Comparison of a daily fixed 2.5-mg warfarin dose with a 5-mg, international normalized ratio adjusted, warfarin dose initially following heart valve replacement.

Patients starting oral anticoagulant therapy after heart valve replacement initially require a lower target international normalized ratio (INR) (2.0, range 1.5 to 2.6) because of a higher risk of bleeding until pericardial wires are removed. In a previous retrospective analysis, we observed a higher sensitivity to warfarin in these patients compared with nonsurgical patients. In a randomized clinical trial, we compared a fixed, lower dose of warfarin (2.5 mg) with the standard treatment consisting of a 5-mg loading dose, then adjusted to the target INR during the first 5 days of anticoagulation. INRs were measured daily, but the fixed dose was only modified on day 3 if the INR was <1.5 or >3.0. One hundred ninety-seven patients were considered eligible for the study. The 2 groups were well matched according to age, gender, body mass index, concomitant treatments, and type of valves implanted. The proportion of INRs >2.6 during the study period was 42.5% in the 5-mg group and 26.2% in the 2.5-mg group (p <0.05), and the proportion of INRs >3.0 on day 3 was 23.9% and 9.5% (p <0.05), respectively. In the 2.5-mg group, 35.7% of patients had an INR <1.5 on day 3 and had the dose increased (vs 3.5%, p <0.001); however, in the 5-mg group, 95.6% had the initial dose reduced, 49.6% had the dose withheld for at least 1 day, and the mean dose during the 5 days of study was 3.08 mg. Average time to achieve therapeutic range was higher in the 2.5-mg group (2.72 vs 1.98 days, p <0.0001), but the approach to the targeted INR was more regular, and the gap between target and mean INR on day 5 was smaller. There were no bleeding or thromboembolic complications in either group. Thus, a lower loading dose of warfarin in patients after heart valve replacement reduces excessive anticoagulation and offers a more regular achievement of the therapeutic target by reducing the number of dose adjustments. Daily monitoring of the INR is still recommended.     

Relationship between international normalized ratio values,vitamin K-dependent clotting factor levels and in vivo prothrombin activation during the early and steady phases of oral anticoagulant treatment

BACKGROUND AND OBJECTIVES: In vitro studies have shown that the rate of prothrombin activation is linearly related to the concentration of factor II (FII) in the assay system, suggesting a key role of prothrombin levels in the expression of the antithrombotic activity of oral anticoagulant treatment (OAT). We investigated the in vivo relationship between prothrombin activation and vitamin K-dependent clotting factor levels during the early and steady phases of OAT in patients and in healthy volunteers. DESIGN AND METHODS: The changes in international normalizezd ratio (INR) and in the plasma levels of FVII, FX, FII, protein C (PC) and prothrombin fragment 1.2 (F1+2) induced by OAT were monitored over 9 days in 10 patients not on heparin starting warfarin after heart valve replacement (HVR) and in 9 healthy volunteers submitted to an 8-day course of warfarin treatment. FII and F1+2 plasma levels were also measured in 100 patients on stable oral anticoagulant treatment with INRs ranging from 1.2 to 6.84. RESULTS: Because HVR patients had subnormal FVII, FX and FII levels after surgery, INR values > 2.0 were attained already 24 hours after the first warfarin dose. In healthy volunteers, INR values greater than 2.0 were first observed after 72 hours. Nadir levels of FVII, PC, FX and FII were reached between 40 and 88 hours in HVR patients and between 72 and 192 hours in healthy volunteers. The FII apparent half-disappearance time (t/2) was 99 hours in HVR patients and 115 hours in healthy volunteers (p = ns). In HVR patients there was no normalization of initially elevated F1+2 levels until day 7 with an apparent t/2 of 132 hours. In healthy volunteers, a decrease to subnormal F1+2 levels was observed by day 8 of treatment (apparent t/2 = 107 hours). In both HVR patients and healthy volunteers, FII and PC levels were independent predictors of the changes in F1+2 levels (p = 0.0001). In patients on stable OAT, only FII levels were independent predictors of the variation in F1+2 levels (p = 0.0001). INTERPRETATION AND CONCLUSIONS: During the early phase of oral anticoagulant treatment in vivo prothrombin activation is a function of the balance between FII and PC levels and is not significantly prevented until nadir levels of FII are obtained. This provides an explanation for the requirement of overlapping heparin and oral anticoagulant treatment for at least 48 hours after the achievement of therapeutic INR values in patients with thromboembolic diseases. In addition, in vivo prothrombin activation is a function of FII levels rather than INR values also in patients on stable oral anticoagulant treatment.     

