The effect of vitamin K supplementation on circulating osteocalcin (bone Gla protein) and urinary calcium excretion

STUDY OBJECTIVE: To determine whether vitamin K administration affects urinary calcium excretion in postmenopausal women. DESIGN: Before- and after-trials with a 2-week treatment period. SUBJECTS: Healthy postmenopausal women (55 to 75 years old) were recruited from the convents in and around Maastricht. Controls (25 to 40 years old) were healthy premenopausal volunteers. INTERVENTION: Daily administration of 1 mg of vitamin K for 2 weeks. MEASUREMENTS: Serum immunoreactive osteocalcin: hydroxylapatite binding (HAB) capacity of serum immunoreactive osteocalcin; excretion of calcium, hydroxyproline, and creatinine in the urine during the last 2 h of a 16-h fasting period. RESULTS: In premenopausal women, no effect of vitamin K administration was seen. In the postmenopausal group, vitamin K induced increased serum immunoreactive osteocalcin concentration; normalization of the HAB capacity of serum immunoreactive osteocalcin (this marker was less than 50% that of the controls in the pretreatment samples); a decrease in urinary calcium excretion, notably in the "fast losers" of calcium; and a parallel decrease in urinary hydroxyproline excretion in the fast losers of calcium. CONCLUSIONS: The serum immunoreactive osteocalcin level may vary with vitamin K status. This variance should be taken into consideration if osteocalcin is used as a marker for osteoblast activity. Vitamin K is one factor that may play a role in the loss of bone mass in postmenopausal osteoporosis.     

Low-dose vitamin K1 versus short-term with holding of acenocoumarol in the treatment of excessive anticoagulation episodes induced by acenocoumarol. A retrospective comparative study

BACKGROUND: No consensus exists about the management of iatrogenically induced excessive hypocoagulability episodes. OBJECTIVE: To compare the two most common therapeutic approaches in such situations (discontinuation of the oral anticoagulant vs. low-dose subcutaneous vitamin K1) when acenocoumarol is the normally used anticoagulant. PATIENTS AND METHODS: The study was retrospective and comparative. Patients received antithrombotic therapy using acenocoumarol. Anticoagulant plasmatic activity was assessed through the international normalized ratio (INR) recorded from December 1994 to December 1997 at two medical centers. RESULTS: INR is brought faster to a safe range in patients treated with low-dose vitamin K1 (p = 0.01). Their long-term behavior is also more stable and predictable and no resistance to the oral anticoagulant was found. CONCLUSION: Low-dose vitamin K1 is a safer therapeutic option compared to simply withholding the oral anticoagulant. Its best scheme of administration, however, has yet to be defined.     

Vitamin D repletion in patients with primary hyperparathyroidism and coexistent vitamin D insufficiency

Vitamin D insufficiency is common in patients with primary hyperparathyroidism (PHPT) and may be associated with more severe and progressive disease. Uncertainty exists, however, as to whether repletion of vitamin D should be undertaken in patients with PHPT. Here we report the effects of vitamin D repletion on biochemical outcomes over 1 yr in a group of 21 patients with mild PHPT [serum calcium <12 mg/dl (3 mmol/liter)] and coexistent vitamin D insufficiency [serum 25 hydroxyvitamin D [25(OH)D] <20 microg/liter (50 nmol/liter)]. In response to vitamin D repletion to a serum 25(OH)D level greater than 20 microg/liter (50 nmol/liter), mean levels of serum calcium and phosphate did not change, and serum calcium did not exceed 12 mg/dl (3 mmol/liter) in any patient. Levels of intact PTH fell by 24% at 6 months (P < 0.01) and 26% at 12 months (P < 0.01). There was an inverse relationship between the change in serum 25(OH)D and that in intact PTH (r = -0.43, P = 0.056). At 12 months, total serum alkaline phosphatase was significantly lower, and urine N-telopeptides tended to be lower than baseline values (P = 0.02 and 0.13, respectively). In two patients, 24-h urinary calcium excretion rose to exceed 400 mg/d, but the group mean 24-h urinary calcium excretion did not change. These preliminary data suggest that vitamin D repletion in patients with PHPT does not exacerbate hypercalcemia and may decrease levels of PTH and bone turnover. Some patients with PHPT may experience an increase in urinary calcium excretion after vitamin D repletion.     

