Anticoagulant

Anti cougalant in atrial fibrillation.

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The Problem

An 82-year-old woman with hypertension and diabetes is seen in the clinic for newly diagnosed atrial fibrillation (AF). She uses a walker and fell twice last year. She completes activities of daily living (ADLs) independently. Should she be prescribed an anticoagulant?

AF markedly increases the risk of ischemic stroke, which often results in disability and threatens independence.1 Anticoagulants reduce stroke rates but simultaneously increase hemorrhage rates. Unfortunately, predictors of benefit and harm overlap considerably; for example, advanced age predicts both stroke and hemorrhage risk. Guidelines give clear-cut therapeutic recommendations based on stroke risk but provide less specific guidance on balancing the increased hemorrhage risk.2 Although risk models help quantify bleeding risk, the consequences of bleeding (e.g., disability) in older adults are ill defined. The result is a quagmire.

The Pros and Cons of Anticoagulant Use in Older Adults with AF

Randomized controlled trials (RCTs) unequivocally demonstrate that anticoagulants reduce stroke rates, including in older adults.3 We have long understood that anticoagulants also increase the risk of intracranial hemorrhage, which is uncommon but devastating. By comparison, many consider the more common extracranial hemorrhage (e.g., gastrointestinal hemorrhage) to be a temporary inconvenience. While this is likely true for younger adults, bleeding may be more consequential for older adults.

Stroke prevention is important because strokes often result in a sudden loss of ADL independence. Now consider that hospitalization for any reason poses a risk to older adults’ independence: one in three develop lasting hospital-acquired disability.4 Even when the underlying disease is treated, hospitalization of older adults may result in lost ADL independence. Given the typical management for hemorrhage (e.g., procedures, not allowing patients to eat), such admissions are bound to result in hospital-acquired disability. Although stroke-associated disability has been reported in RCTs, hemorrhage-associated disability has not been commonly reported.

Older also adults prize quality of life.5 Anticoagulants impose costs to quality of life not captured in RCTs, including so-called nuisance bleeding, delays for urgent procedures, physician visits, medication interactions, and out-of-pocket expenses. Such costs are particularly burdensome to vulnerable older adults. They are hardly a niche population: 80% of older adults with AF are vulnerable with one or more geriatric syndromes (e.g., falls, frailty).6

What We Know

Guidelines recommend using the CHA2DS2-VASc score to estimate stroke risk and offer anticoagulants above a certain threshold — one that nearly all older adults with AF surpass.2,6 The recommendation implies that above the threshold, the benefits outweigh the risks; however, this threshold has not yet been tested with regard to disability and quality of life.

Faced with uncertainty, anticoagulant use in older adults with AF is far below what the guidelines suggest: only 45% consistently use anticoagulants.7 When surveyed about the decision not to treat specific patients in their care, physicians cite frailty, falls, and life expectancy — geriatric features that are under-addressed in RCTs.8,9

The ELDER-AF trial addressed anticoagulant use in older adults with AF.10 The investigators randomly assigned adults 80 years of age or older who were not considered candidates for therapeutic anticoagulation to placebo or low-dose edoxaban, a direct-acting oral anticoagulant. The trial again demonstrated that anticoagulants reduce stroke risk by 66%.

The trial also underscored the trouble with anticoagulants in older adults. Major bleeding, the primary safety outcome, was not statistically higher with treatment. However, this outcome excludes clinically relevant nonmajor bleeding, which is common and consequential.11 Clinically relevant nonmajor bleeding includes hemorrhages requiring interventions like hospitalization, endoscopy, and surgery. Using this more germane end point, anticoagulation increased bleeding risk by 65%. In a trial in which one sixth of all participants had major or clinically relevant nonmajor bleeding, no data were presented on the outcomes of bleeding events. We are left wondering — did bleeding result in lost independence or decrements in quality of life?

What We Need

A trial that compares oral anticoagulants to placebo for older adults with AF where function and quality of life are the primary outcomes would capture the broader impact of therapy that many older adults prioritize. Such a trial would answer straightforward questions: If the 82-year-old woman described at the beginning of this article uses an anticoagulant, will it improve her chances of remaining ADL independent? Will it sustain her quality of life?

The work ahead is to co-design and execute a trial with stakeholders — older adults with AF, caregivers, and physicians — whose decisions we seek to inform. This trial would recruit a population similar to the ELDER-AF trial: older adults with AF for whom physicians have misgivings about anticoagulants or patients who, for any reason, decided not to use anticoagulants despite their physician’s recommendation. Based on projections from disability rates after stroke and hemorrhage, and studies of quality of life in AF,12,13 this trial would need to randomly assign approximately 1600 patients to treatment with 18 months of follow-up to detect a 5% absolute change in ADL independence and a 0.15-SD change in the 36-Item Short Form Health Survey physical component score. The results of such a trial could provide clarity for millions of older adults with AF and their physicians who, with current data, struggle to balance the benefits and harms of anticoagulants.

Oral Anticoagulant Prescription in Patients With Atrial Fibrillation and a Low Risk of Thromboembolism

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In patients with atrial fibrillation (AF) who are at risk for thromboembolism, anticoagulation therapy with warfarin or the newer novel anticoagulants reduces morbidity and mortality.1,2 Because oral anticoagulant use carries a risk of bleeding, the drugs are not recommended in patients with AF who are at a particularly low risk for stroke. Specifically, previous AF guidelines recommend against the use of oral anticoagulation in patients younger than 60 years without heart disease or other known risk factors for thromboembolism,3and more recently updated guidelines do not recommend the use of oral anticoagulation in patients with AF without any established risk factor for stroke.4 We sought to examine the prevalence of oral anticoagulant prescription that does not adhere to the guidelines in young and healthy patients with AF who were at the lowest risk for thromboembolism, as well as the clinical predictors of this practice.

Dabigatran versus Warfarin in Patients with Mechanical Heart Valves.