Initiation of warfarin therapy in elderly medical inpatients: a safe and accurate regimen

PURPOSE: Elderly patients are at high risk of over-anticoagulation when treated with warfarin, especially during treatment induction. We developed a simple low-dose regimen for starting warfarin therapy in elderly inpatients. The daily maintenance dosage is predicted from the international normalized ratio (INR) measured the day after the third daily intake of a 4-mg dose. We conducted a prospective multicenter study to evaluate the accuracy and safety of this regimen. METHODS: We studied 106 elderly (age >or=70 years) inpatients (mean [+/- SD] age, 85 +/- 6 years; range, 71 to 97 years) who had a target INR of 2.0 to 3.0. Accuracy in predicting the daily maintenance dose from INR value on day 3 was evaluated. RESULTS: The predicted daily maintenance warfarin dose (3.1 +/- 1.6 mg/d) correlated closely with the actual maintenance dose (3.2 +/- 1.7 mg/d; R(2) = 0.84). The predicted dose was equal to the actual dose in 77 patients (73%; 95% confidence interval [CI]: 64% to 81%) and within 1 mg in 101 patients (95%; 95% CI: 91% to 99%). The mean time needed to achieve a therapeutic INR was 6.7 +/- 3.3 days (median, 6.0 days); the mean time needed to achieve the maintenance dose was 9.2 +/- 4.5 days (median, 7.0 days). None of the patients had an INR >4.0 during this period. One fatal bleeding event was recorded in a patient with an INR in the therapeutic range. CONCLUSION: Our warfarin induction regimen was simple, safe, and accurate in predicting the daily maintenance warfarin dose in elderly hospitalized patients.     

Low-dose oral vitamin K to normalize the international normalized ratio prior to surgery in patients who require temporary interruption of warfarin

Background In patients who require warfarin interruption before surgery and have an elevated international normalized ratio (INR) before surgery, low-dose vitamin K may normalize the INR in time for surgery. Patients and methods In a retrospective cohort study, we assessed the efficacy of 1 mg oral vitamin K to normalize the INR for surgery and whether resistance to re-anticoagulation occurs when warfarin is restarted after surgery. We studied a cohort of patients with an INR 1.4–1.9 on the day before surgery who received 1 mg oral vitamin K (vitamin K group), and a comparator group of patients with a normal INR (≤1.3) on the day before surgery who did not receive vitamin K (no vitamin K group). In both patient groups, we determined the proportion of patients with a normalized INR on the day of surgery and compared the mean INR after surgery when warfarin was resumed. Results Of 43 patients in the vitamin K group, the INR was normalized (≤1.3) in 33 patients (76.6; 95% confidence interval [CI]: 64.1–89.4), and the INR was normal or near-normal (≤1.4) in 39 patients (90.7; 95% CI: 82.0–99.4) on the day of surgery. The mean (standard deviation) INR in the vitamin K and no vitamin K group 4–8 days after surgery was 1.75 (0.34) and 1.59 (0.36), respectively (P = 0.56). Conclusions In patients requiring interruption of warfarin for surgery, 1 mg oral vitamin K on the day before surgery can normalize the INR by the day of surgery and may not confer resistance to warfarin re-anticoagulation after surgery.     

A comparison of a low-dose warfarin induction regimen with the modified Fennerty regimen in elderly inpatients