Effect of oral anticoagulant treatment on markers for calcium and bone metabolism

Vitamin K-dependent proteins regulate blood coagulation as well as bone growth and calcification. Here, we have compared the effects of oral anticoagulants on circulating vitamin K-dependent proteins and on markers for calcium and bone metabolism. Patients with a clinical indication for antithrombotic therapy were randomized into three groups and treated with either aspirin, regular-intensity anticoagulation [target international normalized ratio (INR) values: 2.5-3.5] or low-intensity anticoagulation (target INR values: 1.1-1.6). At the start and after 1 year of treatment, various biochemical markers were assessed. Both the circulating levels and the degree of carboxylation of the various gamma-carboxyglutamate (Gla)-containing proteins were affected differently by oral anticoagulant treatment. Circulating osteocalcin was more sensitive to poor vitamin K status than other Gla proteins. From the fact that - except for osteocalcin - neither markers for osteoblast nor osteoclast function were affected by oral anticoagulant treatment, we conclude that bone turnover remained unaltered, which is indicative of an unchanged rate of bone loss. Whether the long-term production of undercarboxylated bone Gla proteins may have a negative effect on the quality of bone (e.g. bone strength) cannot be concluded from this study.     

Reduced bone density in patients on long‐term warfarin

Aim: Vitamin K is an essential factor for carboxylation of bone matrix protein. Low vitamin K may be associated with reduced bone mineral density (BMD). The issue of whether long‐term sodium warfarin therapy as oral anticoagulant that antagonizes vitamin K, results in decreased bone density, is controversial. Our purpose in this study was to assess the effects of warfarin on BMD. Methods: We performed a case control study survey of bone density in 70 patients with rheumatic valvular heart disease ‘mechanical valve replacement’ on long‐term warfarin compared with 103 randomly selected matched controls. Results: There was a marked reduction in BMD (g/cm²) and T‐score of lumbar spine between patients and controls (P = 0.048, 0.005). Duration of warfarin use was the only risk factor of significant importance respectively on spinal T‐score (P < 0.03). Conclusions: Screening of patients on long‐term warfarin for reduced bone density should be considered. We strongly suggest the prophylactic use of calcium–vitamin D supplements for these patients.     

The efficacy of oral vitamin A supplementation for measles and respiratory syncytial virus (RSV) infection

Recently, the efficacy of oral vitamin A supplementation for measles and respiratory syncytial (RSV) infection has been evaluated in developing countries. However, in developed countries where vitamin A deficiency is little worth consideration, few studies have been conducted on the effect of vitamin A supplementation. The effect of oral vitamin A (100,000 IU) supplementation was evaluated in 105 children with measles (age 5 months to 4 years) and in 96 children with RSV infection (ages a month to 2.5 years) in Fukushima, Japan. Comparisons were made of clinical signs, duration of hospitalization and complications between treated groups and non-treated groups. Treated group (measles n = 47, RSV n = 54) and non-treated groups (measles n = 58, RSV n = 42) had similar baseline characteristics. Patients with measles given a vitamin A supplementation had a shorter duration of cough (7.2 +/- 1.6 vs 9.2 +/- 1.8 days, p < 0.05) and patients with severe RSV infection given a vitamin A supplementation had a shorter duration of retraction (3.6 +/- 1.4 vs 5.3 +/- 0.8 days, p < 0.05) and wheezing (4.4 +/- 1.7 vs 6.3 +/- 1.5 days, p < 0.05). Toxicities, including excess vomiting and bulging fontanel were not observed. Our findings may suggest the efficacy of oral vitamin A supplementation for measles and severe RSV infection, in children who have no malnutrition.     

Unsuspected hyperhomocysteinemia in chronically anticoagulated patients.

Hyperhomocysteinemia is a risk factor for arterial and venous thrombosis. The aim of this study was to evaluate plasmatic homocysteine levels in patients under chronic anticoagulant treatment with dietary restriction of green vegetables. This kind of food is a very important source not only of vitamin K but also of folates, which are involved in Hcy metabolism. It is known that the lower the folate levels, the higher the Hcy concentration, so we suspected that these patients could show hyperhomocysteinemia. A group of patients receiving oral anticoagulant treatment and a restricted diet (Group I, n = 20) was compared with a group of untreated subjects of a similar age that were not on a restricted diet (Group II, n = 35). Group I showed significantly higher levels of plasmatic Hcy and significantly lower levels of serum folate than Group II. Therefore, a diet restricted in vitamin K applied to oral anticoagulated patients could induce an unwanted increase of homocysteine levels.     

