Bleeding risk in randomized controlled trials comparing warfarin and aspirin: a systematic review and meta‐analysis

Summary. Background: Warfarin and aspirin (acetylsalicylic acid [ASA]) are the most commonly used anticoagulant and antiplatelet drugs in the treatment of cardiovascular disease.Objectives: To provide a pooled estimate of the bleeding risk from randomized controlled trials (RCTs) comparing warfarin and ASA at the dose ranges recommended in evidence‐based guidelines.Patients/Methods: Ovid MEDLINE, Embase and the Cochrane Library, up to September 2011, were searched for RCTs comparing bleeding rates in adult patients randomized to warfarin, target International Normalized Ratio (INR) 2.0–3.5, and ASA, 50–650 mg daily, with at least 3 months of follow‐up. Pooled odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated with the inverse variance method and the random effects model.Results: Four thousand four hundred and forty‐two abstracts were screened, resulting in eight included studies for final analysis. A pooled estimate derived from the 2904 patients enrolled indicated a trend towards an increase in major bleeding risk in those randomized to warfarin (OR 1.27; 95% CI 0.83–1.94). The pooled OR for intracranial hemorrhage in patients treated with warfarin vs. ASA was 1.64 (95% CI 0.71–3.78), and that for extracranial major bleeding was 1.03 (95% CI 0.61–1.75). Minor bleeding, from a 1748‐patient sample, was more common in warfarin patients (OR 1.50; 95% CI 1.13–2.00).Conclusions: This meta‐analysis failed to find a statistically significant difference in major bleeding between warfarin, target INR 2.0–3.5, and ASA, 50–650 mg daily. The trend towards increased bleeding with warfarin appears to be explained by an excess of intracranial bleeding in warfarin patients.     

Reduction in plasma transfusion after enforcement of transfusion guidelines

BACKGROUND: The majority of fresh‐frozen plasma (FFP) is transfused in the United States in the management of acquired bleeding disorders. The prothrombin time (PT), and its derivative the international normalized ratio (INR), is the most common test used to detect the presence and gauge the severity of these disorders. Observation studies have shown that the PT correlates poorly with clinical bleeding and that transfusion of plasma often achieves no measurable change in the INR nor is of any known clinical benefit. STUDY DESIGN AND METHODS: Data on FFP and red blood cell transfusions and measures of hospital activity and mortality were collected over a 12‐year period. The first 3 years were baseline years, the next 3 years were physician education years, and in the last 6 years all requests for FFP were screened. Orders were discouraged if the INR was less than 2.0 in the absence of active bleeding and the use of vitamin K was encouraged if the patient was taking warfarin. RESULTS: This program ultimately resulted in an approximate 80% reduction in transfused FFP using the average of the baseline years compared to the average of the last 3 years (157 ± 19 units FFP/1000 discharges vs. 30 ± 15, p < 0.01, respectively). Overall, hospital activity remained largely unchanged or increased. No unexpected bleeding was reported, which was attributed to a failure to transfuse FFP, and inpatient mortality rate decreased during these 12 years. CONCLUSIONS: A program of engagement and interdiction using evidence‐based guidelines can successfully decrease the use of FFP without any observable increase in unexpected bleeding.     

No increased bleeding events with continuation of oral anticoagulation therapy for patients undergoing cardiac device procedure