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Prosthetic heart-valve replacement is recommended for many patients with severe valvular heart disease and is performed in several hundred thousand patients worldwide each year.1 Mechanical valves are more durable than bioprosthetic valves2 but typically require lifelong anticoagulant therapy. The use of vitamin K antagonists provides excellent protection against thromboembolic complications in patients with mechanical heart valves3 but requires restrictions on food, alcohol, and drugs and lifelong coagulation monitoring. Because of the limitations of vitamin K antagonists, many patients opt for a bioprosthesis rather than a mechanical valve, despite the higher risk of premature valve failure requiring repeat valve-replacement surgery with bioprostheses.

Dabigatran etexilate (dabigatran) is an oral direct thrombin inhibitor that was shown to be effective as an anticoagulant in the treatment of patients with atrial fibrillation in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study.4-6 Prompted by these data and the promising results of studies in animals, which showed the efficacy of dabigatran in preventing valve thrombosis,7-9 we conducted the Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement (RE-ALIGN). The primary aim of RE-ALIGN was to validate a new regimen for the administration of dabigatran to prevent thromboembolic complications in patients with mechanical heart valves

DISCUSSION

The primary goal of RE-ALIGN was to validate a new dabigatran dosing regimen for the prevention of thromboembolic complications in patients with mechanical heart valves. However, the trial was stopped early because of an excess of thromboembolic and bleeding events in the dabigatran group, as compared with the warfarin group. Most thromboembolic events among patients in the dabigatran group occurred in population A (patients who had started a study drug within 7 days after valve surgery), with fewer occurring in population B (patients who had undergone valve implantation more than 3 months before randomization). Excess bleeding events among patients receiving dabigatran occurred in the two study populations.

Possible explanations for the increase in thromboembolic complications with dabigatran include inadequate plasma levels of the drug and a mechanism of action that differs from that of warfarin. Trough plasma levels of dabigatran in population A were lower during the first few weeks after surgery than they were subsequently, and low drug levels soon after valve surgery may have allowed for early formation of blood clots that were not clinically manifested until later. However, thromboembolic events also occurred among patients with higher trough plasma levels of dabigatran early after surgery and among those in population B who had higher plasma levels than those in population A, suggesting that lower-than-expected drug levels cannot fully explain the increase in the rate of thromboembolic events.

The choice of a target trough plasma level of 50 ng of dabigatran per milliliter was primarily based on data from the RE-LY trial, in which dabigatran at a dose of 150 mg twice daily, as compared with warfarin, had superior efficacy and similar safety in patients with atrial fibrillation. We cannot exclude the possibility that targeting a higher trough level of dabigatran would have been more effective for the prevention of thromboembolic complications. At the same time, it is likely that the use of higher dabigatran doses would have led to unacceptably high bleeding rates, since dabigatran caused excess bleeding at the doses studied. It is also possible that more frequent administration of dabigatran (e.g., three times a day) without an increase in the total daily dose might have resulted in higher trough and lower peak levels, thereby increasing antithrombotic efficacy and reducing bleeding, but this approach was not tested.

Differences in the mechanisms of action of dabigatran and warfarin may also in part explain our findings. In patients with atrial fibrillation, thrombi form in the left atrial appendage under low-flow, low-shear conditions in which thrombin generation is believed to be triggered by stasis and endothelial dysfunction.19 In contrast, in patients with a mechanical heart valve, coagulation activation and thrombin generation induced by the release of tissue factor from damaged tissues during surgery may partly explain the high risk of early thromboembolic complications. In addition, thrombin generation can be triggered by exposure of the blood to the artificial surface of the valve leaflets and sewing ring, which induce activation of the contact pathway of coagulation. The majority of thrombi in patients with prosthetic heart valves appear to arise from the sewing ring,20 which does not undergo endothelialization for at least several weeks after surgery. It is thought that the sewing ring becomes less thrombogenic once endothelial tissue has formed around it. Warfarin is likely to be more effective than dabigatran at suppressing coagulation activation because it inhibits the activation of both tissue factor–induced coagulation (by inhibiting the synthesis of coagulation factor VII) and contact pathway–induced coagulation by inhibiting the synthesis of factor IX), as well as inhibiting the synthesis of factor X and thrombin in the common pathway,21 whereas dabigatran exclusively inhibits thrombin.22 If contact activation is intense, the resulting thrombin generation may overwhelm local levels of dabigatran, which can lead to thrombus formation on the surface of the valve and related embolic complications.

RE-ALIGN was an open-label trial and thus subject to reporting biases. However, clinical outcomes were prespecified, objectively defined, and independently adjudicated by experts who were unaware of the study-group assignments, all factors that minimize the potential for bias.

The results of our study indicate that dabigatran is not appropriate as an alternative to warfarin for the prevention of thromboembolic complications in patients who require anticoagulation after the implantation of a prosthetic heart valve. The results may also be relevant to studies of other new oral anticoagulants in patients with mechanical heart valves. Like dabigatran, the direct factor Xa inhibitors are effective for stroke prevention in patients with atrial fibrillation,23,24 but these data cannot be extrapolated to patients with mechanical heart valves because the mechanisms of thrombosis are different. Rivaroxaban has been successfully tested for the prevention of thromboembolic complications associated with mechanical heart valves in preclinical studies,25 but our study did not provide evidence of the safety and efficacy of the selected dosing algorithm, despite favorable results of preclinical studies.7-9

In conclusion, the results of our phase 2 study indicate that at the doses tested, dabigatran was not as effective as warfarin for the prevention of thromboembolic complications in patients with mechanical heart valves and was associated with an increased risk of bleeding. These results might be explained by the relative inability of dabigatran to suppress activation of coagulation that occurs when blood is exposed to the artificial surfaces of the valve prosthesis. The use of dabigatran has no positive value and was associated with excess risk in patients with mechanical heart valves.

 

Source: NEJM

 

New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding.

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Abstract

Background & Aims A new generation of oral anticoagulants (nOAC), which includes thrombin and factor Xa inhibitors, has been shown to be effective, but little is known about whether these drugs increase patients’ risk for gastrointestinal bleeding (GIB). Patients who require OAC therapy frequently have significant comorbidities and may also take aspirin and/or thienopyridines. We performed a systematic review and meta-analysis of the risk of GIB and clinically relevant bleeding in patients taking nOAC.

