

The following factors, alone or in combination, may be responsible for INCREASED PT/INR response: ENDOGENOUS FACTORS: blood dyscrasias — diarrhea hyperthyroidism see CONTRAINDICATIONS elevated temperature poor nutritional state cancer hepatic disorders steatorrhea collagen vascular disease infectious hepatitis vitamin K deficiency congestive heart failure jaundice EXOGENOUS FACTORS: Potential drug interactions with warfarin sodium tablets are listed below by drug class and by specific drugs. Classes of Drug also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations * Increased and decreased PT/INR responses have been reported (oral) (17-Alkyl Penicillins, intravenous, Gout Treatment Agents Testosterone Derivatives) (fluoroquinolones) (topical) ogen dextran (intravaginal, oral, systemic) activator (t-PA) dextrothyroxine moricizine hydrochloride* tolbutamide diazoxide nalidixic acid tramadol diclofenac naproxen trimethoprim/sulfamethoxazole dicumarol neomycin urokinase diflunisal norfloxacin valdecoxib disulfiram ofloxacin valproate doxycycline olsalazine vitamin E erythromycin omeprazole zafirlukast esomeprazole oxandrolone zileuton ethacrynic acid oxaprozin ezetimibe oxymetholone fenofibrate pantoprazole

The factors that may be responsible for an elevated INR include:

• Endogenous factors:
  • Blood dyscrasias
  • Diarrhea
  • Hyperthyroidism
  • Elevated temperature
  • Poor nutritional state
  • Cancer
  • Hepatic disorders
  • Steatorrhea
  • Collagen vascular disease
  • Infectious hepatitis
  • Vitamin K deficiency
  • Congestive heart failure
  • Jaundice
• Exogenous factors:
  • Other medications affecting blood elements
  • Dietary deficiencies
  • Prolonged hot weather
  • Unreliable PT/INR determinations
  • Specific drugs such as 17-Alkyl Penicillins, fluoroquinolones, and others 2 2

From the Research

Elevated INR: Management and Treatment

• Elevated INR is a common problem with warfarin therapy and can lead to major or life-threatening bleeding 3, 4.
• Patients who have an elevated INR will need more frequent testing and may also require vitamin K1 3.
• For example, a nonbleeding patient with an INR of 9 can be given low-dose vitamin K1 (eg, 2.5 mg phytonadione, by mouth) 3.
• Patients who have an excessive INR with clinically important bleeding require clotting factors (eg, fresh-frozen plasma) as well as vitamin K1 3.

Reversal of Warfarin Anticoagulation

• Prothrombin complex concentrates (PCCs) offer an alternative to fresh frozen plasma (FFP) for rapidly replacing deficient clotting factors and correcting the international normalized ratio (INR) 5, 6.
• PCCs have been found to be more effective in shortening the time to INR correction and are associated with a low risk of thrombotic adverse events compared to FFP 6, 7.
• A systematic review and meta-analysis found that PCC use was associated with a significant reduction in all-cause mortality compared to FFP, and resulted in a shorter time to INR correction 7.

Treatment Options

• Treatment options for urgent reversal of warfarin include the combination of vitamin K and coagulation factor replacement with either prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP) 7.
• PCC use is more likely to achieve normalization of international normalized ratio (INR) and resulted in a shorter time to INR correction compared to FFP 7.
• Patients receiving PCC had a lower risk of post-transfusion volume overload compared to FFP 7.