Vitamin K deficiency amplifies anticoagulation response to ximelagatran: possible implications for direct thrombin inhibitors and their clinical safety

Dietary vitamin K is known to influence the anticoagulation response to warfarin. It is possible that dietary vitamin K availability also influences the pharmacological activity of other oral anticoagulants, which target the vitamin-K dependent clotting proteins in the coagulation cascade. This study examined whether vitamin K insufficiency affected anticoagulation response to the direct thrombin inhibitor, ximelagatran. Anticoagulation response to ximelagatran and warfarin in rats on a normal diet was compared to those on a vitamin K deficient diet. Ximelagatran and warfarin increased prothrombin time (PT) by 1.4- and 1.3-fold, activated partial thromboplastin time (APTT) by 1.8- and 1.4-fold and ecarin clotting time (ECT) by 6.8- and 1.2-fold, respectively, in rats on normal diet. Vitamin K deficient diet alone caused modest increases in PT, APTT and ECT. The anticoagulant activity of both ximelagatran and warfarin was significantly greater in rats on vitamin K deficient diet (6.1- and 12.3-fold for PT, 2.6- and 5.1-fold for APTT and 2.9- and 1.6-fold for ECT, respectively) compared to those on normal diet. Factor II activity was reduced by both ximelagatran (58%) and warfarin (44%) in rats on normal diet. However, factor II activity was virtually abolished (<0.1%) by both drugs in rats on vitamin K deficient diet. The results suggest that oral anticoagulant drugs, whose primary site of action is not within the vitamin K cycle, may also exhibit variability in clinical response due to dietary variation as the established coumarin drugs such as warfarin.     

Acute effects of etidronate on glucocorticoid-induced bone degradation

OBJECTIVES: To study the acute short-term effects on the biochemical parameters of calcium and bone homeostasis in post-menopausal women treated with a high dose of prednisone alone or with additional etidronate, before and during 5 days of treatment. METHODS: Serum calcium, phosphorus, creatinine, alkaline phosphatase activity, osteocalcin, carboxy-terminal propeptide of type I procollagen (PICP), cross-linked carboxy-terminal telopeptide of type I collagen (ICTP), parathyroid hormone (PTH), 25-hydroxyvitamin D and urinary excretion of calcium over 24 h were measured before and during 5 days of treatment in 14 post-menopausal women treated with a high dose of prednisone (60 mg/day) alone (group A) or combined with cyclical etidronate (group B). RESULTS: Significant differences from baseline were found in osteocalcin and urinary excretion of calcium in both groups and for ICTP in group B. Significant differences between groups were calculated at day 5 of the study for osteocalcin, ICTP and 24 h urine calcium excretion (P < 0.01). Urinary excretion of calcium over 24 h increased in group A (+14.7%; P < 0.05) and decreased in group B (-22.1%; P < 0.01). Osteocalcin levels decreased in group A (- 38.1%) and increased in group B (+27.4%; both P < 0.01). ICTP decreased only in group B (-19.4%; P < 0.01). CONCLUSIONS: The results are consistent with the fact that etidronate is acutely able to prevent bone resorption due to corticosteroids. The increase in osteocalcin in the etidronate-treated group is a new feature. A direct or indirect (PTH, 1,25 vitamin D?) stimulatory effect of etidronate on the osteoblast cannot be excluded.     

Resolution of vitamin D insufficiency in osteopenic patients results in rapid recovery of bone mineral density.

Vitamin D insufficiency is characterized biochemically by the presence of secondary hyperparathyroidism, which can contribute to bone loss in osteopenic patients. Over a 2-yr period of evaluation of 118 consecutive, free living patients with osteopenia or osteoporosis, we identified 18 subjects with depressed serum 25-hydroxyvitamin D (250HD; < or = 14 ng/mL). Twelve of these subjects harbored a low 25OHD level and consented to undergo replacement with 50,000 IU vitamin D2 twice weekly for 5 weeks. Five hundred thousand units of oral vitamin D2 resulted in significant increases in 25OHD (+24.3+/-16.9 ng/mL; P < 0.001) and the fasting urinary calcium/creatinine excretion ratio (+0.06+/-0.004; P = 0.01) and significant decreases in the serum concentration of PTH (-32.9+/-36.9 pg/mL; P < 0.001) and osteocalcin (-4.9+/-2.4 ng/mL; P < 0.001). Vitamin D repletion was associated with a significant 4-5% annualized increase in bone mineral density at both the lumbar spine (P < 0.001) and the femoral neck (P = 0.03), indicating that resolution of vitamin D insufficiency in a population of patients with low bone mass results in a rapid rebound increase in bone mineral density.     