Methods We queried MEDLINE, EMbase, and the Cochrane library (through July 2012) without language restrictions. We analyzed data from 43 randomized controlled trials (151,578 patients) that compared nOAC (regardless of indication) with standard care for risk of bleeding (19 trials on GIB). Odds ratios (ORs) were estimated using a random-effects model. Heterogeneity was assessed with the Cochran Q test and the Higgins I2test.

Results The overall OR for GIB among patients taking nOAC was 1.45 (95% confidence interval [CI], 1.07–1.97), but there was substantial heterogeneity among studies (I2, 61%). Subgroup analyses showed that the OR for atrial fibrillation was 1.21 (95% CI, 0.91–1.61), for thromboprophylaxis after orthopedic surgery the OR was 0.78 (95% CI, 0.31–1.96), for treatment of venous thrombosis the OR was 1.59 (95% CI, 1.03–2.44), and for acute coronary syndrome the OR was 5.21 (95% CI, 2.58–10.53). Among the drugs studied, the OR for apixaban was 1.23 (95% CI, 0.56–2.73), the OR for dabigatran was 1.58 (95% CI, 1.29–1.93), the OR for edoxaban was 0.31 (95% CI, 0.01–7.69), and the OR for rivaroxaban was 1.48 (95% CI, 1.21–1.82). The overall OR for clinically relevant bleeding in patients taking nOAC was 1.16 (95% CI, 1.00–1.34), with similar trends among subgroups.

Conclusions Studies on treatment of venous thrombosis or acute coronary syndrome have shown that patients treated with nOAC have an increased risk of GIB, compared with those who receive standard care. Better reporting of GIB events in future trials could allow stratification of patients for therapy with gastroprotective agents.

Introduction

Gastrointestinal bleeding (GIB) is a serious medical condition that causes considerable morbidity and mortality (5%–15%) and poses an enormous burden on global health care use.[1] The mean hospital costs are reported to range from $2500 to $7300 for upper GIB, $4800 for lower GIB, and around $40,000 for small-bowel bleeding.[2] The expanding indications and increasingly intensive treatment with antithrombotic agents have increased the burden of GIB related to these agents.[3] Antiplatelet agents (eg, aspirin and thienopyridine derivatives) can give rise to GIB by producing ulcers and erosions throughout the gastrointestinal tract. Anticoagulants (ie, vitamin K antagonists [VKA]) and heparins might precipitate bleeding from pre-existing lesions.[4] The relative risk of GIB varies from 1.5 for low-dose aspirin compared with nonuse[5]and more than 5 for the combination of aspirin and VKA.[3] In light of their efficacy, the increased risk of bleeding induced by the therapy is acceptable. Two important limitations of the traditional antithrombotic agents comprise the need for international normalized ratio monitoring with tailored VKA dosing, or subcutaneous administration of low-molecular-weight heparins (LMWH).

New oral anticoagulants (nOAC) (eg, factor IIa [thrombin] or factor Xa inhibitors) have been developed and theoretically lack these limitations.[6–8] These drugs are as effective as current therapy. Some randomized controlled trials (RCTs) reported an isolated higher GIB risk,[9,10] which is potentially fatal, costly, and avoidable. It is therefore important to carefully review the literature on GIB risk attributable to use of nOAC. This is particularly relevant because patients on nOAC often use concomitant low-dose aspirin and/or thienopyridines, which may add substantially to the as yet unknown GIB risk. Furthermore, in contrast with the traditional OAC, no clinically tested antidote is currently available for the novel agents, hampering therapeutic options in case of GIB.[11] For these reasons, we conducted a systematic review focusing on the risk of GIB of all nOAC. Because not all trials separately reported GIB risk, we also reviewed the evidence on risk of clinically relevant bleeding associated with nOAC use.

 

Study Definitions

The exposure of interest was defined as the (approximated) indication-specific recommended daily dose of the nOAC either by the European Medicines Agency[12] or the Food and Drug Administration[13] for registered nOAC. When nOAC was not registered for the indication for which it was studied, the indication-specific daily dose was defined according to the pharmaceutical manufacturer.

Standard care was defined as either low-molecular-weight heparin, vitamin K antagonist, antiplatelet therapy, or no (additional) therapy/placebo, depending on the (inter)national guidelines regarding antithrombotic therapy for the concerning indication.

The primary outcome of this systematic review was the risk of GIB. GIB was considered as at least one episode of clinically apparent hematemesis (frank blood or coffee-ground material that tested positive for blood), melena, or spontaneous rectal bleeding (if more than a few spots) or endoscopically confirmed bleeding, and was judged as major or clinically relevant nonmajor depending on the severity.[14]

The secondary outcome was the risk of clinically relevant bleeding (encompassing both major bleeding and clinically relevant nonmajor bleeding). Major bleeding and clinically relevant nonmajor bleeding in the included studies were defined by the following: (1) the International Society on Thrombosis and Haemostasis, [15,16] (2) the Thrombolysis In Myocardial Infarction,[17] or (3) an adjustment of the International Society on Thrombosis and Haemostasis definition (see Table 1 for exact definitions).

Data Sources and Searches

A comprehensive literature search was conducted to identify RCTs reporting GIB or clinically relevant bleeding in patients receiving nOAC compared with standard treatment. Medline with PubMed as interface, EMbase, and the Cochrane Central Register of Controlled Trials were searched from inception to July 2012. Medical subject heading terms and keywords used to identify RCTs included “apixaban,” “rivaroxaban,” “dabigatran,” “edoxaban,” “betrixaban,” “humans,” and “randomized controlled trial.” No language restrictions were applied. The electronic search strategy was complemented by a manual review of reference lists of included articles. References of recent reviews on nOAC also were examined.[11,18-23]

Study Selection

Search results were combined and duplicates were removed. Studies were first screened based on title and abstract for relevance, after which the full text was reviewed. This was performed independently by 2 reviewers (I.L.H. and V.E.V.). Inter-rater agreement was assessed using the k statistic. Any discrepancies were resolved by consensus, contacting a third author (E.T.T.L.T.). Studies had to meet the following inclusion criteria: (1) the study compared nOAC with the current standard care in a randomized setting; (2) results included bleeding events as a safety outcome; (3) the study was conducted in the target population of the drug and not in healthy volunteers; and (4) it was published as a full-text article. If any of the 4 criteria were not met, the study was excluded. If data from the same study were published in multiple languages, data from the English article were extracted. In case of suspicion of double reporting of the same patient populations, data from the main publication were extracted.