OBJECTIVES: To compare a new low-dose warfarin induction regimen with the Fennerty regimen in elderly inpatients. DESIGN: Age-stratified, randomized prospective study. SUBJECTS: 120 age-stratified elderly inpatients. INTERVENTIONS: Each patient was randomized to either the new induction regimen or to a modified Fennerty regimen. MAIN OUTCOMES MEASURES: Days to therapeutic International Normalized Ratio (INR >2); days in the therapeutic range (INR 2-3) during induction; number of patients with INR >4.5; ability of day 4 INR to predict day 8 warfarin dose. RESULTS: The mean time to therapeutic INR was longer for the new induction regimen than modified Fennerty regimen in patients aged 65-75 years [4.6 (mean) +/- 1.6 (SD) days vs 3.8 +/- 0.8 days; P = 0.03] and in patients aged >75 years (4.5 +/- 1.4 days vs 3.5 +/- 0.7 days; P = 0.003). Patients spent more time in the therapeutic INR range with the new induction regimen [3.0 +/- 1.3 days vs 2.7 +/- 1.3 days (P = 0.03) for those aged 65-75 years and 2.9 +/- 1.1 days vs 2.4 +/- 1.3 days (P = 0.04 for those aged >75 years]. Fewer patients using the new regimen had INRs >4.5 in the first 8 days [1 (3%) vs 6 (20%) for 65-75 years (P < 0.05) and 1 (3%) vs 11 (37%) for >75 years (P < 0.01)]. The ability to predict the maintenance dose to within 1 mg was 55% for both regimens. CONCLUSION: The low-dose regimen has important clinical advantages over the Fennerty regimen for anticoagulating elderly inpatients.     

Safety of warfarin anticoagulation in patients with heparin-induced thrombocytopenia

OBJECTIVES: Venous limb gangrene has been reported to occur after high warfarin doses in heparin-induced thrombocytopenia (HIT), and this observation has been used to exclude warfarin management in this condition. The outcome of patients receiving modest doses of warfarin was studied. DESIGN: Retrospective study of 114 consecutive HIT patients who received diagnoses by platelet aggregometry; 51 of the 114 patients received warfarin. SETTING: Tertiary-care medical center. RESULTS: Thirty-five patients received warfarin for non-HIT indications, and 16 received warfarin for heparin-associated thrombosis. Warfarin was given to 23 patients (47%) 2.4 +/- 0.4 days prior to the onset of HIT, in 19 while receiving IV heparin for an overlap of 2.7 +/- 0.4 days. Twenty-eight patients (53%) received warfarin 2.8 +/- 1.0 days after the diagnosis of HIT. Patients received 11 +/- 1 doses of warfarin over 16 +/- 2 days, with a mean daily dose of 3.5 +/- 0.5 and a maximum dose of 9 +/- 0.5 mg. Prothrombin time at discharge was 17.3 +/- 0.4 s with a maximum of 22.8 +/- 0.8. The final international normalized ratio was 2.9 +/- 0. 3, and the maximum was 7.5 +/- 1.4. The minimum therapeutic range was reached in 59% of determinations. When compared to the 63 patients who did not receive warfarin, warfarin patients received more IV heparin (86% vs 41%; p < 0.001), open heart surgery (78% vs 43%; p < 0.001), and had a lower mortality (8% vs 43%; p < 0.001), but had no differences in thrombosis. CONCLUSIONS: Modest doses of warfarin were not associated with a worse outcome in patients with HIT.     

Warfarin dose reduction vs watchful waiting for mild elevations in the international normalized ratio

BACKGROUND: Whether clinicians should decrease the warfarin dose in response to a mild, asymptomatic elevation in the international normalized ratio (INR) is unknown. OBJECTIVES: The study objectives were as follows: (1) to evaluate the safety of an anticoagulation service (ACS) policy advocating that the warfarin dose not be changed for isolated, asymptomatic INRs of < or = 3.4; (2) to compare the dosing strategies of an ACS and primary care providers (PCPs); and (3) to quantify the relationship between reduction of the warfarin dose and the subsequent fall in the INR. DESIGN AND SETTING: Randomized controlled study of health maintenance organization outpatients who were receiving warfarin. PATIENTS: We identified 231 patients with a target INR of 2.5 and an isolated, asymptomatic INR between 3.2 and 3.4. Our ACS monitored 103 of the patients; PCPs monitored the remaining 128 patients. MEASUREMENTS: From all 231 patients, we obtained INRs and warfarin dosing history. From the 103 ACS enrollees, we also recorded adverse events. RESULTS: One ACS patient had epistaxis in the 30 days after the elevated INR. Twenty-three percent of ACS enrollees and 47% of PCP patients reduced their warfarin dose (p < 0.001). The median follow-up INRs were similar in both cohorts: 2.7 in the ACS enrollees and 2.6 in the PCP patients. However, in a subgroup analysis of 190 patients who presented with an INR of 3.2 or 3.3, ACS enrollees were more likely to have a follow-up INR in the range of 2 to 3 (p = 0.03). The median follow-up INR was 2.7 in 148 patients who maintained their warfarin dose, 2.5 in 77 patients who decreased their dose by 1 to 20%, and 1.7 in 6 patients who decreased their dose by 21 to 43% (p < 0.001). CONCLUSIONS: These findings support maintaining the same warfarin dose in asymptomatic patients with an INR of < or = 3.3, and reducing the dose for patients who have a greater INR or an increased risk of hemorrhage. Warfarin dose reductions > 20% should be avoided for mildly elevated INRs.     