The same annual dose of 292000 IU of vitamin D3 (cholecalciferol) on either daily or four monthly basis for elderly women: 1‐year comparative study of the effects on serum 25(OH)D3 concentrations and renal function

Objective Daily dosing of vitamin D supplements may be difficult among older people. Infrequent administration of ‘megadoses’ controlled by health care personnel may overcome adherence problem. We compared the efficacy and safety of two oral dosages (800 IU daily or 97333 IU four monthly) of vitamin D₃ resulting in the equal annual dose of 292000 IU. Design Randomized, double‐blind, double‐dummy parallel group comparison. Patients Forty women aged 69·3–78·8 years. Interventions Vitamin D₃ 400 IU twice daily (D group) or vitamin D₃ oil 97333 IU every 4 months (4 M group) for 1 year. All received 1 g of calcium daily. Measurements Serum 25‐hydroxyvitamin D₃ [25(OH)D₃] in relation to the target levels of 50–75 nmol/l, PTH, serum type I procollagen aminoterminal propeptide (PINP), serum and urine calcium, renal function. Results A quantity of 25OHD₃ increased more in D group than in 4 M group (P < 0·0001). All participants in D group and 67% in 4 M group had 25(OH)D₃ above 50 nmol/l at 12 months; the target level of 75 nmol/l was reached by 47% and 28% respectively. PTH did not show any seasonal perturbation in either group. PINP declined and urinary calcium rose similarly in the study groups over time (P < 0·0001). Renal function did not worsen in either group. Conclusions In terms of serum 25(OH)D₃ concentrations, 800 IU daily was more efficient than a 97333 IU every 4 months. However, to increase adherence, the latter is still worth developing. Both treatments increased urinary excretion of calcium, but did not worsen renal function.     

Treatment of warfarin-associated coagulopathy with vitamin K

Warfarin is the most common form of oral anticoagulant therapy. Although it has indisputable benefit in the management of thromboembolic disease, warfarin-associated coagulopathy (WAC) is a well-documented complication of its use. As warfarin exerts its effect by impairing formation of the vitamin K-dependent clotting factors, a cornerstone of WAC management is vitamin K replacement. Daily vitamin K supplementation is an emerging approach to regulate international normalized ratios in difficult-to-control patients. Mild WAC without bleeding can often be managed with warfarin withdrawal alone. For excessive international normalized ratio elevation in the absence of bleeding, low-dose oral vitamin K (1?2.5 mg) is sufficient and achieves the same degree of international normalized ratio correction by 24 h as intravenous therapy. The stable patient with WAC and minor bleeding can also be given oral vitamin K, with correction of the underlying defect. Major bleeding should first be managed with factor replacement for immediate correction of the coagulopathy, using either a prothrombin complex concentrate or fresh-frozen plasma. High-dose vitamin K (10 mg) should be given concurrently via intravenous infusion to confer lasting correction. Warfarin resistance and vitamin K-associated anaphylaxis are rare. Despite development of new oral anticoagulant therapy compounds, warfarin will probably retain a prominent role in thromboembolism management for several years to come.     

Prospective study of supplemental vitamin K therapy in patients on oral anticoagulants with unstable international normalized ratios

Background It is not known whether patients on oral vitamin K antagonists who have unstable INRs achieve more stable INRs with daily vitamin K supplementation. We sought to determine whether vitamin K supplementation may decrease INR variability in patients with a history of unstable INRs, how soon the INR decreases after vitamin K therapy is initiated, the time to reach a therapeutic INR after vitamin K initiation, and how much of an increase in oral anticoagulant dose is needed to maintain the INR in the desired range. Methods This is a prospective open label crossover study of patients on warfarin with a history of fluctuating INRs. A 9 week observation phase was followed by an 8 week period with patients receiving 500 μg of oral vitamin K daily. INRs were determined once weekly with a home point of care monitoring instrument. Results Vitamin K supplementation led to a decrease in INR variability in five of the nine patients studied (56%). INR decrease occurred 2–7 days after initiation of vitamin K. Therapeutic INRs were achieved 2–35 days after vitamin K therapy was initiated and an increase in warfarin dose of 6–95% was required to bring the INR back into the therapeutic range. Conclusions INR fluctuations may decrease in selected patients with unstable INRs who receive vitamin K supplementation. A study with a larger sample size and longer follow-up period is needed. The results of the present study can help design such a study.     