Data Extraction

The included studies were divided by clinical indication of anticoagulant therapy into the following indication groups: (1) prevention of stroke and systemic embolism in patients with atrial fibrillation (AF); (2) prevention of venous thromboembolism after orthopedic surgery (OS); (3) prevention of venous thromboembolism in medically ill patients; (4) treatment of acute deep vein thrombosis (DVT) or pulmonary embolism (PE); and (5) treatment of acute coronary syndrome (ACS). For each included study, we recorded the number of trial participants, follow-up period, and the number of patients who developed the primary safety end points for both treatment arms. The mean age at baseline and the percentage of males were assessed, as well as other characteristics of the study population such as relevant concomitant medications that may affect bleeding risk. This was performed independently by 2 authors (I.L.H. and V.E.V.). Finally, we contacted the main investigator for missing data. Furthermore, given the heterogeneity of the studies, an individual patient data analysis was attempted. All authors were contacted and requested to provide individual patient data. We received responses from 7 of 23 authors (covering 12 of 43 studies). Unfortunately, no one agreed to share this information.

Quality Assessment

The quality of included studies was assessed according to the Cochrane Reviewers’ Handbook.[24] Both manuscript and protocol, if available online, were scanned for relevant information on quality.

Data Synthesis and Analysis

Odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated for each RCT and were the bases for the meta-analyses. To include studies with null events in either the active treatment arm or the standard care arm, 0.5 events were added to all cells with study results. In case of null events in both arms, no OR was calculated. To quantify how many patients needed to be exposed to nOAC therapy to cause one additional GIB compared with standard care the number needed to harm (NNH) was assessed.

To explore between-study variability the Cochran Q test and the Higgins I2 test for heterogeneity were used. Significant heterogeneity was assumed when the Cochran Q P value was less than .10 and the I2 was greater than 50%. To reduce the impact of heterogeneity, we used a random-effects model in these cases.

To account for possible sources of heterogeneity, we performed prespecified subgroup analyses according to type of nOAC and indication. Heterogeneity between subgroups was evaluated further by a post hoc meta-regression analysis by indication, type of nOAC, and comparator. Comprehensive meta-analysis v2.0 (Biostat, Englewood, NJ) was used to perform the meta-analysis. Meta-regression was performed using PASW statistics 20.0 for Windows (SPSS, IBM, Armonk, New York).

Sensitivity analysis was performed to exclude studies that compared the bleeding risk of nOAC use with the use of placebo as standard care because this intervention is unlikely to increase bleeding risk. Because we only included published data, publication bias was quantified with the Egger regression test, with the results considered to indicate publication bias when the P value was less than .10. In addition, funnel plots were examined for asymmetry.

 

Results

Studies

Our initial search identified 375 records (Figure 1A). A total of 42 studies were eligible for inclusion. The agreement between reviewers for trial inclusion was excellent (κ, 0.94). The clinical indication comprised AF in 8 studies,[9,10,25–30] OS in 21 studies, [31–51]medically ill patients in 2 studies,[52,53] DVT/PE in 6 studies (reporting on 7 trials),[54–59] and ACS in 5 studies (Figure 1B).[60-64]

To gain insight into the performance per drug, the information on bleeding risk was summarized per individual drug (Figure 1C). Rivaroxaban was studied most frequently (15 studies reporting on 16 trials),[10,32–35,39–41,44,54,55,58,59,61,63] followed by apixaban (12 trials),[28–30,38,45,48,49,52,53,56,60,62] dabigatran (10 trials),[9,25,31,36,37,42,46,51,57,64] edoxaban (4 trials),[26,27,47,50] and betrixaban (1 trial).[43] The main characteristics of the 43 included trials are summarized in Supplementary Tables 1–5.

Study Characteristics

A total of 151,578 patients were included in the 43 trials. Duration of follow-up evaluation ranged from 3 weeks to 31 months, with shorter durations of follow-up evaluation for the OS studies and longer durations for AF studies. Patients with a recent history of peptic ulcer disease or patients with an otherwise increased risk of GIB (eg, patients with a thrombocytopenia or coagulation disorder) were excluded in all 43 trials. Concomitant use of any co-medication affecting coagulation was prohibited in 19% of trials, only low-dose aspirin (<160 mg) was allowed in 14%, only short-acting nonsteroidal anti-inflammatory drugs (NSAIDs) (<17 hours) were allowed in 16%, and short-acting NSAIDs/cyclooxygenase-2 inhibitors and/or low-dose aspirin and/or thienopyridines was allowed in 44%, mostly with the addition that it was discouraged. Information on the allowance of antithrombotic co-medication was absent in 7% of trials (Supplementary Tables 1–5).

Study Exposure

First, the risk estimates from each study were pooled by indication because the registered/recommended dose for each individual nOAC differs per indication (Supplementary Table 6). A total of 125,354 patients (83%) were enrolled in the therapeutic arms relevant to this review. Of the 8 trials on AF, 7 trials compared one of the novel agents with dose-adjusted warfarin. Of the 21 trials on thromboprophylaxis after OS, 19 compared a nOAC with LMWH (Supplementary Tables 1–5). All trials, except one trial[58] on DVT/PE treatment, compared a nOAC with LMWH followed by VKA. The trials on treatment of ACS compared nOAC with placebo, in addition to standard (double) antiplatelet therapy.

Publication Bias

The result of the Egger regression test for publication bias was not significant (intercept, 0.7; 95% CI, –0.4 to 1.7; P = .20) and no funnel plot asymmetry was observed (Supplementary Figure 1), indicating no evidence of publication bias.

