A randomized, crossover comparison of warfarin products in the treatment of chronic atrial fibrillation.

OBJECTIVE: To compare the dosing requirements and international normalized ratios (INRs) associated with two bioequivalent crystalline warfarin sodium products in patients with chronic atrial fibrillation. METHODS: A multicenter, single-blind (prescriber), randomized, crossover evaluation of Apothecon warfarin and DuPont warfarin (Coumadin) was conducted in consenting adults with chronic or paroxysmal atrial fibrillation who had been receiving DuPont warfarin chronically for the prevention of thromboembolism. Patients were randomly assigned to initially either continue DuPont warfarin or receive Apothecon warfarin for four weeks, with weekly evaluation of dosage and INR changes, safety, and efficacy. Subsequently, patients crossed over and received the other product for four weeks. RESULTS: There were 113 patients randomized to receive study treatment. Neither the propensity for a dosage change or an INR change nor the magnitude of a dosage change or INR change appeared related to a particular warfarin product (NS for each variable after each study period). After four weeks of treatment, the same number of patients (n = 7) experienced a > or = 20% change in warfarin dosage from the respective baseline with each product. The number of patients with INRs outside the desired protocol range after four weeks of treatment was similar for both groups (< 1.8, n = 9 for both products, or > 3.2, n = 9 for DuPont, n = 10 for Apothecon). No major hemorrhagic or thromboemoblic events occurred. CONCLUSIONS: The results of this study show that Apothecon warfarin and DuPont warfarin provide equivalent anticoagulation in patients with chronic or paroxysmal atrial fibrillation.

Correction of excessive anticoagulation with low-dose oral vitamin K1.

BACKGROUND: Despite earlier acceptance of oral vitamin K1 (phytonadione) for the treatment of excessive anticoagulation, some recent guidelines do not recommend its use. OBJECTIVE: To reevaluate the efficacy of oral vitamin K1 in correcting excessive anticoagulation. DESIGN: Case series. SETTING: Anticoagulation clinics at two university medical centers. PATIENTS: 81 outpatients who had an international normalized ratio (INR) greater than 5.0 but did not have significant bleeding. INTERVENTIONS: Withholding 1 or 2 doses of warfarin, administering 2.5 mg of oral vitamin K1, measuring the INR after 24 to 48 hours, and adjusting the warfarin dose. MEASUREMENTS: INRs were obtained from a portable capillary fingerstick monitor or from an automated photooptical coagulometer. RESULTS: In 68 of 71 patients (96%), oral vitamin K1 lowered the INR from between 5.0 and 10.0 to less than 5.0 without inducing resistance to further anticoagulation. CONCLUSIONS: Withholding 1 or 2 doses of warfarin and administering 2.5 mg of oral vitamin K1 is a reliable, safe, and inexpensive way to rapidly correct excessive anticoagulation (INR > 5.0) in patients who do not have serious bleeding episodes and have an INR of less than 10.0.

The international normalized ratio (INR) for monitoring warfarin therapy: reliability and relation to other monitoring methods.

OBJECTIVE: To enhance understanding of the reliability of the international normalized ratio (INR) for monitoring warfarin therapy and its relation to other monitoring techniques. DESIGN: Prospective cohort study. SETTING: A university hospital. PATIENTS: 79 patients attending an anticoagulation clinic. MEASUREMENTS: International normalized ratios obtained with a portable capillary monitor (Coumatrak) and the following from a simultaneous plasma sample: INRs from prothrombin times done with six thromboplastins, prothrombin-proconvertin (P&P) test activity, specific prothrombin activity, and native prothrombin antigen. RESULTS: Converting to INRs failed to standardize prothrombin time results obtained with high- and low-sensitivity thromboplastins. Coumatrak INRs correlated best with INRs obtained with high-sensitivity thromboplastins. The INR range of 2.0 to 3.0 corresponded to a P&P range of 30% to 13%, a native plasma prothrombin antigen range of 56 to 24 micrograms/mL, and a specific prothrombin activity range of 43% to 21%. CONCLUSIONS: Low-sensitivity thromboplastins may give erroneously high INRs in the upper therapeutic range. Plasma prothrombin times should be done with a high-sensitivity thromboplastin, particularly in patients maintained at the upper limit of the therapeutic range. An INR so obtained correlated well with an INR obtained with a portable capillary blood monitor.

Oral anticoagulant therapy in patients undergoing dental surgery.

The literature on dental surgery in patients receiving oral anticoagulants is reviewed, and methods of managing anticoagulant therapy to minimize the risk of complications are discussed. Although blood loss during and after oral surgery in patients receiving oral anticoagulant drugs can be substantial, research indicates that most bleeding incidents are not serious and can be controlled by local measures. Studies of 241 anticoagulant-treated patients undergoing more than 500 dental extractions during the 1950s and 1960s showed that only 9 had postoperative bleeding. More recent studies indicate that continued anticoagulation can increase the frequency of prolonged bleeding and delay wound healing. An antifibrinolytic mouthwash containing tranexamic acid can effectively suppress postoperative bleeding. Gelatin sponges, oxidized cellulose, and microcrystalline collagen are other useful hemostatic agents. A reduction in the intensity of anticoagulation therapy has been recommended; the prothrombin time should be measured shortly before the procedure in such patients. In many patients the duration of subtherapeutic anticoagulation must be minimized to reduce the possibility of thromboembolism. An option for high-risk patients is to switch them to heparin. Each patient must be evaluated individually, and the level of risk of the dental procedure and the risk of thromboembolism should be taken into account. In patients taking oral anticoagulants who must undergo dental surgery, careful control of the intensity of anticoagulation and improved methods of local hemostasis can minimize the risk of hemorrhagic complications and thromboembolism.