Background: Switching warfarin for heparin has been a practice for managing periprocedural anticoagulation in high‐risk patients undergoing device‐related procedures. We sought to investigate whether continuation of warfarin sodium therapy without heparin bridging is safe and, when it is continued, the optimal international normalized ratio (INR) without increased bleeding risk at time of device‐related procedure. Methods and Results: We retrospectively studied 766 consecutive patients taking warfarin long term who underwent device‐related procedures. Patients were grouped by treatment: discontinued warfarin (?warfarin, n = 243), no interruption of warfarin (+warfarin, n = 324), and discontinued warfarin with heparin bridging (+heparin, n = 199). The study primary endpoint was systemic bleeding or formation of moderate or severe pocket hematoma within 30 days of the procedure. Thirty‐one (4%) patients had bleeding events, including pocket hematoma in 29 patients. The bleeding events occurred more often for +heparin (7.0%) than ?warfarin (2.1%) or +warfarin (3.7%, P = 0.029). For +warfarin group, INR of 2.0–2.5 at time of procedure did not increase bleeding risk compared with INR less than 1.5 (3.7% vs 3.4%; P = 0.72), but INR greater than 2.5 increased the bleeding risk (10.0% vs 3.4%; P = 0.029). Concomitant aspirin use with warfarin significantly increased bleeding risk than warfarin alone (5.6% vs 1.4%, P = 0.02). Median length of hospitalization was significantly shorter for +warfarin than +heparin (1 vs 6 days; P < 0.001). Conclusion: Continuation of oral anticoagulation therapy with an INR level of <2.5 does not impose increased risk of bleeding for device‐related procedures, although precaution is necessary to avoid supratherapeutic anticoagulation levels. (PACE 2011; 34:868–874)     

Protocolized use of Factor Eight Inhibitor Bypassing Activity (FEIBA) for the reversal of warfarin induced coagulopathy

IntroductionCoagulopathy due to warfarin in patients with major bleeding was traditionally reversed with fresh frozen plasma and intravenous (IV) vitamin K, but prothrombin complex concentrates (PCC) are increasingly used in the treatment of these patients. Factor Eight Inhibitor Bypassing Activity (FEIBA) is an activated four-factor PCC most commonly used in patients with hemophilia. We aimed to evaluate the efficacy and safety of FEIBA and IV vitamin K for the reversal of warfarin-associated coagulopathy in patients with major bleeding, by measuring the percentage of patients who achieved target INR ≤ 1.5 and the incidence of thrombotic adverse events (TAE).MethodsIn this prospective observational study, we enrolled patients presenting to the Emergency Department (ED) with warfarin associated coagulopathy (INR > 1.5) and major bleeding. Patients received FEIBA using an INR based dosing strategy and IV vitamin K.ResultsIn 43 patients, median initial INR was 4.0 (2.7, 7.3 interquartile range (IQR)). Median time to result the second INR was 45 min (38, 55 IQR) and the median INR was 1.4 (1.3, 1.6 IQR). Out of the 43 patients, 93% achieved the target INR of ≤1.5. In-hospital mortality was 40% (17 patients). There were 11 TAEs in 6 patients (14%); 4 events in 2 patients (5%) were attributed to FEIBA.ConclusionA protocolized use of FEIBA and IV vitamin K resulted in the efficacious reversal of warfarin-induced coagulopathy in patients with major bleeding. TAEs occurred in 14% of patients and were attributed to FEIBA in 5% of patients.     

Multi-centered evaluation of a novel fixed-dose four-factor prothrombin complex concentrate protocol for warfarin reversal

IntroductionPrevious studies have shown fixed-dose 4PCC to be as effective as standard-dose 4PCC for warfarin reversal. However, certain patient populations such as those with high total body weight (TBW) or elevated baseline INR may be at increased risk for treatment failure. The purpose of this study was to validate the efficacy of a novel fixed-dose 4PCC protocol for warfarin reversal.MethodsThis was a multi-centered observational comparison of patients who received 4PCC for warfarin reversal. Fixed-dose patients received 1500 units of 4PCC with the dose increased to 2000 units in patients with a baseline INR ≥ 7.5, a TBW ≥ 100 kg, or for intracranial hemorrhage (ICH). Standard-dosing followed manufacturer recommendations. The primary outcome was achievement of a post-4PCC INR of ≤1.4. Secondary outcomes included target INR achievement among patients with a baseline INR ≥ 7.5, a TBW ≥ 100 kg, or neurologic bleeding indications; hospital length of stay; cost of therapy; and thromboembolic complications.ResultsA total of 116 patients were included in the standard-dose group and 75 in the fixed-dose group. There was no difference in the primary outcome (65% vs 57%, p = 0.32). There was no difference in secondary outcomes aside from cost of therapy in which fixed-dose 4PCC was less expensive than standard-dose 4PCC.ConclusionA fixed-dose 4PCC regimen for warfarin reversal of 1500 units, with an increased dose of 2000 units for select patients, is as effective as standard-dose 4PCC for INR reversal.     