Warfarin Therapy in the HIV Medical Home Model: Low Rates of Therapeutic Anticoagulation Despite Adherence and Differences in Dosing Based on Specific Antiretrovirals

Abstract To determine the indications for, rates of therapeutic anticoagulation during, and complications of warfarin therapy in HIV-infected individuals, in whom long-term anticoagulation is frequently indicated. To identify risk factors for nonoptimal anticoagulation and to determine if warfarin dosing is differentially affected by specific antiretroviral agents. Retrospective study of a dedicated anticoagulation program at one of the largest clinics for HIV-infected individuals in the United States. Seventy-three HIV-infected individuals on warfarin were followed for a total of 911 visits. The rate of therapeutic internation normalized ratio (INR) levels was 34.5% when including only visits at which patients were assessed to be adherent with warfarin. In multivariable analysis, injection drug use at baseline was an independent risk factor for subtherapeutic INR (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.3-4.7, p=0.01). Additionally, warfarin adherence was protective of both subtherapeutic (OR 0.4, 95% CI 0.2-0.6, p<0.0001) and supratherapeutic (OR 0.5, 95% CI 0.3-0.9, p=0.02) INR status. Efavirenz-based antiretroviral regimens were associated with lower weekly warfarin doses (46?mg) to maintain therapeutic INR compared to lopinavir/ritonavir-based regimens (68?mg; p=0.01) and atazanavir/ritonavir-based regimens (71?mg; p=0.007). Consistently therapeutic warfarin therapy is difficult to achieve in HIV-infected individuals, even with a dedicated anticoagulation program. Adherence to warfarin therapy is important but rates of therapeutic INR levels are nonetheless low. Lower warfarin dosing was required for efavirenz compared to two commonly used protease inhibitor-based regimens. Because of these factors, the emergence of new oral anticoagulants is an important development for HIV-infected individuals who require long term anticoagulation therapy.     

Comparison of the efficacy and safety profiles of intravenous vitamin K and fresh frozen plasma as treatment of warfarin-related over-anticoagulation in patients with mechanical heart valves

Patients on warfarin for mechanical heart valves are at increased risk for thromboembolic events and intracranial hemmorhage. In current guidelines, a low dose of vitamin K is the recommended treatment for moderate over-anticoagulation based on studies in which only minority patients participating had mechanical heart valves.We performed a randomized controlled trial to compare the efficacy and safety profile of low-dose intravenous vitamin K and fresh frozen plasma (FFP) for patients with mechanical heart valves and mild to moderate over-anticoagulation (international normalized ratio [INR] 4 to 7). In a 24-month period, we randomized 102 patients to (1) vitamin K or (2) FFP. The baseline INR at presentation between the vitamin K group and the FFP group was 4.61 +/- 0.007 vs 4.78 +/- 0.07 (p = 0.11). Six hours after treatment, patients in the FFP group had a significantly lower mean INR compared with the vitamin K group (2.75 +/- 0.06 vs 3.44 +/- 0.10, p = 0.01). No patient in both groups had over-correction (INR < 2). One week later, there was no significant difference in mean INR between both groups (2.7 +/- 0.11 vs 2.56 +/- 0.12, p = 0.41). Fifty-eight percent of patients in the FFP group and 51% in the vitamin K group had an INR within the target range. There were no adverse reactions or outcomes in both groups. In conclusion, intravenous low-dose vitamin K is a safe alternative to FFP infusion for warfarin overdose in patients with mechanical heart valves.     