Methodologic Quality of Included Studies

Supplementary Table 7 presents an overview of the methodologic quality of included RCTs. The majority of trials mentioned the method used for randomization (93%) and adequate concealment of allocation (72%). Seventy percent of studies applied a double-blind design, 23% had a single-blind design, and 7% followed an open-label design. An independent blinded committee identified all suspected outcome events in each study. Ninety-three percent of studies used an intention-to-treat analysis at least for the safety analysis. The number of patients lost to follow-up evaluation varied between 0.1% and 2.5%, but were reported in only 53% of studies.

Gastrointestinal Bleeding

Nineteen trials (44%) reported separate data on GIB. Two small trials yielded null events in both groups and therefore were excluded from the GIB analyses.[35,38] A total of 1101 GIB events in 75,081 patients were reported (1.5%) (Supplementary Table 8). These GIBs were predominantly major bleeds (89%). The percentage of GI bleeds per trial in the nOAC group was low in the trials on OS (nOAC, 0.1%; control, 0.2%), intermediate in the trials on AF (nOAC, 2.1%; control, 1.6%) and DVT/PE (nOAC, 3.0%; control, 1.9%), and high in the trials on ACS (nOAC, 5.3%; control, 1.0%). The NNH was 500 (95% CI, -10,000 to 200), meaning that if 1000 patients were treated with the nOAC instead of standard care, this would result in 2 additional GIBs.

Four of 17 studies showed an increased risk, 12 a comparable risk, and 1 a lower risk of GIB when the nOAC was administered compared with the standard care. After pooling the results of 17 RCTs, the nOAC were found to be associated with a higher risk of GIB compared with standard care (pooled OR, 1.45; 95% CI, 1.07–1.97), but with substantial heterogeneity (I2, 61%). First, a considerable part of the increased risk could be attributed to the 2 trials on ACS (pooled OR, 5.21; 95% CI, 2.58–10.53; I2, 0%). To illustrate, the NNH was 24 (95% CI, 17–42), meaning that per 24 patients treated with the nOAC on top of standard care for ACS, 1 extra GIB would occur. Second, the risk of GIB with nOAC was increased for the 2 trials on DVT/PE (pooled OR, 1.59; 95% CI, 1.03–2.44; I2 27%), but not for other indications for nOAC. The calculated OR (95% CI) of each trial is shown in Figure 2A and 2B. With post hoc meta-regression, we studied the effect of indication of use (therapeutic use of nOAC vs prophylactic use). This showed no difference between therapeutic or prophylactic use when adjusted for comparator (placebo vs antithrombotic agent).

Forrest plot of GIB with subgroup analysis by indication. (B) Forrest plot of GIB with subgroup analysis by drug. Data are presented as OR (95% CI) using a random-effects model and I2 test for heterogeneity. Api, apixaban; bet, betrixaban; dab, dabigatran; edo, edoxaban; riv, rivaroxaban; ACS, acute coronary syndrome; AF, atrial fibrillation; DVT, deep vein thrombosis; Med ill, medically ill; OS, orthopedic surgery; PE, pulmonary embolism.

In a subgroup analysis of individual drugs, dabigatran (3 studies;[9,57,64] I2, 36%), and rivaroxaban (5 studies;[10,33,39,41,58] I2, 0%) were associated with a significant increase in risk of GIB, whereas apixaban (8 studies; I2, 0%) and edoxaban (1 study[27]) were not. The pooled OR of GIB associated with dabigatran use was 1.58 (95% CI, 1.29–1.93) (Figure 2B). Expressed in terms of NNH: per 83 patients treated with dabigatran compared with standard care, 1 additional GIB would occur (95% CI, 59–143). The GIB risk associated with use of rivaroxaban had an OR of 1.48 (95% CI, 1.21–1.82). When adjusting for indication of use (therapeutic vs prophylactic), the risk of rivaroxaban remained significantly higher than that of apixaban (OR, 1.77; 95% CI, 1.32–2.38). Analysis by comparator, adjusted for indication of use, revealed no significant differences between different comparators.

In the sensitivity analysis, we excluded studies that compared nOAC with placebo therapy. No major deviations were seen, except for the risk of GIB during DVT/PE treatment, which reduced and became inconclusive (OR, 1.53; 95% CI, 0.99–2.36). Complete results of this sensitivity analysis are shown in Supplementary Table 8.

Clinically Relevant Bleeding

Because GIB is a substantial component of clinically relevant bleeding, we also included this in our analysis. All 43 trials reported on clinically relevant bleeding. The overall risk of clinically relevant bleeding was significantly higher with the use of nOAC compared with standard care (OR, 1.16; 95% CI, 1.00–1.34). Considerable overall heterogeneity, however, was observed (I2, 83%).

In a subgroup analysis in which different indications for nOAC therapy were considered, we found that patients treated for ACS have an increased risk of bleeding (OR, 2.06; I2, 22%) in contrast to patients receiving thromboprophylaxis during OS (OR, 1.05; I2, 36%). The other indications did not show a significantly increased risk, but this may be hampered by the substantial heterogeneity. Subgroup analysis by individual drug showed a slightly increased risk of rivaroxaban compared with standard care (OR, 1.31; 95% CI, 1.04–1.64), but likewise was marked by heterogeneity (I2, 85%), limiting a solid conclusion on the risk of clinically relevant bleeding (Figure 3 and Supplementary Table 8). The risk of clinically relevant bleeding did not differ by drug when adjusted for indication of use.

Forrest plot of clinically relevant bleeding summarized by indication and by drug. Data are presented as OR (95% CI) using a random effects model and an I2 test for heterogeneity. ACS, acute coronary syndrome; AF, atrial fibrillation; DVT, deep vein thrombosis; Med ill, medically ill; OS, orthopedic surgery; PE, pulmonary embolism.

In the sensitivity analysis, excluding studies comparing with placebo, the overall clinically relevant bleeding risk was not increased (OR, 0.98; 95% CI, 0.88–1.10; I2, 65%) .