Warfarin for atrial fibrillation in community‐based practise

Summary. Background: Previous studies of anticoagulation for atrial fibrillation (AF) have predominantly occurred in academic settings or randomized trials, limiting their generalizability.Objective: To describe the management of patients with AF anticoagulated with warfarin in community‐based practise.Methods: We enrolled 3396 patients from 101 community‐based practises in 38 states. Data included demographics, comorbidities, and International Normalized Ratio (INR) values. Outcomes included time in therapeutic INR range (TTR), stroke, and major hemorrhage.Results: The mean TTR was 66.5%, but varied widely among patients: 37% had TTR above 75%, while 34% had TTR below 60%. The yearly rates of major hemorrhage and stroke were 1.90 per 100 person‐years and 1.00 per 100 person‐years. Four percent of patients (n = 127) were intentionally targeted to a lower INR, and spent 42.7% of time with an INR below 2.0, compared to 18.8% for patients with a 2.0–3.0 range (P < 0.001). Mean TTR for new warfarin users (57.5%) remained below that of prevalent users through the first six months. Patients with interruptions of warfarin therapy had lower TTR than all others (61.6% vs. 67.2%, P < 0.001), which corrected after deleting low peri‐procedural INR values (67.0% vs. 67.4%, P = 0.73).Conclusions: Anticoagulation control varies widely among patients taking warfarin for AF. TTR is affected by new warfarin use, procedural interruptions, and INR target range. In this community‐based cohort of predominantly prevalent warfarin users, rates of hemorrhage and stroke were low. The risk versus benefit of a lower INR target range to offset bleeding risk remains uncertain.     

Urgent reversal of warfarin with prothrombin complex concentrate

BACKGROUND: When life-threatening bleeding occurs in patients on warfarin, timely reversal becomes imperative. In the USA, warfarin effect is commonly reversed with fresh frozen plasma (FFP). The use of FFP is complicated by delays in correction, volume overload and often, inadequate correction. OBJECTIVE: Evaluate the feasibility and efficacy of a protocol for rapid administration of prothrombin complex concentrate (PCC) in the setting of the urgent need for reversal of warfarin. METHODS/PATIENTS: We instituted a policy for rapid delivery and administration of PCC. Appropriate patients received 25-50 U kg(-1) of PCC. The prothrombin time (PT)/International Normalized Ratios (INR) was recorded before and immediately after dosing, and 24 h postdosing. Patients requiring surgical interventions were cleared for the operating room (OR) immediately. Fifty-eight patients were treated, with a median age of 75.5 years (range 26-92). RESULTS: The median INR on presentation was 3.8 (1.4-52.8). Immediately following PCC administration the median INR was 1.3 (0.9-5.7), only two patients with INRs exceeding 2.0. The benefit was maintained at 24 h with a median INR of 1.5 (1.1-3.4). Four patients experienced thrombotic events during their hospitalization, (two deep vein thrombosis, two non-q-wave myocardial infarction) although none was attributed to PPC therapy. CONCLUSIONS: PCC administration is an effective treatment modality for the correction of warfarin anticoagulation in the urgent setting. Advantages over FFP include more timely correction, absence of volume overload and potentially more complete correction. Broader use of PCC in this setting appears to be appropriate.     

Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in gastrointestinal hemorrhage due to warfarin usage in the ED

Objectives

High International Normalized Ratio (INR) level resulting from warfarin use increases the risk of gastrointestinal hemorrhages. We aimed to compare the efficacy of prothrombin complex concentrates (PCC) and fresh frozen plasma (FFP) at lowering the INR level, decreasing active hemorrhages visible by endoscopy, and shortening the length of stay at the emergency department (ED).