Reversal of asymptomatic over-anticoagulation by orally administered vitamin K

Over-anticoagulation with warfarin is common. There is good reason to reverse significantly high international normalised ratios (INRs), however, in practice, there is wide variation in the means to achieve this. Randomised controlled trials have provided evidence for using low dose orally administered phytomenadione for the reversal of asymptomatic over-anticoagulation. We devised an oral regimen using the intravenous preparation of phytomenadione (vitamin K1). Patients with an asymptomatic INR between 8.0 and 11.9 (n = 166) received 2.5 mg and those with an INR of 12.0-20.0 (n = 36) or >20 (n = 21) received 5 mg. Median INRs for the three groups of patients on day 1 (approximately 14 h) after vitamin K administration were 3.5, 3.0 and 2.9 respectively. In the patients given 2.5 mg, 77% had INRs between 2.0 and 4.9 on day 1. In the patients given 5 mg, 52% of those presenting with INRs of 12.0-20.0 returned between 2.0 and 4.9 1 d after administration of vitamin K. In the INR >20 group 44% returned with an INR between 2.0 and 4.9. Warfarin was reintroduced once the INR was <5 and the majority of patients remained stable for the following 14 d. This regimen for non-urgent correction is therefore effective and returns patients to a safe INR level without over-reversing anticoagulation.     

Impact of preemptive warfarin dose reduction on anticoagulation after initiation of trimethoprim-sulfamethoxazole or levofloxacin

BACKGROUND: Antibiotics can potentiate warfarin anticoagulation. While preemptive warfarin dose reduction (DR) upon initiation of antibiotics has been advocated by experts, there are no published data regarding the efficacy of this strategy vs. the conventional strategy of not changing warfarin dose and carefully following international normalized ratio (INR) results. METHODS AND RESULTS: We compared the efficacy of preemptive 10-20% DR vs. no change in warfarin dosing in 40 chronically anticoagulated patients initiating trimethoprim-sulfamethoxazole (TMP-SMX) or levofloxacin. Eighteen patients received preemptive warfarin DR and 22 control patients underwent no change in warfarin dosing. There was no difference between the DR and control groups in the mean INR before beginning antibiotic therapy (2.53 +/- 0.12 vs. 2.52 +/- 0.11; P > 0.9). Mean interval between initiation of antibiotic and next INR was 5.1 +/- 0.4 vs. 4.7 +/- 0.5 days for DR vs. control patients, respectively (P > 0.5). For both TMP-SMX and levofloxacin, patients managed with a preemptive warfarin DR strategy did not exhibit a statistically significant change in the INR after initiating antibiotic therapy. In contrast, for each antibiotic, control group patients exhibited a significant increase in mean post-antibiotic INR compared to mean pre-antibiotic INR, though the effect was more pronounced in patients treated with TMP-SMX than with levofloxacin. Of DR group patients who were treated with TMP-SMX, none (0/8) developed a subtherapeutic INR, while 40% (4/10) of levofloxacin-treated patients developed a sub-therapeutic INR. Supra-therapeutic INR results led to transient interruption of warfarin dosing in 2 patients (11%) in the DR group vs. 12 patients (55%) in the control group (P = 0.007). CONCLUSIONS: Prophylactic warfarin DR of 10-20% is effective in maintaining therapeutic anticoagulation in patients initiating TMP-SMX. An expectant strategy consisting of no change in warfarin dosing with short-term INR follow-up appears reasonable in patients treated with levofloxacin.     

Safe introduction of warfarin for thrombotic prophylaxis in atrial fibrillation requiring only a weekly INR

A new protocol for initiating warfarin therapy was introduced to reduce the workload in the Anticoagulant Clinic. A total of 200 outpatients, with a median age of 74 years, requiring anticoagulation for atrial fibrillation, commenced warfarin 3 mg daily for 1 week. Patients were initially seen weekly, and subsequent warfarin doses were dictated by the International Normalized Ratio (INR) on days 8 and 15; 84% of patients followed the protocol correctly: of these 86% had an INR > or =2 by day 15 and >98% had INR >2 by day 22. By day 22, 58% of patients achieved a stable dose, 85% by day 29 and >95% by day 36. Day 8 INR was predictive of the final maintenance dose required. No patient suffered any thrombotic or haemorrhagic complications in the first month: only three patients had an INR >3 on day 8, and 11 patients had an INR >4 on day 15. Patient age and sex were not sufficiently related to warfarin requirement to provide useful predictive information. This protocol, requiring only weekly INRs, has proved safe and effective for outpatient warfarinization, and has reduced clinic attendances in this population.     

