Warfarin and coronary calcification

MAASTRICHT, THE NETHERLANDS. Arterial calcification is commonly associated with atherosclerosis and involves the deposition of calcium phosphate (hydroxyapatite) on artery walls. Atherosclerosis is a major risk factor for ischemic stroke so it is indeed ironic that warfarin has been implicated in the formation of arterial calcification. Australian researchers have reported that rats treated with warfarin develop extensive arterial calcification and concluded that, “It is likely that humans on long-term warfarin treatment have extrahepatic vitamin K deficiency and hence are potentially at increased risk of developing arterial calcification.”[1] US doctors recently reported the case of an otherwise healthy man who developed extensive calcification of the coronary arteries after long-term warfarin treatment. They conclude “that physicians prescribing long-term warfarin treatment should consider arterial calcification as one of its potential consequences.”[2] Dutch researchers have confirmed that a vitamin K deficiency, such as would be induced by warfarin treatment, increases the risk of arterial calcification and conclude that the current RDA for vitamin K is too low.[3]

Unfortunately, the common advice given by physicians to their warfarin-treated patients is to avoid dark green leafy vegetables (the major dietary source of vitamin K) and to strictly avoid vitamin K-containing supplements – thus guaranteeing a vitamin K deficiency.

A group of cardiologists from the University of Maastricht now report that otherwise healthy afibbers treated, often unnecessarily, with warfarin also develop coronary calcification. Their study included 157 atrial fibrillation (AF) patients (69% male) with an average age of 57 years. All participants had a low risk of cardiovascular disease as defined as no hypertension, no diabetes, normal cholesterol levels, age below 70 years, no history of coronary artery disease or stroke, normal kidney function, no cancer, thyroid or pulmonary disease, and no congestive heart failure. Perhaps most significant, none of the study participants had evidence of structural heart disease, so would be classified as lone afibbers. All participants underwent echocardiography and had a 64-slice coronary calcium scan. The Agatston score was used to quantify the degree of calcification as shown in the table below.

Degree of Calcification
Agatston Score
None
0
Minimal
1 - 10
Mild
11 - 100
Moderate
101 - 400
Severe
greater than 400

Out of the total of 157 patients, 79 had an Agatston score above zero, while the remaining 78 patients did not have any detectable calcium in the coronary blood vessels (Agatston score of 0). The authors of the study noted that 71 (45%) of the patients were on warfarin even though their CHA2DS2-VASc score was zero (55 patients) or 1 (all because of female gender). The remaining 86 patients had never been on warfarin. Among patients with an Agatston score of 0, only 32% were on warfarin as compared to 58% in the group with an Agatston score greater than 0. The average Agatston score increased significantly with duration of warfarin use.

The average score among non-users was 53 as compared to 90 for 6 to 60 months of use, and 236 for greater than 60 months of use. In multivariate analysis, older age and duration of warfarin were independent predictors of increased coronary calcium score. The Dutch researchers conclude that many low-risk AF patients are overtreated with warfarin and that such overtreatment should be avoided, especially in young, low-risk afibbers facing a lifelong career as warfarin users.

Weijs, B, Crijns, HJGM, et al. Patients using vitamin K antagonists show increased levels of coronary calcification: an observational study in low-risk atrial fibrillation patients. European Heart Journal, July 20, 2011 [Epub ahead of print]

Editor’s comment: The lesson to be learned from this study is that overtreatment with warfarin is common and should be avoided in order to prevent coronary calcification and the many other adverse effects associated with warfarin usage. See Living with Warfarin for details. Fortunately, another group of researchers from Maastricht University has reported that a high intake of vitamin K2 (menaquinone) is associated with a significantly reduced risk of arterial calcification and coronary heart disease.[4] Furthermore, other studies have reported that warfarin has little effect on the activity of vitamin K2 and that a vitamin K2 intake of 100 micrograms/day has very little effect on INR.[5,6]

Considering the above findings it is tempting to conclude that daily supplementation with menaquinone (100 micrograms/day of the MK-7 form of vitamin K2) would be highly beneficial in reducing arterial calcification (whether warfarin-induced or not), coronary heart disease, and overall mortality without impacting on warfarin’s role in reducing the level of coagulation factors. In other words, supplementing with moderate amounts of vitamin K2 should not affect INR levels. Clinical trials, of course, should and hopefully will be carried out to substantiate or negate this hypothesis.

  1. Howe, AM and Webster, WS. Warfarin exposure and calcification of the arterial system in the rat. Int J Exp Pathol., Vol. 81, No. 1, February 2000, pp. 51-56
  2. Schori, TR and Stungis, GE Long-term warfarin treatment may induce arterial calcification in humans: case report. Clin Invest Med., Vol. 27, No. 2, April 2004, pp. 107-09
  3. Schurgers, LJ, et al. Role of vitamin K and vitamin K-dependent proteins in vascular calcification. Z Kardiol., Vol. 90, Suppl. 3, 2001, pp. 57-63
  4. Geleijnse, JM, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. Journal of Nutrition, Vol. 134, 2004, pp. 3100-05
  5. Sconce, E, et al. Patients with unstable control have a poorer dietary intake of vitamin K compared to patients with stable control of anticoagulation. Thrombosis and Haemostasis, Vol. 93, May 2005, pp. 872-75
  6. Reedstrom, CK and Suttie, JW. Comparative distribution, metabolism, and utilization of phylloquinone and menaquinon-9 in rat liver. Proc Soc Exp Biol Med., Vol. 209, No. 4, September 1995, pp. 403-09