Early Intervention With Intravenous or Pulse Oral Vitamin D Therapy Is More Effective in the Treatment of Secondary Hyperparathyroidism

The K/DOQI clinical practice guidelines recommend vitamin D therapy should be started when the intact parathyroid hormone (iPTH) exceeds 300 pg/mL in patients with secondary hyperparathyroidism. To examine whether the effect of vitamin D therapy on mineral metabolism and parathyroid gland growth varies according to the stage of secondary hyperparathyroidism and iPTH level, 47 patients with secondary hyperparathyroidism received either intravenous or pulse oral vitamin D therapy. The patients were divided into two groups based on the iPTH level at the start of vitamin D therapy: the P_<300 group (N = 23) with iPTH <300 pg/mL; and the P^≥300 group (N = 24) with iPTH ≥300 pg/mL. We examined serial changes in several serum mineral parameters and parathyroid gland volume and the cumulative incidence of parathyroidectomy in the first two years. Serum calcium, phosphorus, calcium–phosphorus product, and iPTH levels of the P^≥300 group were significantly higher than those of the P_<300 group, and could not be maintained within the target ranges set by the K/DOQI guidelines. In contrast, the serum levels of phosphorus, calcium–phosphorus product, and iPTH were maintained within the target ranges and the parathyroid gland did not enlarge in the P_<300 group. The cumulative incidence of parathyroidectomy in the P^≥300 group was significantly higher than in the P_<300 group. Early intervention with intravenous or pulse oral vitamin D therapy at serum iPTH <300 pg/mL can control serum phosphorus, calcium–phosphorus product, and PTH levels to the target ranges and slow the progression of secondary hyperparathyroidism.     

Hemorrhagic complications during warfarin treatment

Bleeding is probably the major complication of anticoagulant treatment with vitamin K antagonists represented nowadays mostly by warfarin in the Czech Republic. The main risk factors in hemorrhagic complications of warfarinisation are the intensity and instability of the anticoagulant treatment, individual patient characteristics, warfarin interactions with other drugs and the length of the anticoagulant therapy. Severe bleeding in warfarin patients is most effectively brought about by a fast and complete undoing of the anticoagulation effect of the drug employing the prothrombin complex concentrate and slow i.v. vitamin K1 infusion regardless of the reason for the anticoagulation. This approach can secure the minimalisation of the bleeding's negative consequences. A less severe bleeding or asymptomatic increase in the international normalized ratio can be treated effectively by skipping or decreasing of the warfarin dosage and/or oral administration of vitamin K1 (i.v. administration only in selected higher risk cases) that does result only in a partial consolidation of coagulopathy but of such type that the risk of thrombotic event requires. The article's goal is to contribute to the treatment standardization in patients with warfarin overdose and/or with hemorrhagic complications due to warfarin treatment and it is available at www.thrombosis.cz. The guidelines include a ready-reference chart whose objective is immediate and quick crash course in the clinical practice.     

Actions of thiazide on vitamin D metabolism: a controlled therapeutic trial in normal women early in the postmenopause

The effect of thiazide on vitamin D metabolism in normal postmenopausal women was studied during a twelve-month placebo-controlled clinical study. Nineteen healthy women in their early menopause were randomized for treatment with bendroflumethiazide (5 mg/d) (n = 11) or placebo (n = 8) for twelve months. All participants were given a calcium supplement of 0.5 g/d throughout the study. A significant increase (p less than 0.01) in the serum concentration of 24,25-dihydroxycholecalciferol was observed in the thiazide group. Moreover, this group showed a tendency toward decreased serum 1,25-dihydroxycholecalciferol, whereas the mean serum 25-hydroxycholecalciferol was unchanged. Except for a highly significant decrease in urinary calcium in the thiazide group (P less than 0.01) all other biochemical indices of calcium metabolism were unchanged. The present data indicate that thiazide given to early postmenopausal women has a primary effect on the renal tubules followed by a secondary change in vitamin D metabolism leading to an increase in serum 24,25-dihydroxycholecalciferol.     

Vitamin K1 supplementation to improve the stability of anticoagulation therapy with vitamin K antagonists: a dose-finding study

Background

Poor anticoagulant stability in patients using vitamin K antagonists is a risk factor for both bleeding and thrombosis. In previous studies supplementation with low dose vitamin K₁ was shown to improve the stability of anticoagulant control. We set up a study to confirm earlier reports and to determine the optimal daily dose of vitamin K₁ in preparation of a large study with clinical endpoints.