Effect of influenza vaccine in patients receiving long-term warfarin therapy.

The effect of influenza vaccine on anticoagulant response in 12 patients receiving long-term warfarin therapy was studied. Study criteria required that all patients have stable prothrombin times and be on stable warfarin dosages before immunization. Patients were immunized with 1982-83 trivalent influenza vaccine (subvirion), types A and B 0.5 mL i.m. on day 0 of the study. Prothrombin times were determined on days--7, 0, 2, 5, 7, 14, and 21, and results were reported as ratios with control values. Influenza immunization produced a small but significant increase in the prothrombin-time ratio. Before immunization the mean ratio was 1.68, and the mean ratio increased to 1.81 after immunization. The maximal increase occurred on day 14 and represented a 7.6% increase over the baseline (day 0) value. The prothrombin-time ratio was not influenced by warfarin sodium dosage (less than or equal to 5 mg/day versus greater than 5 mg/day) or by the sex of the patient. During the 1984-85 influenza season, an additional 26 patients were immunized with the 1984-85 trivalent influenza vaccine (subvirion), types A and B. The prothrombin-time ratio on days 0 and 14 were not significantly different in these patients. Although the administration of influenza vaccine to patients receiving long-term treatment with warfarin appears to be safe, patients should be monitored after immunization for possible increases in anticoagulant response.

Warfarin-griseofulvin interaction.

A 61-year-old man with a mitral valve replacement who had been therapeutically anticoagulated with warfarin for the previous 12 months had a decrease in his prothrombin time after starting treatment with griseofulvin. Over a three-month period his warfarin dose was gradually increased. An overall increase of 41 percent was needed to maintain therapeutic anticoagulation. A reduction in the griseofulvin dose resulted in an increase in the prothrombin time and, subsequently, a lowering of the warfarin dose. No other potential causes for the decreased response to warfarin were identified. While there previously has only been limited documentation of this interaction, it appears that a substantial decrease in the response to warfarin can occur following initiation of griseofulvin therapy. Immediate adjustment of the warfarin dose at the onset of griseofulvin therapy is not needed. However, the prothrombin time should be monitored at weekly intervals and the dose of warfarin increased according to the patient's response.

"Purple toes" syndrome.

"Purple toes" syndrome and a generalized skin eruption developed in a 73-year-old woman who was taking warfarin sodium (Coumadin) as well as antiarrhythmic agents after a stroke. Both the rash and the discoloration of her feet were apparently related to use of warfarin and gradually resolved after discontinuation of the drug.

A study of salicylate and caffeine excretion in the breast milk of two nursing mothers.

Salicylate excretion was studied in the breast milk of a nursing mother (Patient A) taking chronic therapeutic doses of aspirin, and caffeine excretion was monitored in the breast milk of a nursing mother (Patient B) who was a heavy coffee drinker. Salicylate concentrations were maximal in serum at 2.25 hours (10.8 mg/dL) and in milk at 3.00 hours (1.0 mg/dL) following 975 mg of aspirin in Patient A. Caffeine concentrations peaked at 5.50 hours in serum (2.14 micrograms/mL) and at 2.00 hours in milk (1.15 micrograms/mL) during a period of steady coffee drinking by Patient B. Milk:serum concentration ratios ranged up to 0.08 for patient A and up to 0.63 for Patient B, demonstrating that relatively more caffeine than salicylate was excreted into milk. Sodium, potassium, pH, and percent solute remained essentially unchanged in milk samples from both patients throughout the study periods so that changes in the state of hydration of pH of the milk could not be implicated for the observed excretion patterns. More than 25 liters of milk at its peak drug concentration would have to be consumed by the infants of Patients A and B respectively to provide the salicylate content of one aspirin tablet or the caffeine content of an average cup of coffee.

Potentiation of warfarin anticoagulation by sulfisoxazole.

The prothrombin time (PT) of a patient undergoing warfarin sodium anticoagulation became elevated when sulfisoxazole was given concurrently. The warfarin dose index is used to demonstrate that this PT prolongation was the result of a warfarin-sulfisoxazole interaction. The mechanism of this interaction may involve displacement of warfarin from serum albumin. Sulfisoxazole should be used cautiously, if at all, in patients taking warfarin.

Carbenicillin-gentamicin interaction in acute renal failure.

A case is reported in which carbenicillin inactivation of gentamicin resulted in subtherapeutic serum gentamicin levels in a 77-year-old man with acute renal failure. The drugs were administered separately to prevent in vitro inactivation. Carbenicillin inactivation of gentamicin resulted in subtherapeutic serum gentamicin levels (less than 2 microgram/ml) even with unusually large doses of gentamicin (1.8 mg/kg/day). The large dose of carbenicillin (15 g/day) resulted in serum carbenicillin levels more than 500 microgram/ml and an increased rate of gentamicin inactivation. After carbenicillin was discontinued, therapeutic serum gentamicin levels were achieved and maintained with doses of 0.9 - 1.8 mg/kg/day. It is suggested that if the combination of carbenicillin and gentamicin is used in patients with severe renal failure, the dose of carbenicillin should be reduced to prevent rapid inactivation of gentamicin. Further, to assure therapeutic gentamicin levels, serum levels of both drugs should be monitored frequently.