Discussion

This systematic review and meta-analysis on 43 trials shows that the nOACs are associated with a modest, but significantly higher, risk of GIB compared with current standard care. This risk is the highest in patients treated for thrombosis (ACS and DVT/PE). In ACS, nOACs were administered on top of other antithrombotic medication, increasing the well-known cumulative risk of GIB.[5] The risk of GIB in patients treated for DVT/PE or receiving thromboprophylaxis for AF is higher than in patients receiving thromboprophylaxis after OS, this might suggest a dose and/or duration effect on top of difference in risk caused by patient characteristics in the different indication groups. However, within the subgroup of AF patients, only patients treated with dabigatran and rivaroxaban carry a higher GIB risk, but not with apixaban. Because head-to-head studies between nOAC in AF have not been performed, it is not possible to determine the drugs with the lowest GIB risk in AF without applying statistically indirect comparisons. A network meta-analysis on overall safety was conducted by others on OS patients and showed no significant differences.[65]

The major strength of this meta-analysis was its focus on GIB. We provide a complete review of 43 trials with a total of 151,578 patients. Given the implementation of nOAC on a large scale, all currently available types of nOAC and all present indications were included because GI physicians will have to deal with GIB complications, irrespective of drug or indication. The data conveyed are corroborated by 2 small meta-analyses with GIB as a secondary safety outcome and in which in total only 3 studies for AF were reviewed. [66,67] For optimal clinical relevance, we included only data obtained with the indication-specific registered/recommended dose per drug, instead of combining all levels of dosages per trial, which was performed in meta-analyses assessing overall risk/benefit of thromboprophylaxis after OS.[8,65]

Two limitations of the current study need to be addressed: (1) study design and GIB report of included studies, and (2) heterogeneity between studies. First, all included studies have been designed for showing noninferior or superior efficacy of nOAC vs current standard care. As a consequence, GIB is not reported as a safety outcome in the majority of studies and will have to be assessed by future studies or by a critical assessment of published studies. A large number of included studies reported only on the composite end point of bleeding outcomes in general. Although the use of this end point has the advantage of increased power, a difference in GIB risk therefore cannot be investigated. However, when studies separately reported on GIB, this was performed for major bleedings, but mostly not for clinically relevant nonmajor bleedings. This led to an underestimation of the risk of all clinically relevant GIBs (ie, composed of both major and clinically relevant nonmajor GIBs). In addition, for GIB there was no standard definition according to a scientific commission, but most trials reported used a uniform definition to identify GIB. Regarding heterogeneity, which is inevitable with current available data, we applied a random-effects model and excluded observational cohorts, healthy volunteer studies, nonregistered drugs, and unpublished data. Furthermore, we addressed all perceived sources of heterogeneity by prespecified subgroup analysis and meta-regression by indication, type of nOAC, and comparator. Analysis by concomitant use of antiplatelet therapy was not feasible owing to lack of stratification of outcome by use of antiplatelet therapy.

Some statistical issues merit clarification. First, we calculated risk estimates per study by means of ORs. Although it would have been preferable to calculate hazard ratios, the rationale to compute ORs was that the mean follow-up time until GIB was not reported per treatment arm for any study. The OR can be interpreted as an estimate of the relative risk because the overall occurrence of GIB is rare (1.5%). Second, for the analysis on GIB, following standard practice, we excluded 2 studies that had no events in both arms. This exclusion was performed because such studies do not provide any indication of either the direction or magnitude of the relative treatment effect, whereas exclusion of the 2 trials would not affect the point estimate. Both studies were of relatively small size (and thus would have had a low weight in the meta-analyses, together equaling approximately 2%).

As evidence of the superior efficacy of nOAC accumulates,[8,65,67] it is important to consider 2 crucial issues. First, most trials used extensive exclusion criteria to enroll only those patients with a presumed low risk of GIB complications attributable to anticoagulants. It is estimated that when these drugs are marketed for daily clinical practice, almost 25%–40% of future users are high-risk patients and the risk of hemorrhage can be as much as 3- to 15-fold increased.[68] It is tempting to speculate that the balance between efficacy and safety will shift unfavorably in these patients because the bleeding risk increases to a much greater extent than the risk of thromboembolism. Second, data on concomitant proton pump inhibitor (PPI) use was not available, except for one trial.[62] A recent consensus guideline states that PPIs should be considered in any person with a risk factor for GIB receiving any type of antithrombotic agent[69] because PPIs have proven to reduce the risk of upper GIB among both traditional NSAID users, low-dose aspirin users, and among patients taking clopidogrel.[70] Future trials, investigating whether gastroprotective agents could increase NNH in patients on nOAC, are warranted. This is of importance because many patients may use nOAC for a considerable duration of time and mostly have significant comorbidity.

In conclusion, we have shown that the gastrointestinal bleeding risk associated with nOAC use might be higher compared with standard care. The current evidence, however, is based on a highly selected patient group with a low bleeding risk, disallowing a true reflection of future patients in daily clinical practice. We recommend that future studies specifically report on the gastrointestinal bleeding risk to further elucidate the true incidence and associated risk. Subsequently, co-administration of gastroprotective agents could be beneficial and warrants further investigations.

 

Source: Medscape.com

 

AMPLIFY: Apixaban in Acute VTE as Effective But Safer Than Standard Anticoagulation.

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The oral factor Xa inhibitorapixaban (Eliquis, Pfizer/Bristol-Myers Squibb) was as effective as standard enoxaparin plus warfarin in treating acute venous thromboembolism (VTE) in a large randomized trial, one in which treatment with apixaban also led to a 69% drop in risk of major bleeding complications[1].

“The efficacy of apixaban in the patients with pulmonary embolism was similar to that in patients with deep vein thrombosis [DVT], and the relative effect was maintained in the approximately 40% of patients who presented with extensive disease,” write Dr Giancarlo Agnelli (University of Perugia, Italy) and associates, in the New England Journal of Medicine.

