Despite taking higher doses of warfarin, my patient’s INR won’t budge. What am I missing?

Poor compliance is probably the most common and least “exciting” explanation for low INRs despite seemingly adequate or high warfarin doses.  Otherwise, consider the following: 

Increased vitamin K intake: Since warfarin acts by inhibiting vitamin K recycling by VKORC1 (Vitamin K epOxide Reductase Complex), find out if your patient takes multivitamins or loves foods or products rich in vitamin K, ranging from leafy green vegetables to nutritional supplements( eg, Ensure) and even chewing tobacco!1 

Drug interactions: Warfarin is notorious for interacting with many drugs, although its effect is more often enhanced than counteracted. Run the patient’s med list and look for “counteractors” of warfarin,  including carbamazepine, phenobarbital, phenytoin, rifampin, and dexamethasone.2 

Hypothyroidism: Thyroid hormone seems to be necessary for efficient clearance of the vitamin K-dependent clotting factors (II, VII, IX, and X). Thus, larger doses of warfarin may be needed when patients are hypothyroid.3 

Hyperlipidemia and obesity: High lipid levels may allow for high vitamin K levels (since it’s lipid-soluble and carried in VLDL), especially at the start of therapy.4,5 

What if the INR is falsely low? This is usually not the problem although one major trial took a lot of heat for using a point of care INR device that gave low readings in anemic patients.6  When in doubt, check a chromogenic factor Xa test to confirm; 20-30% activity correlates with a true INR of 2-3.7

If none of these explanations fit the bill, consider genetic testing for warfarin resistance.8,9

Bonus Pearl: Did you know that use of warfarin (introduced in 1948 as a rodenticide) has already led to some selective pressure for VKORC1 mutations in exposed rat populations.10

References

  1. Kuykendall JR, et al. Possible warfarin failure due to interaction with smokeless tobacco. Ann Pharmacother. 2004 Apr;38(4):595-7. https://www.ncbi.nlm.nih.gov/pubmed/14766993
  2. Zhou SF, et al. Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. https://www.ncbi.nlm.nih.gov/pubmed/19515014
  3. Bucerius J, et al. Impact of short-term hypothyroidism on systemic anticoagulation in patients with thyroid cancer and coumarin therapy. Thyroid. 2006 Apr;16(4):369-74. https://www.ncbi.nlm.nih.gov/pubmed/16646683
  4. Robinson A, et al. Lipids and warfarin requirements. Thromb Haemost. 1990;63:148–149. https://www.ncbi.nlm.nih.gov/pubmed/16646683
  5. Wallace JL, et al. Comparison of initial warfarin response in obese patients versus non-obese patients. J Thromb Thrombolysis. 2013 Jul;36(1):96-101. https://www.ncbi.nlm.nih.gov/pubmed/23015280
  6. Cohen D. Rivaroxaban: can we trust the evidence? BMJ 2016;352:i575. https://www.bmj.com/content/352/bmj.i575/rapid-responses
  7. Sanfelippo MJ, et al. Use of Chromogenic Assay of Factor X to Accept or Reject INR Results in Warfarin Treated Patients. Clin Med Res. 2009 Sep; 7(3): 103–105. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757431/
  8. Rost S, et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature. 2004;427:537–41. https://www.ncbi.nlm.nih.gov/pubmed/14765194
  9. Schwarz UI, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med. 2008 Mar 6;358(10):999-1008. https://www.ncbi.nlm.nih.gov/pubmed/18322281
  10. Rost S, et al. Novel mutations in the VKORC1 gene of wild rats and mice–a response to 50 years of selection pressure by warfarin? BMC Genet. 2009 Feb 6;10:4. https://bmcgenet.biomedcentral.com/articles/10.1186/1471-2156-10-4

Contributed by Nicholas B Bodnar, Harvard Medical School student, Boston, MA.

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Despite taking higher doses of warfarin, my patient’s INR won’t budge. What am I missing?

Should I consider a direct oral anticoagulant for treatment of pulmonary embolism in my obese patient?

Evidence supporting the efficacy of direct oral anticoagulants (DOACs) in obesity is limited. A major concern is the possibility of subtherapeutic anticoagulation in obese patients when standard doses of DOACs are used.

The International Society on Thrombosis and Haemostasis recommends1:

  • Standard fixed dosing of DOACs for patients with BMI ≤ 40 kg/m2 or weight ≤ 120 kg.
  • Avoiding DOACs in patients with BMI > 40 kg/m2 or weight > 120 kg. However, if a DOAC is needed, laboratory confirmation of therapeutic drug concentrations (eg, by checking anti-factor Xa depending on the agent) should be performed, and if subtherapeutic, a vitamin K antagonist (eg, warfarin) is recommended instead.

Based on the individual comparison of DOACs with warfarin in patients with “high” body weight (cut-off of 90 kg or 100 kg, depending on the study) and limited data, apixaban may be more effective in preventing recurrent venous thromboembolism or its related deaths. However, other DOACs, such as rivaroxaban, dabigatran, and edoxaban have also been used in patients with high body weight2.  