Management and dosing of warfarin therapy

When initiating warfarin therapy, clinicians should avoid loading doses that can raise the International Normalized Ratio (INR) excessively; instead, warfarin should be initiated with a 5-mg dose (or 2 to 4 mg in the very elderly). With a 5-mg initial dose, the INR will not rise appreciably in the first 24 hours, except in rare patients who will ultimately require a very small daily dose (0.5 to 2.0 mg). Adjusting a steady-state warfarin dose depends on the measured INR values and clinical factors: the dose does not need to be adjusted for a single INR that is slightly out of range, and most changes should alter the total weekly dose by 5% to 20%. The INR should be monitored frequently (eg, 2 to 4 times per week) immediately after initiation of warfarin; subsequently, the interval between INR tests can be lengthened gradually (up to a maximum of 4 to 6 weeks) in patients with stable INR values. Patients who have an elevated INR will need more frequent testing and may also require vitamin K1. For example, a nonbleeding patient with an INR of 9 can be given low-dose vitamin K1 (eg, 2.5 mg phytonadione, by mouth). Patients who have an excessive INR with clinically important bleeding require clotting factors (eg, fresh-frozen plasma) as well as vitamin K1.     

老年心房颤动病人华法林抗凝治疗的有效性安全性评价

目的　评价华法林用于老年心房颤动病人抗凝治疗的有效性、安全性。方法　选择符合本研究抗凝标准的132例老年心房颤动病人随机分为两组 ,华法林治疗组 (治疗组 ) 5 8例 ,给予华法林 3mg/ d开始 ,监测凝血酶原时间(PT)及国际标准化比值 (INR) ,7～ 15 d使 INR达到 1.8～ 2 .5范围内 ,以后每月查 1次 INR。若病人增加或减少药物有出血倾向时随时再测 INR。阿司匹林对照组 (对照组 ) 74例 ,给予阿司匹林 30 0 mg/ d,分 2次口服 ,密切随访。结果　治疗组 7～ 15 d,平均 (9.1± 2 .8) d,INR达 1.8～ 3.0 (平均 2 .1± 0 .13) ,其中 INR在 1.8～ 2 .5 (平均 1.92±0 .2 3)之间者占 92 .7% ,治疗组有 1例心瓣膜病人出现脑梗死 ,而对照组有 7例发生脑梗死 ,差异显著 ,其余不良反应率两组差异无显著性。结论　老年心房颤动病人选择华法林 2～ 3mg/ d时 ,加强服药后监测及各药物间的相互作用 ,使 INR保持在 1.8～ 2 .5之间是有效、安全的     

A retrospective analysis of the periprocedural management of oral anticoagulants in patients undergoing interventional radiology procedures

Limited evidence is available to guide periprocedural management of oral anticoagulants in the setting of interventional radiology (IR) procedures. For direct oral anticoagulants, therapy interruption (TI) is based on medication half-life and procedural bleeding risk. Periprocedural management of warfarin includes INR monitoring, and possible bridging with parenteral anticoagulants. It is unknown if these recommendations apply to IR procedures. To evaluate bleeding complications and thromboembolic events following periprocedural management of the factor Xa (FXa) inhibitors or warfarin in patients undergoing IR procedures. We performed a retrospective, observational study at NYU Langone Health (NYULH) of all adult patients who underwent an IR procedure from January 2015 to July 2017 and were receiving apixaban, rivaroxaban, or warfarin. Patients who were pregnant or who had a mechanical heart valve were excluded. At NYULH, TI is not required for FXa inhibitors, and an INR?<?3 is recommended for patients on warfarin undergoing low risk procedures. For moderate/high risk procedures, TI for 48 h or 72 h with reduced renal function, is recommended for FXa inhibitors, and an INR?<?1.5 is recommended for patients on warfarin. We evaluated 350 IR procedures, with a total of 174 low bleeding risk and 176 moderate/high bleeding risk. The 30-day major bleeding rate was 0.9%, clinically relevant non-major bleeding rate was 3%, minor bleeding rate was 1% and thromboembolic event rate was 1%. The periprocedural oral anticoagulation management strategy at NYULH appears safe given the low 30-day incidence of bleeding and thromboembolic events.     