Design and Methods

Four hundred patients from two anticoagulation clinics starting with vitamin K antagonists, independently of a possible history of instable anticoagulation, were randomized to receive either placebo or 100, 150 or 200 μg of vitamin K₁ together with their treatment with vitamin K antagonists. The treatment was administered for 6 to 12 months. Anticoagulation stability, expressed as the percentage of time that the International Normalized Ratio was within the therapeutic range, was compared between the groups.

Results

After adjustment for age, sex, vitamin K antagonist used, anticoagulation clinic and interacting drugs as confounding factors the difference in percentage of time with the International Normalized Ratio within the therapeutic range between the placebo group and the vitamin K₁ groups was 2.1% (95% CI: −3.2% – 7.4%) for the group taking 100 μg, 2.7% (95% CI: −2.3% –7.6%) for the group taking 150 μg and 0.9% (95% CI: −4.5% – 6.3%) for the group taking 200 μg vitamin K₁ group, in favor of the vitamin K₁ groups. The patients from both the 100 μg group and the 150 μg group had a 2-fold higher chance of reaching at least 85% of time with the International Normalized Ratio within the therapeutic range. There were no differences in thromboembolic or hemorrhagic complications between the groups.

Conclusions

In patients starting vitamin K antagonists, supplementation with low dose vitamin K₁ resulted in an improvement of time that anticoagulation was within the therapeutic range. Differences between doses were, however, small and the improvement is unlikely to be of clinical relevance. For future studies we recommend selecting only patients with instable anticoagulant control. (This study was registered at www.isrctn.org as ISRCTN37109430)     

Preventive effects of vitamin K on recurrent disease in patients with hepatocellular carcinoma arising from hepatitis C viral infection

BACKGROUND: Despite the progression of therapeutic approaches, a high frequency of recurrence is what determines the long-term prognosis of patients with hepatocellular carcinoma (HCC). In this study, the chemopreventive effects of vitamin K2 on the recurrence and survival of patients with HCC after curative therapy were evaluated. METHODS: Sixty patients who were diagnosed to be free of HCC after radiofrequency ablation therapy or surgery were randomly assigned to either the vitamin K2 group (n = 30 patients) or the control group (n = 30 patients). All patients were positive for the hepatitis C virus (HCV) antibody and hepatitis B surface antigen positive patients were excluded from this study. Patients in the vitamin K2 group received an oral dose of menatetrenone at 45 mg per day. Disease recurrence and the survival rates were analyzed in patients with HCC. RESULTS: The cumulative recurrence-free rates in the vitamin K2 group were 92.3% at 12 months, 48.6% at 24 months and 38.8% at 36 months; and those in the control group were 71.7%, 35.9% and 9.9%, respectively (P = 0.045). The cumulative survival rates in the vitamin K2 group were 100% at 12 months, 95.0% at 24 months and 77.5% at 36 months; and those in the control group were 95.8%, 90.2% and 66.4%, respectively (P = 0.70). CONCLUSIONS: Vitamin K2 may have a suppressive effect on the recurrence of HCC and a beneficial effect on tumor recurrence. However, there was no significant difference in the survival rates. The chemopreventive effects of vitamin K2 are not sufficient. The development of a further regimen such as combination therapy is required.     

Antithrombotic therapy in nonvalvular atrial fibrillation: a narrative review

Atrial fibrillation (AF) is an important and potentially modifiable cause of stroke. It has been known since 1989 that oral anticoagulant drugs, such as warfarin, lead to a dramatic decrease in stroke associated with AF. The best risk-benefit ratio is obtained with intensity of oral anticoagulant treatment for an INR of 2-3, even in the elderly. Given the risks of anticoagulant therapy, including bleeding, individual thromboembolic risk must be assessed in patients with AF. In 2009, dabigatran was shown to be a reasonable alternative to vitamin K antagonists, establishing itself as a major alternative to warfarin in AF patients. Rivaroxaban and apixaban have subsequently also been shown to be alternatives to warfarin. When there are contraindications to vitamin K antagonists, antiplatelet agents can produce a therapeutic effect, although much less than oral anticoagulants. Apixaban may be a better alternative to aspirin in this setting. Patients with low-risk atrial fibrillation (no risk factors) have not been the subjects of specific clinical trials. It is unclear what would be the best therapeutic choice for these patients.