Method

This study is a prospective cohort study of consecutive patents with gastrointestinal hemorrhages that received either PCC or FFP. With strict exclusion criteria, only patients over 18 years of age with a high INR level (> 2.1) due to warfarin usage were included.

Results

A total of 40 patients (18 female) were included in the study, 20 each in the PCC and FFP groups. For the PCC group, the mean INR levels at the second and sixth hours were lower than those for the FFP group (second hour INR: 1.53 vs 4.50, P < .01, sixth hour INR: 1.52 vs 2.41, P < .01). Seven patients experienced active bleeding (Forrest 1) in the FFP group, whereas no patient experienced active bleeding in the PCC group based on the Forrest classification (35% vs 0%, P < .01), and only 3 patients in the FFP group underwent invasive/surgical treatment (15% vs 0%, P < .01). The ED length of stay was lower for the PCC group (1.62 days vs 3.46 days, P < .01).

Conclusion

For patients experiencing a gastrointestinal hemorrhage, INR levels were reversed more quickly, there was less active bleeding on endoscopy, and the ED length of stay was lower in the PCC group than in the FFP group.     

Air Ambulance Delivery and Administration of Four‐factor Prothrombin Complex Concentrate Is Feasible and Decreases Time to Anticoagulation Reversal

Objectives

The objective was to evaluate the feasibility, safety, and preliminary efficacy of four‐factor prothrombin complex concentrate (4‐factor PCC) administration by an air ambulance service prior to or during transfer of patients with warfarin‐associated major hemorrhage to a tertiary care center for definitive management (interventional arm) compared to patients receiving 4‐factor PCC following transfer by air ambulance or ground without 4‐factor PCC treatment (conventional arm).

Methods

This was a retrospective chart review of patients presenting to a large academic medical center. All patients presenting to the emergency department (ED) treated with 4‐factor PCC from April 1, 2014, through June 30, 2016, were identified. For this study, only transfer patients with an International Normalized Ratio (INR) > 1.5 actively treated with warfarin were included. The primary outcome was the proportion of patients with an INR ≤ 1.5 upon tertiary care hospital arrival, and the secondary efficacy outcome was difference in time to achievement of INR ≤ 1.5. Additional safety and efficacy objectives included difference in thromboembolic complications, length of stay, intensive care unit length of stay, and inpatient mortality between groups.

Results

Of the 72 included patients, a higher proportion of patients in the interventional group had an INR ≤ 1.5 on ED arrival (proportion difference = 0.82, 95% confidence interval = 0.64–0.92, p < 0.0001) and significantly reduced time to observed INR ≤ 1.5 (181 minutes vs. 541 minutes, p = 0.001). No differences were observed in thromboembolic complications or patient‐centered outcomes with the exception of mortality, which was significantly higher in patients in the interventional group. This group was also observed to have lower Glasgow Coma Scale score and higher intubation rates prior to transfer and treatment.

Conclusions

Dispatch of an air ambulance carrying 4‐factor PCC with administration prior to transfer is feasible and leads to more rapid improvement in INR among patients with warfarin‐associated major hemorrhage.

     

Fresh Frozen Plasma Dosing for Warfarin Reversal: A Practical Formula

ObjectiveTo provide a practical formula for fresh frozen plasma (FFP) dosing for warfarin reversal.Patients and MethodsWe reviewed data on all adult patients who received a total of 7778 units of FFP for warfarin reversal at Sentara Norfolk General Hospital (Norfolk, VA) between April 1, 2009, and March 31, 2010. Patients with advanced liver disease, consumptive or dilutional coagulopathy, and administration of activated factor VII or prothrombin complex concentrate were excluded. First, we used regression analysis on the FFP1 subset (patients whose international normalized ratio [INR] was checked before and after 1 FFP administration) and derived a simple formula: DeltaINR (PreINR – PostINR) after 1 FFP = a × PreINR + b, where PreINR and PostINR are the INR values before and after FFP administration, respectively, and a and b are constants. In the validation step, the formula obtained for the FFP1 subset was repeatedly applied to the FFP2 (patients who received 2 units of FFP back-to-back without an intervening INR check), FFP3, and FFP4 subsets.ResultsA total of 956 patients were included. The formula DeltaINR after 1 FFP = 0.57 × PreINR – 0.72 explained 82.6% of the total variance in INR change in the FFP1 subset (n=308; P<.01). Including age, sex, weight, FFP-to-PostINR interval, or administration of vitamin K marginally improved the model. Repeated application of the FFP1 formula to the FFP2 to 4 subsets combined confirmed the accuracy of the FFP1 formula across the entire data set (n=643; R²=95% between predicted and actual DeltaINR; P<.01).ConclusionThis formula provides a practical and accurate method for FFP dosing for warfarin reversal.     

Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy

Aims

The purpose of this study was to evaluate the effectiveness of a new, fixed, yet individualized dosing regimen of activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for warfarin reversal in the setting of a life-threatening bleeding in a secondary care center.

Methods

In this report we present a retrospective chart review of 72 patients who received FEIBA and 69 patients who received fresh-frozen plasma (FFP) to reverse the effects of warfarin in a setting of a life-threatening bleeding. In the FEIBA cohort, patients received 500 units of FEIBA when the initial INR was <5 or 1,000 units of FEIBA when initial INR was ≥5.

Results

FEIBA administration resulted in lower subsequent INR when compared with FFP and shorter time elapsed from drug administration to an INR ≤1.4 when compared with FFP. No significant differences in survival or in the length of hospital stay were observed. A higher FEIBA dose induced a bigger decrease in INR than the lower dose. We observed five adverse events (7%) that could potentially be related to FEIBA administration.

Conclusions

The presented dosing regimen results in safe reversal of warfarin-induced coagulopathy, which appears to be faster and more profound than following FFP. Moreover, the use of activated PCC (FEIBA) does not appear to carry an increased risk of thrombotic events when compared to the rate reported for several non-activated PCC preparations.     

The patterns of anticoagulation control and the risk of stroke,bleeding and mortality in patients with non‐valvular atrial fibrillation

Summary. Background: Anticoagulation control is often summarized using the percentage of time spent in a therapeutic range (TTR). This method does not describe the timing and severity of fluctuations in the International Normalised Ratio (INR).Objective: To evaluate whether the TTR method can be improved by considering the patterns of INR over time.Methods: The cohort included adults aged 40+ years with atrial fibrillation (AF) and laboratory records of INR as recorded in the UK Clinical Practice Research Datalink. Statistical clustering techniques based on simple INR measures were used to describe the patterns of INR. Nested case–control studies calculated the odds ratios (ORs) for the risk of stroke, bleeding and mortality with TTR and different INR patterns. It was also evaluated whether cluster analyses improved the prediction of outcomes over TTR.Results: A number of 27 381 patients were studied with a mean age of 73 years. The OR for mortality was 3.76 (95% confidence interval [CI] 3.03–4.68) in patients with < 30% TTR compared with patients with 100% TTR. INR patterns were found to be best described by six different clusters. The cluster with the most unstable pattern was associated with the largest risk of mortality (OR 10.7, 95% CI 8.27–13.85) and stroke (OR 3.42, 95% CI 2.08–5.63). INR measures that predicted death independent of the TTR‐included absolute difference between two subsequent INR measurements and change relative to the mean over time.Conclusion: Cluster analysis of INR patterns improved the prediction of clinical outcomes over TTR and may help to identify warfarin users who need additional anticoagulation monitoring.     

Clinical manifestations and outcomes of severe warfarin overanticoagulation: from the EWA study

Introduction: Severe warfarin overanticoagulation is a risk factor for bleeding, but there is little information on its manifestations, prognosis and factors affecting the outcome. We describe the manifestations and clinical outcomes of severe warfarin overanticoagulation in a large group of patients with atrial fibrillation (AF).