Proton pump inhibitors may increase the risk of delayed bleeding complications after open heart surgery if used concomitantly with warfarin

OBJECTIVES: The American Food and Drug Administration has suggested that proton pump inhibitors increase the international normalized ratio (INR) when used concomitantly with warfarin, by being metabolized by cytochrome P450 2C19. We therefore reviewed patients taking warfarin. METHODS AND RESULTS: Two hundred and forty patients who took warfarin after surgery were divided into two groups: Group I (n = 114) had rabeprazole (10 mg/day) and Group II (n = 126) had lansoprazole (15 mg/day). The initial dose of warfarin was 3 mg and INR was initially assessed on postoperative day 4. Initial INR was significantly lower in Group I (1.66 +/- 0.87) than in Group II (2.06 +/- 1.03, P = 0.0011). Delayed cardiac tamponade and hemothorax occurred as complications in 6 and 1 patients, respectively, in Group II from 5 days to 3 months postoperatively. At the time of the occurrence of complications, the average INR increased to 3.95 (range from 3.11 to 5.86). There were no patients with delayed bleeding in Group I ( P = 0.015). CONCLUSIONS: These results suggest that lansoprazole emphasizes the effects of warfarin. Rabeprazole could be safely used concomitantly with warfarin.     

Segurança da Ablação por Cateter de Fibrilação Atrial sob Uso Ininterrupto de Rivaroxabana

Background:Atrial fibrillation (AF) ablation under uninterrupted warfarin use is safe and recommended by experts. However, there is some controversy regarding direct-acting oral anticoagulants for the same purpose.Objective:To evaluate the safety of AF ablation under uninterrupted anticoagulation with rivaroxaban.Methods:A series of 130 patients underwent AF radiofrequency ablation under uninterrupted rivaroxaban use (RIV group) and was compared to a control group of 110 patients under uninterrupted warfarin use (WFR group) and therapeutic International Normalized Ratio (INR). We analyzed death, rates of thromboembolic events, major and minor bleedings, activated clotting time (ACT) levels, and heparin dose in the procedure. The ablation protocol basically consisted of circumferential isolation of the pulmonary veins guided by electroanatomic mapping. It was adopted a statistical significance of 5%.Results:The clinical characteristics of the groups were similar, and the paroxysmal AF was the most frequent type (63% and 59%, RIV and WFR groups). A thromboembolic event occurred in the RIV group. There were 3 patients with major bleeding (RIV = 1 and WFR = 2; p = 0.5); no deaths. Basal INR was higher in the WFR group (2.5 vs. 1.2 ± 0.02; p < 0.0001), with similar basal ACT levels (123.7 ± 3 vs. 118 ± 4; p= 0, 34). A higher dose of venous heparin was used in the RIV group (9,414 ± 199 vs. 6,019 ± 185 IU; p < 0.0001) to maintain similar mean ACT levels during the procedure (350 ± 3 vs. 348.9 ± 4; p = 0.79).Conclusion:In the study population, AF ablation under uninterrupted rivaroxaban showed a safety profile that was equivalent to uninterrupted warfarin use with therapeutic INR.     

机械瓣置换术后华法林抗凝治疗的临床研究

目的探讨心脏人工机械瓣置换术后抗凝药物华法林治疗的给药方法、影响因素和可达到理想抗凝效果的国际标准化比值(INR)。方法从2003年7月至2006年4月,对113例因瓣膜疾病行人工瓣膜置换的患者进行了回顾性的临床研究。术后按计划采用抗凝药物华法林治疗,出院后复查随访由专人负责按照设计时间做INR值的测定。观察出血、栓塞、死亡等瓣膜相关病态事件的发生率及其临床意义。结果手术后住院期间无死亡,出院死亡4例,占3.54%,脑出血1例,占0.09%,泌尿系出血1例,占0.09%。出院随访因抗凝出现病态事件的发生率与国外文献报道相近。结论心脏机械瓣置换术后服用抗凝药物华法林,与患者的年龄、性别、体重无关,与患者当时的肝功能有关系。手术后前4天给等剂量华法林,大多患者INR呈持续上升,应根据病情及国人的生理特点给个体化药量。我们推荐INR值在1.8～2.6之间就可以达到理想的抗凝效果,且相对安全。     

Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin

BACKGROUND: An elevated international normalized ratio (INR) increases the risk for major hemorrhage during warfarin therapy. Optimal management of patients with asymptomatic elevations in INR is hampered by the lack of understanding of the time course of INR decay after cessation of warfarin therapy. OBJECTIVE: To identify predictors of the rate of INR normalization after excessive anticoagulation. DESIGN: Retrospective cohort study. SETTING: Outpatient anticoagulant therapy unit. PATIENTS: Outpatients with an INR greater than 6.0 were identified from August 1993 to September 1998. Patients in whom two doses of warfarin were withheld and a follow-up INR was obtained on the second calendar day were enrolled. No patient received vitamin K(1). MEASUREMENTS: The INR was measured 2 days after an INR greater than 6.0 was recorded. RESULTS: Of 633 study patients with an initial INR greater than 6.0, 232 (37%) still had an INR of 4.0 or greater after two doses of warfarin were withheld. Patients who required larger weekly maintenance doses of warfarin were less likely to have an INR of 4.0 or greater on day 2 (adjusted odds ratio per 10 mg of warfarin, 0.87 [95% CI, 0.79 to 0.97]). Other risk factors for having an INR of 4.0 or greater on day 2 included age (odds ratio per decade of life, 1.18 [CI, 1.01 to 1.38]), index INR (odds ratio per unit, 1.25 [CI, 1.14 to 1.37]), decompensated congestive heart failure (odds ratio, 2.79 [CI, 1.30 to 5.98]), and active cancer (odds ratio, 2.48 [CI, 1.11 to 5.57]). CONCLUSIONS: Steady-state warfarin dose, advanced age, and extreme elevation in INR are risk factors for prolonged delay in return of the INR to within the therapeutic range. Decompensated congestive heart failure and active cancer greatly increase this risk.     

Incidence of new thromboembolic stroke in persons 62 years and older with chronic atrial fibrillation treated with warfarin versus aspirin

OBJECTIVE: To investigate the incidence of new thromboembolic (TE) stroke in older persons with chronic atrial fibrillation treated with oral warfarin versus aspirin. DESIGN: In an observational study of 312 older persons with chronic atrial fibrillation, long-term aspirin 325 mg daily was administered to 187 persons, and oral warfarin, in a dose adjusted to maintain the international normalized ratio (INR) between 2.0 and 3.0, was administered to 115 persons. The incidence of new TE stroke was analyzed in persons treated with warfarin versus aspirin at 36 +/- 17 months (1 to 99 months) follow-up. SETTING: A large, long-term healthcare facility. PATIENTS: The patients included 208 women and 104 men, mean age 84 +/- 7 years (range 62 to 101 years). MEASUREMENTS AND MAIN RESULTS: Four of 125 persons (3%) on warfarin stopped taking warfarin compared with four of 187 persons (2%) on aspirin who stopped taking aspirin because of adverse effects (P not significant). In persons with prior stroke, the incidence of new TE stroke was 40% (27 of 67) in persons treated with warfarin versus 81% (56 of 69) in persons treated with aspirin (P < .001). In persons with no prior stroke, the incidence of new TE stroke was 22% (13 of 58) in persons treated with warfarin versus 56% (66 of 118) in persons treated with aspirin (P < .001). The incidence of new TE stroke in all subjects was 32% (40 of 125) in persons treated with warfarin versus 65% (122 of 187) in persons treated with aspirin (P < .001). Cox regression analysis showed that persons taking warfarin had a 76% less chance of developing a new TE stroke than those taking aspirin after controlling the confounding effects of other risk factors. CONCLUSION: In an observational study of older persons with chronic atrial fibrillation, persons treated with oral warfarin to maintain an INR between 2.0 and 3.0 had a significantly lower incidence of new TE stroke than persons treated with oral aspirin 325 mg daily.