Their report on the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy (AMPLIFY) trial, conducted at 358 centers in 28 countries, was slated for publication July 1, 2013 in conjunction with the study’s scheduled presentation here at the 2013 Congress of the International Society on Thrombosis and Haemostasis. The New England Journal of Medicine lifted its embargo on AMPLIFY coverage on June 30, following, it said, an embargo break by Reuters

“After 60 years of warfarin, it is an exciting time in thrombosis care,” writes Dr Mary Cushman(University of Vermont, Burlington) in an accompanying editorial [2]. However, “shifting with care to new treatments is essential to safe and effective practice.” She cautions that “new anticoagulants are not for every patient” and notes developments that have helped make warfarin management less burdensome, including the advent of prothrombin-time self-testing, anticoagulation clinics, and reduced monitoring frequency for some patients.

Also, she notes, a lot remains to be learned about the new oral agents, apixaban along with dabigatran(Pradaxa, Boehringer Ingelheim) and rivaroxaban (Xarelto, Bayer/Johnson & Johnson), including reversal strategies, monitoring (eg, in the presence of interacting drugs, extremes of patient weight, or bleeding or thrombosis complications), [and] approaches to treatment failure.”

The trial randomized 5395 patients with acute, symptomatic proximal VTE and/or pulmonary embolism (PE) to receive, with double blinding, either apixaban (n=2691) or subcutaneous enoxaparin followed by warfarin (n=2704). The factor Xa inhibitor was given as 10 mg twice daily for seven days followed by 5 mg twice daily for six months; enoxaparin was given for at least five days (median 6.5 days), with warfarin continued for six months.

The primary efficacy outcome was seen in 2.3% of patients taking apixaban and 2.7% of those on conventional therapy, which handily met the prespecified criteria for apixaban noninferiority (p<0.001). The results were nearly identical in each of the two VTE subgroups: those who entered with DVT and those who had PE.

Major bleeding occurred in 0.6% of the apixaban and 1.8% of the conventional-therapy groups, for a 69% drop in relative risk with the factor Xa inhibitor (p<0.001 for superiority). The composite of major bleeding or clinically relevant nonmajor bleeding fell by 56% (p<0.001 for superiority). VTE recurred within 30 days in 0.2% and 0.3%, respectively.

Relative Risk (95% CI) for Outcomes Apixaban vs Conventional Therapy

End points RR (95% CI)
First recurrent VTE or VTE-related death* 0.84 (0.60–1.18)
Major bleeding 0.31 (0.17–0.55)
Major or clinically relevant nonmajor bleeding 0.44 (0.36–0.55)
Death during treatment period 0.79 (0.53–1.19)
VTE or CV death 0.80 (0.57–1.11)
VTE, VTE-related death, or major bleeding 0.62 (0.47–0.83)

*Primary efficacy outcome

“The efficacy and safety of apixaban were consistent across a broad range of subgroups, including those based on clinically important features such as an age of more than 75 years, a body weight of more than 100 kg, use of parenteral anticoagulant treatment before randomization, and the duration of such treatment,” suggesting that the findings are likely generalizable across a broad spectrum of patients, according to the group. The findings at participating centers where warfarin-treated patients were more often maintained in a therapeutic INR range were also consistent with trial’s overall results, they write.

“On the basis of the results of this trial, together with those of the [AMPLIFY-EXT] trial, apixaban provided a simple, effective, and safe regimen for the initial and long-term treatment of venous thromboembolism.”

In AMPLIFY-EXT, as heartwire reported late last year, the risk of recurrent VTE or death was significantly reduced among patients who completed a full six-month course of anticoagulation for VTE and then stayed on apixaban another six to 12 months, so-called extended therapy for VTE, compared with anticoagulated patients who were then given placebo.

The trial was funded by Pfizer and Bristol-Myers Squibb. Agnelli discloses receiving personal fees from Pfizer in relation to the conduct of the trial, and other personal fees from Boehringer Ingelheim, Sanofi, Daiichi-Sankyo, and Bayer Healthcare. Disclosures for the coauthors are listed on the journal’s website. Cushman had no disclosures.

http://www.medscape.com

 

ti�ue�&� �t� effects. If you’re taking a supplement, it’s a good idea to check the FDA website periodically for updates.

 

Source: Mayo clinic

 

 

white�pn�t� X1� font-size:9.0pt;font-family:”Arial”,”sans-serif”;color:#666666′>And, I’ll tell you right now, after this last year, leaving Waiheke Island, going to Hawaii (as detailed in Going Out On A Limb), well… I feel freer, happier, more peaceful and more my true self than I ever have in 35 years and I categorically COULD NOT have done it if I had not reached out for support.

 

So, I implore you, if you are someone who is afraid to reach out for support, please… for the love of all things… swallow your fears, your negative self-talk, your pride or whatever is keeping you stuck and please, please put your freaking hand up! The Universe will deliver what you need if you will only step up to help yourself. People will materialise to support you. Information will find its way to you when you move forward to open your arms to receive it. You will find help in the most unlikely of places if you are willing to step outside your comfort zone. Do not judge how things may have gone before… perhaps once before you reached out and you didn’t get the response and support you needed. The past is gone and it has no bearing now. Life is short, don’t waste one second of it when the support you need lies all around you, beckoning you to call upon it.

 

Preventing Venous Thromboembolism After Hip Replacement.

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Aspirin is noninferior to low-molecular-weight heparin for extended VTE prophylaxis.

 

The risk for venous thromboembolism (VTE) persists for several weeks after a major orthopedic procedure, leading to recommendations that anticoagulant therapy continue for up to 5 weeks postoperatively. Such prophylaxis can be accomplished by daily subcutaneous injections of low-molecular-weight heparin (LMWH), but this adds to the discomfort and cost of the procedure.

To determine if aspirin might be a safe and effective substitute for LMWH in this setting, Canadian investigators conducted a multicenter, blinded, randomized, controlled trial involving 778 participants who underwent total hip arthroplasty. All patients initially received dalteparin LMWH (5000 U daily by subcutaneous injection) for 8 to 10 days postoperatively and then were randomized to continue dalteparin or receive aspirin (81 mg daily) for 28 more days.