Material and methods: All international normalized ratio (INR) samples (n?=?961,431) in the Turku University Hospital region between 2003 and 2015 were screened. A total of 412?AF patients with INR ≥9 were compared to 405 patients with stable warfarin anticoagulation for AF. Electronic patient records were manually reviewed to collect comprehensive data.

Results: Of the 412 patients with INR ≥9, bleeding was the primary manifestation in 105 (25.5%). Non-bleeding symptoms were recorded in 165 (40.0%) patients and 142 (34.5%) had no symptoms. A total of 17 (16.2%) patients with a bleed and 67 (21.8%) without bleeding died within 30 days after the event. Intracranial haemorrhage strongly predicted death within 30 days. Other significant predictors were non-bleeding symptoms, active malignancies, recent bleed, history of myocardial infarction, older age, renal dysfunction and a recent treatment episode.

Conclusions: Bleeds are not the major determinant of the poor prognosis in severe overanticoagulation, as coincidental INR ≥9 findings also associate with high mortality.

• KEY MESSAGES

• Only a quarter of AF patients with INR ≥9 suffered a bleeding event and the clinical manifestation of INR ≥9 had a significant impact on patient outcome.

• The 30-day mortality rate in patients with INR ≥9 was high ranging from 9.2 to 32.7%.

• Several significant predictors of 30-day mortality after INR ≥9 were identified.

     

Impact of therapeutic hypothermia on bleeding events in adult patients treated with extracorporeal life support peri-cardiac arrest

PurposeWhether therapeutic hypothermia (TH) adds to the risk of bleeding in patients on extracorporeal life support (ECLS) peri-cardiac arrest remains unknown.Material and methodsSingle center retrospective study on patients receiving veno-arterial ECLS peri-cardiac arrest ± TH at 32–34 °C (January 2009–December 2015). Primary outcome: major bleeding (including intracerebral hemorrhage, ICH) < 72 h of cardiac arrest. Logistic regression and marginal structural models were used to analyze associations with major bleeding.ResultsOf 66 patients receiving ECLS, 36 were treated with TH. Major bleeding occurred in 14 patients (39%) treated with ECLS+TH and in 17 patients (57%) with ECLS alone. ICH was reported in 3 (8%) and one patient (3%), respectively. There was no difference in mortality, but lung injury occurred more often in ECLS+TH. A platelet count <60 × 10⁹/L but not TH was associated with major bleeding (including ICH). The estimated causal risk ratio of TH on the occurrence of major bleeding (including ICH) at 72 h post cardiac arrest was 0.95 (95%CI 0.62–1.45).ConclusionsBleeding complications were common in our study. However, TH (32–34 °C) was not associated with an increased risk of major bleeding in patients on ECLS peri-cardiac arrest.     

Modified version of the American College of Cardiology's recommendation for low-dose prothrombin complex concentrate is effective for warfarin reversal

BackgroundDosing of four factor prothrombin complex concentrate (4PCC) for warfarin reversal remains controversial. Recently, the American College of Cardiology (ACC) recommended a low-dose PCC regimen as an option for warfarin reversal in acute major bleeding. We performed a retrospective study evaluating if a modified version of the ACC guideline recommendations was effective for warfarin reversal in acute major bleeds when compared to traditional variable dosing.MethodsThis was a retrospective cohort study of patients who received 4PCC for warfarin reversal in a 12 month period. We included patients that were ≥18 years of age, received 4PCC for warfarin reversal, and had an initial International Normalized Ratio (INR) of >2. Our primary outcome was the number of patients who had a post-4PCC infusion INR of <1.6.ResultsA total of 60 patients were included in the final analysis with 30 patients stratified to the traditional dosing and low-dose groups, respectively. Patient demographics were similar between both groups. We found no difference in the number of patients who had a post-4PCC infusion INR <1.6 between the traditional dosing and low dosing group (90.0% vs. 86.7%; p = 0.68). Additionally, we found no difference between post-infusion median INRs in each group (1.35 vs. 1.30; p = 0.16). Approximately 1000 units per patient were spared when utilizing the low-dose regimen.ConclusionA modified version of the ACC's low-dose 4PCC option for warfarin reversal achieves similar outcomes for lowering INR values compared to traditional variable dosing regimens.     