To add to the controversy, the efficacy of fixed dose dabigatran in obese patients has been questioned3 and some have recommended avoiding DOACs altogether in patients with BMI ≥ 35 kg/m2 or weight > 120 kg, until more data become available4.

As in many situations in medicine, a case-by-case decision based on clinical judgment and patient preferences may be the best way to go!

References

  1. Martin K, Beyer-Westendorf J, Davidson BL, et al. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14: 1308–13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936273
  2. Di Minno MN, Lupoli R, Di Minno A, et al. Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: A meta-analysis of randomized controlled trials. Ann Med 2015; 47: 61-8. https://www.ncbi.nlm.nih.gov/pubmed/25665582
  3. Breuer L, Ringwald J, Schwab S, et al. Ischemic Stroke in an Obese Patient Receiving Dabigatran. N Engl J Med 2013; 368: 2440–2. http://www.nejm.org/doi/pdf/10.1056/NEJMc1215900
  4. Burnett AE, Mahan CE, Vasquez SR, et al. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE Treatment. J Thromb Thrombolysis 2016; 41: 206-32. https://www.ncbi.nlm.nih.gov/pubmed/26780747

 

Contributed by Mahesh Vidula, MD, Mass General Hospital, Boston, MA.

Should I consider a direct oral anticoagulant for treatment of pulmonary embolism in my obese patient?

What is the utility of bedside skin-fold test in diagnosing Cushing’s syndrome?

Skin atrophy is a common feature of Cushing’s syndrome (CS), a hypercortisol state,  with multiple studies reporting radiographic evidence of reduced skin thickness in this condition1,2.

Measurement of skin thickness on the dorsal aspect of the 2nd or 3rd proximal phalanges on the non-dominant hand by using ECG calipers to pinch together a fold of skin has also been reported to assess skin atrophy in CS, with thickness less than 18 mm correlating strongly with CS3,4; the minimal subcutaneous fat at this location allows for a more accurate measurement of skin thickness.

However, caution should be exercised in interpreting the results of this study. Specifically, some overlap was observed between normal controls and patients with CS.  In addition, the study population was limited to women of reproductive age presenting with oligomenorrhea and hirsutism for at least 2 years, a subset of patients that may account for only 40% of cases with CS5,6.  Further studies are clearly needed to determine the clinical utility of the skin-fold test in patients suspected of CS.

References

  1. Sheppard RH, Meema HE. Skin thickness in endocrine disease. A roentgenographic study. Ann Intern Med 1967;66:531-9.
  2. Ferguson JK, Donald RA, Weston TS, et al. Skin thickness in patients with acromegaly and Cushing’s syndrome and response to treatment. Clin Endocrinol (Oxf) 1983;18:347-53.
  3. Corenblum B, Kwan T, Gee S, et al. Bedside assessment of skin-fold thickness: A useful measurement for distinguishing Cushing’s disease from other causes of hirsutism and oligomenorrhea. Arch Intern Med. 1994;154:777-781.
  4. Loriaux DL. Diagnosis and differential diagnosis of Cushing’s syndrome. N Engl J Med 2017;376:1451-9.
  5. Lindholm J, Juul S, Jorgensen JOL, et al: Incidence and late prognosis of Cushing’s syndrome: a population-based study. J Clin Endocrinol Metab 2001;86:117–123.
  6. Lado-Abeal J, Rodriguez-Arnao J, Newell-Price JD, et al. Menstrual abnormalities in women with Cushing’s disease are correlated with hypercortisolemia rather than raised circulating androgen levels. J Clin Endocrinol Metab. 1998;83:3083-8.

Contributed by Sagar Raju, Medical Student, Harvard Medical School

What is the utility of bedside skin-fold test in diagnosing Cushing’s syndrome?

How does obesity lower serum brain natriuretic peptide (BNP) levels in patients with heart failure?

The association between high body mass index (BMI) and low serum BNP levels  has been reported in heart failure patients with diminished or preserved left ventricular systolic function (1).  

However, The exact mechanism underlying the inverse relationship of BNP levels with BMI is unclear.  Decreased production of BNP by myocytes, increased clearance of BNP and decreased sensitivity of the myocytes to stretch have been proposed (1). 

Of interest, in obese patients who undergo gastric bypass surgery, serum BNP levels increases significantly postoperatively and correlates with weight loss  (2).  

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References 

  1. Stavrakis S, Pakala A, Thomas J et al. Obesity, brain natriuretic peptide levels and mortality in patients hospitalized with heart failure and preserved left ventricular systolic function. Am J Med Sci 2013;345:211-217. https://www.ncbi.nlm.nih.gov/pubmed/23422653
  2. Changchien EM, Shushmita A, Betti F, et al. B-type natriuretic peptide increases after gastric bypass surgery and correlates with weight loss. Surg Endosc 2011;25:2338-2343. https://www.ncbi.nlm.nih.gov/pubmed/21424205
How does obesity lower serum brain natriuretic peptide (BNP) levels in patients with heart failure?