During a 90 day follow-up period, VTE events occurred in 5 dalteparin recipients (1.3%) and in 1 aspirin recipient (0.3%), indicating that aspirin was noninferior (P<0.001) but not superior (P=0.22) to dalteparin. Major bleeding occurred in 1 dalteparin recipient and no aspirin recipients; clinically significant nonmajor bleeding events occurred in 4 dalteparin recipients and 2 aspirin recipients. A composite analysis of VTE and bleeding events favored aspirin (0.8% vs. 2.5%, P=0.09).

Comment: This investigation suggests that aspirin is as safe and effective as dalteparin LMWH. However, only 17.7% of screened patients participated in the trial, and very few events occurred, so the results might not be generalizable to the larger population of patients undergoing hip arthroplasty or other major orthopedic procedures. Nevertheless, future studies assessing new antithrombotic agents should include aspirin as a comparator.

 

Source: Journal Watch Oncology and Hematology

 

 

Pacemaker or Defibrillator Surgery without Interruption of Anticoagulation.

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BACKGROUND

Many patients requiring pacemaker or implantable cardioverter–defibrillator (ICD) surgery are taking warfarin. For patients at high risk for thromboembolic events, guidelines recommend bridging therapy with heparin; however, case series suggest that it may be safe to perform surgery without interrupting warfarin treatment. There have been few results from clinical trials to support the safety and efficacy of this approach.

METHODS

We randomly assigned patients with an annual risk of thromboembolic events of 5% or more to continued warfarin treatment or to bridging therapy with heparin. The primary outcome was clinically significant device-pocket hematoma, which was defined as device-pocket hematoma that necessitated prolonged hospitalization, interruption of anticoagulation therapy, or further surgery (e.g., hematoma evacuation).

RESULTS

The data and safety monitoring board recommended termination of the trial after the second prespecified interim analysis. Clinically significant device-pocket hematoma occurred in 12 of 343 patients (3.5%) in the continued-warfarin group, as compared with 54 of 338 (16.0%) in the heparin-bridging group (relative risk, 0.19; 95% confidence interval, 0.10 to 0.36; P<0.001). Major surgical and thromboembolic complications were rare and did not differ significantly between the study groups. They included one episode of cardiac tamponade and one myocardial infarction in the heparin-bridging group and one stroke and one transient ischemic attack in the continued-warfarin group.

CONCLUSIONS

As compared with bridging therapy with heparin, a strategy of continued warfarin treatment at the time of pacemaker or ICD surgery markedly reduced the incidence of clinically significant device-pocket hematoma.

Source: NEJM

 

Stroke Survivors Should Continue Antithrombotics During Dental Procedures.

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Patients who’ve had a stroke should continue taking warfarin or aspirin when undergoing dental procedures, according to new guidelines from the American Academy of Neurology.

The guidelines, published in Neurology, also state that stroke patients should probably continue aspirin during invasive ocular anesthesia, cataract surgery, dermatologic procedures, transrectal ultrasound-guided prostate biopsy, spinal or epidural procedures, and carpal tunnel surgery. However, clinicians should counsel patients that aspirin likely increases bleeding risk during orthopedic hip procedures.

Stroke patients should probably continue warfarin for dermatologic procedures, the guidelines also note.

Source: Neurology 

Burning Bridges: Must Warfarin Be Stopped for Device Implantation?

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In a randomized trial, heparin bridging for implantation of a pacemaker or implantable cardioverter-defibrillator was associated with an increase in device-pocket hematoma.

Warfarin increases the risk for bleeding. Surgery is associated with bleeding. The intuitive inference that patients should discontinue chronic warfarin therapy before undergoing surgery, combined with concern about the ensuing thromboembolic risk, has led to the standard use of intravenous heparin or subcutaneous low-molecular-weight heparin as an anticoagulation “bridge” during warfarin washout. However, some practitioners question the benefits of this practice.

In a multicenter trial, 681 warfarin recipients undergoing permanent pacemaker or implantable cardioverter-defibrillator implantation were randomized to continue warfarin or to discontinue warfarin with a heparin bridge for 5 days before surgery. All patients had an estimated annual risk for thromboembolism of 

≥5% (mean CHADS2 score, 3.4). The trial was stopped early because of a strongly significant increase in the rate of device-pocket hematoma in the heparin-bridging group compared with the warfarin-continuation group (16.0% vs. 3.5%). Two patients in the warfarin-continuation group experienced stroke or transient ischemic attack (compared with none in the heparin-bridging group); however, both had subtherapeutic international normalized ratios at the time of surgery.

Comment: These data confirm what many surgeons and electrophysiologists observe on a daily basis — heparin bridging during warfarin interruption increases bleeding risk even more than continuing warfarin does. The findings are important for patients with atrial fibrillation and a high annual risk for thromboembolism. Whether warfarin can be withheldwithout bridging in individuals at low risk for thromboembolism remains unstudied. For such patients, an effective strategy might be to stop warfarin 1 or 2 days — rather than the traditional 5 days — before surgery.

 

Source:Journal Watch Cardiology

 

 

 

Continued Warfarin Better Approach to Cardiac Device Surgery.

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Higher-risk patients undergoing cardiac device surgery are better off continuing warfarin than switching to heparin as guidelines recommend, according to a New England Journal of Medicine study.

The study included nearly 700 patients at moderate-to-high risk for thromboembolic events who were taking warfarin and required nonemergency pacemaker or implantable cardioverter-defibrillator surgery. Patients were randomized to either continue warfarin (target INR: 3.0 or less; 3.5 or less for patients with mechanical valves) or receive bridging therapy with heparin as recommended by the American College of Chest Physicians.

The study was stopped early after an interim analysis found that the primary outcome — device-pocket hematoma — had occurred four times as often with heparin as with warfarin (16% vs. 3.5%). Continued warfarin didn’t increase major perioperative bleeding.

One explanation for the “counterintuitive” finding, the authors write, “is the concept of an ‘anticoagulant stress test.’ That is, if patients undergo surgery while receiving full-dose anticoagulation therapy, any excessive bleeding will be detectable and appropriately managed while the wound is still open. In contrast, if bridging therapy with heparin is used, such bleeding may be apparent only when full-dose anticoagulation therapy is resumed postoperatively.”

Source: NEJM