Anticoagulation‐related nephropathy

Anticoagulation‐related nephropathy (ARN) is a significant but underdiagnosed complication of anticoagulation that is associated with increased renal morbidity and all‐cause mortality. Originally described in patients receiving supratherapeutic doses of warfarin who had a distinct pattern of glomerular hemorrhage on kidney biopsy, ARN is currently defined as acute kidney injury (AKI) without obvious etiology in the setting of an International Normalized Ratio (INR) of > 3.0. The underlying molecular mechanism is thought to be warfarin‐induced thrombin depletion; however, newer studies have hinted at an alternative mechanism involving reductions in activated protein C and endothelial protein C receptor signaling. Prompt recognition of ARN is critical, as it is associated with accelerated progression of chronic kidney disease, and significant increases in short‐term and long‐term all‐cause mortality. Prior investigations into ARN have almost universally focused on anticoagulation with warfarin; however, recent case reports and animal studies suggest that it can also occur in patients taking novel oral anticoagulants. Differences in the incidence and severity of ARN between patients taking warfarin and those taking novel oral anticoagulants are unknown; a post hoc analysis of routinely reported adverse renal outcomes in clinical trials comparing warfarin and novel oral anticoagulants found no significant difference in the rates of AKI, a prerequisite for ARN. Given the significant impact of ARN on renal function and all‐cause mortality, a thorough understanding of the pathophysiology, molecular mechanisms, clinical spectrum and therapeutic interventions for ARN is crucial to balance the risks and benefits of anticoagulation and optimize treatment.     

INR targets and site‐level anticoagulation control: results from the Veterans AffaiRs Study to Improve Anticoagulation (VARIA)

Summary. Background: Not all clinicians target the same International Normalized Ratio (INR) for patients with a guideline‐recommended target range of 2–3. A patient’s mean INR value suggests the INR that was actually targeted. We hypothesized that sites would vary by mean INR, and that sites of care with mean values nearest to 2.5 would achieve better anticoagulation control, as measured by per cent time in therapeutic range (TTR).Objectives: To examine variations among sites in mean INR and the relationship with anticoagulation control in an integrated system of care.Patients/Methods: We studied 103 897 patients receiving oral anticoagulation with an expected INR target between 2 and 3 at 100 Veterans Health Administration (VA) sites from 1 October 2006 to 30 September 2008. Key site‐level variables were: proportion near 2.5 (that is, percentage of patients with mean INR between 2.3 and 2.7) and mean risk‐adjusted TTR.Results: Site mean INR ranged from 2.22 to 2.89; proportion near 2.5, from 30 to 64%. Sites’ proportions of patients near 2.5, below 2.3 and above 2.7 were consistent from year to year. A 10 percentage point increase in the proportion near 2.5 predicted a 3.8 percentage point increase in risk‐adjusted TTR (P < 0.001).Conclusions: Proportion of patients with mean INR near 2.5 is a site‐level ‘signature’ of care and an implicit measure of targeted INR. This proportion varies by site and is strongly associated with site‐level TTR. Our study suggests that sites wishing to improve TTR, and thereby improve patient outcomes, should avoid the explicit or implicit pursuit of non‐standard INR targets.     

Effectiveness of prothrombin complex concentrate for the treatment of bleeding: A systematic review and meta‐analysis

