Summary
The periprocedural management of patients receiving chronic therapy with oral anticoagulants (OACs), including vitamin K antagonists (VKAs) such as warfarin and direct OACs (DOACs), is a ...common clinical problem. The optimal perioperative management of patients receiving chronic OAC therapy is anchored on four key principles: (i) risk stratification of patient‐related and procedure‐related risks of thrombosis and bleeding; (ii) the clinical consequences of a thrombotic or bleeding event; (iii) discontinuation and reinitiation of OAC therapy on the basis of the pharmacokinetic properties of each agent; and (iv) whether aggressive management such as the use of periprocedural heparin bridging has advantages for the prevention of postoperative thromboembolism at the cost of a possible increase in bleeding risk. Recent data from randomized trials in patients receiving VKAs undergoing pacemaker/defibrillator implantation or using heparin bridging therapy for elective procedures or surgeries can now inform best practice. There are also emerging data on periprocedural outcomes in the DOAC trials for patients with non‐valvular atrial fibrillation. This review summarizes the evidence for the periprocedural management of patients receiving chronic OAC therapy, focusing on recent randomized trials and large outcome studies, to address three key clinical scenarios: (i) can OAC therapy be safely continued for minor procedures or surgeries; (ii) if therapy with VKAs (especially warfarin) needs to be temporarily interrupted for an elective procedure/surgery, is heparin bridging necessary; and (iii) what is the optimal periprocedural management of the DOACs? In answering these questions, we aim to provide updated clinical guidance for the periprocedural management of patients receiving VKA or DOAC therapy, including the use of heparin bridging.
Summary
Background
Treatment of venous thromboembolism (VTE) in patients with cancer has a high rate of recurrence and bleeding complications. Guidelines recommend low‐molecular‐weight heparin (LMWH) ...for at least 3–6 months and possibly indefinitely for patients with active malignancy. There are, however, few data supporting treatment with LMWH beyond 6 months. The primary aim of the DALTECAN study (NCT00942968) was to determine the safety of dalteparin between 6 and 12 months in cancer‐associated VTE.
Methods
Patients with active cancer and newly diagnosed VTE were enrolled in a prospective, multicenter study and received subcutaneous dalteparin for 12 months. The rates of bleeding and recurrent VTE were evaluated at months 1, 2–6 and 7–12.
Findings
Of 334 patients enrolled, 185 and 109 completed 6 and 12 months of therapy; 49.1% had deep vein thrombosis (DVT); 38.9% had pulmonary embolism (PE); and 12.0% had both on presentation. The overall frequency of major bleeding was 10.2% (34/334). Major bleeding occurred in 3.6% (12/334) in the first month, and 1.1% (14/1237) and 0.7% (8/1086) per patient‐month during months 2–6 and 7–12, respectively. Recurrent VTE occurred in 11.1% (37/334); the incidence rate was 5.7% (19/334) for month 1, 3.4% (10/296) during months 2–6, and 4.1% (8/194) during months 7–12. One hundred and sixteen patients died, four due to recurrent VTE and two due to bleeding.
Conclusion
Major bleeding was less frequent during dalteparin therapy beyond 6 months. The risk of developing major bleeding complications or VTE recurrence was greatest in the first month of therapy and lower over the subsequent 11 months.
In acutely ill patients, 10 days of rivaroxaban was noninferior to 10 days of enoxaparin for thromboprophylaxis. Extended-duration rivaroxaban treatment (35 days) reduced the risk of venous ...thromboembolism. Rivaroxaban was associated with an increased risk of bleeding.
Patients with active cancer, stroke, myocardial infarction, or acute exacerbations of a variety of medical conditions are at increased risk for venous thromboembolism.
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Prolonged immobilization and risk factors such as an age older than 75 years, chronic heart failure, a history of venous thromboembolism, and obesity can increase this risk further.
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Randomized, controlled trials involving hospitalized patients at increased risk for venous thromboembolism have shown the benefits of administering anticoagulant agents for up to 14 days,
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and guidelines recommend the use of unfractionated heparin, low-molecular-weight heparins, or fondaparinux in such patients.
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There is some evidence that the risk . . .
See also Greinacher A. Immunogenic but effective: the HIT‐fondaparinux brain puzzler. This issue, pp 2386–8; Goldfarb MJ, Blostein MD. Fondaparinux in acute heparin‐induced thrombocytopenia: a case ...series. This issue, pp 2501–3.