Prothrombin complex concentrate (PCC) is increasingly being used as a treatment for major bleeding in patients who are not taking anticoagulants. The aim of this systematic review and meta‐analysis is to evaluate the effectiveness of PCC administration for the treatment of bleeding in patients not taking anticoagulants. Studies investigating the effectivity of PCC to treat bleeding in adult patients and providing data on either mortality or blood loss were eligible. Data were pooled using Mantel‐Haenszel random effects meta‐analysis or inverse variance random effects meta‐analysis. From 4668 identified studies, 17 observational studies were included. In all patient groups combined, PCC administration was not associated with mortality (odds ratio = 0.83; 95% confidence interval [CI], 0.66‐1.06; P = .13; I² = 0%). However, in trauma patients, PCC administration, in addition to fresh frozen plasma, was associated with reduced mortality (odds ratio = 0.64; CI, 0.46‐0.88; P = .007; I² = 0%). PCC administration was associated with a reduction in blood loss in cardiac surgery patients (mean difference: ?384; CI, ?640 to ?128, P = .003, I² = 81%) and a decreased need for red blood cell transfusions when compared with standard care across a wide range of bleeding patients not taking anticoagulants (mean difference: ?1.80; CI, ?3.22 to ?0.38; P = .01; I² = 92%). In conclusion, PCC administration was not associated with reduced mortality in the whole cohort but did reduce mortality in trauma patients. In bleeding patients, PCC reduced the need for red blood cell transfusions when compared with treatment strategies not involving PCC. In bleeding cardiac surgery patients, PCC administration reduced blood loss.     

High versus low fixed-dose four factor-prothrombin complex concentrate for warfarin reversal in patients with intracranial hemorrhage

BackgroundFour-factor prothrombin complex concentrate 4F-PCC is the standard of care for warfarin reversal in patients with major bleed or requiring urgent surgery. Although the 4F-PCC dose is weight and international normalized ratio (INR) based, for practical purposes, a fixed-dose approach has been explored, especially for rapid reversal. We report our experience using two different fixed-dose 4F-PCC for warfarin reversal in patients presenting with intracranial hemorrhage (ICH).Study design and methodsWe completed a retrospective chart review comparing high (4000 units) versus low (2000 units) dose 4F-PCC by evaluating patient characteristics, laboratory data, and pre-and post-4F-PCC brain imaging.ResultsThere was no significant difference between patient characteristics or INR correction (≤1.5) between the two groups. Eighty percent (12/15) of patients who received the low dose 4F-PCC had either improved or stable brain imaging as compared to 88% (14/16) of patients who received the high dose PCC. When the eight patients (4 from each arm of the study) who required neurosurgery were excluded, only two patients in each arm had worse imaging after 4F-PCC.ConclusionThere was no significant difference between the INR correction and the brain imaging changes in patients with an ICH who received either the high or the low fixed-dose 4F-PCC for warfarin reversal.     

Four-factor prothrombin complex concentrate for life-threatening bleeds or emergent surgery: A retrospective evaluation

PurposePrevious trials investigating usage of four-factor prothrombin complex concentrate (4F-PCC) excluded patients with various thrombotic risk factors. The objective of this study was to evaluate the safety and effectiveness of 4F-PCC in a real-world setting based on an institutional protocol that does not have strict exclusion criteria.MethodsThis was a retrospective study of adult patients who received 4F-PCC. The primary outcome was a confirmed thromboembolism within 14 days after 4F-PCC administration. Secondary outcomes included international normalized ratio (INR) correction to <1.5 at first draw and incidence of INR rebound for patients undergoing reversal of warfarin and hemostatic effectiveness for patients experiencing a bleed.ResultsNinety-three patients received 4F-PCC. Sixty-three (67.7%) were reversed for bleeding and 30 (32.3%) for surgery. Eleven patients (11.8%) developed a thromboembolism within 14 days. The median (interquartile range) time to event was 5 (2-7) days. Significant risk factors were heparin-induced thrombocytopenia (P= .01) and major surgery within 14 days (P= .02), as well as the presence of >6 thrombotic risk factors (P= .01). For patients post-warfarin reversal, 45/63 (71.4%) achieved INR correction at first draw, 55/63 (87.3%) achieved INR correction within 24 hours, and 14/55 (25.5%) experienced INR rebound. Of these 14 patients, 8 (57.1%) did not receive concomitant vitamin K.Conclusions4F-PCC was associated with a notable thromboembolic risk. All patient-specific risk factors should be considered prior to administration. 4F-PCC remains a useful agent for warfarin reversal. Lack of concomitant vitamin K may contribute to INR rebound.