Summary. Background: Fondaparinux is theoretically an attractive agent for the treatment of immune heparin‐induced thrombocytopenia (HIT), a prothrombotic disorder caused by platelet‐activating anti‐platelet factor 4/heparin antibodies. Although reports of the use of fondaparinux for this indication have thus far been favorable, the diagnosis of HIT in most cases was not based on definitive laboratory confirmation of heparin‐dependent, platelet‐activating antibodies. Objectives: To report thrombotic and major bleeding outcomes with fondaparinux in patients with a high likelihood of having acute HIT based on clinical features and a positive result in the confirmatory platelet serotonin‐release assay (SRA), a sensitive and specific test for platelet‐activating HIT antibodies. Methods/Patients: We reviewed consecutive eligible patients with SRA‐positive HIT (mean peak serotonin release, 91% normal, < 20%; mean IgG‐specific PF4/heparin enzyme immunoassay result, 2.53 optical density units normal, < 0.45 units) in one medical center over a 30‐month period who received fondaparinux for anticoagulation during acute HIT (platelet count, < 150 × 109 L−1). Where available, plasma samples were used to measure thrombin–antithrombin (TAT) complex levels. Results: Sixteen patients with SRA‐positive HIT received fondaparinux: 14 surgical (11 after cardiac surgery; three after vascular surgery) and two medical (acute stroke). Fifty‐six per cent of patients had HIT‐associated thrombosis at the time of diagnosis. No patient developed new, recurrent or progressive thrombosis; one patient developed a major bleed (calf hematoma). One patient judged to have irreversible tissue necrosis before receiving fondaparinux therapy ultimately required limb amputation. TAT complex levels were reduced within 24 h of starting fondaparinux, and 13 of 13 patients were successfully switched to warfarin. Conclusion: Fondaparinux shows promise for the treatment of patients with SRA‐positive acute HIT.
Reports from single countries suggest regional differences in Guillain-Barré syndrome (GBS), but no comparative studies have been conducted. Doets et al. present the first results from the ...International GBS Outcome Study, and show that factors related to geography strongly influence clinical phenotype, disease severity, electrophysiological subtype and outcome.
Abstract
Guillain-Barré syndrome is a heterogeneous disorder regarding the clinical presentation, electrophysiological subtype and outcome. Previous single country reports indicate that Guillain-Barré syndrome may differ among regions, but no systematic comparative studies have been conducted. Comparative studies are required to identify factors determining disease susceptibility, variation and prognosis, and to improve diagnostic criteria. The International Guillain-Barré Syndrome Outcome Study is a prospective, observational cohort study including all patients within the diagnostic spectrum, aiming to describe the heterogeneity of Guillain-Barré syndrome worldwide. The current study was based on the first 1000 inclusions with a follow-up of at least 1 year and confirmed the variation in clinical presentation, course and outcome between patients. The full clinical spectrum of Guillain-Barré syndrome was observed in patients from all countries participating in the International Guillain-Barré Syndrome Outcome Study, but the frequency of variants differed between regions. We compared three regions based on geography, income and previous reports of Guillain-Barré syndrome subtypes: 'Europe/Americas', 'Asia' (without Bangladesh), and 'Bangladesh'. We excluded 75 (8%) patients because of alternative diagnoses, protocol violations, or missing data. The predominant clinical variant was sensorimotor in Europe/Americas (n = 387/562, 69%) and Asia (n = 27/63, 43%), and pure motor in Bangladesh (n = 74/107, 69%). Miller Fisher syndrome and Miller Fisher-Guillain-Barré overlap syndrome were more common in Asia (n = 14/63, 22%) than in the other two regions (Europe/Americas: n = 64/562, 11%; Bangladesh: n = 1/107, 1%) (P < 0.001). The predominant electrophysiological subtype was demyelinating in all regions (Europe/Americas: n = 312/573, 55%; Asia: n = 29/65, 45%; Bangladesh: n = 38/94, 40%). The axonal subtype occurred more often in Bangladesh (n = 34/94, 36%) than in Europe/Americas (n = 33/573, 6%) and other Asian countries (n = 4/65, 6%) (P < 0.001). In all regions, patients with the axonal subtype were younger, had fewer sensory deficits, and showed a trend towards poorer recovery compared to patients with the demyelinating subtype. The proportion of patients able to walk unaided after 1 year varied between Asia (n = 31/34, 91%), Europe/Americas (n = 334/404, 83%) and Bangladesh (n = 67/97, 69%) (P = 0.003). A similar variation was seen for mortality, being higher in Bangladesh (n = 19/114, 17%) than in Europe/Americas (n = 23/486, 5%) and Asia (n = 1/45, 2%) (P < 0.001). This study showed that factors related to geography have a major influence on clinical phenotype, disease severity, electrophysiological subtype, and outcome of Guillain-Barré syndrome.
Summary
Background
D‐dimer concentrations have not been evaluated extensively as a predictor of increased venous thromboembolism (VTE) risk in acutely ill, hospitalized medical patients.
Objectives
...To analyze the relationships between D‐dimer concentration, VTE and bleeding in the MAGELLAN trial (NCT00571649).
Patients/methods
This was a multicenter, randomized, controlled trial. Patients aged ≥ 40 years, hospitalized for acute medical illnesses with risk factors for VTE received subcutaneous enoxaparin 40 mg once daily for 10 ± 4 days then placebo up to day 35, or oral rivaroxaban 10 mg once daily for 35 ± 4 days. Patients (n = 7581) were grouped by baseline D−dimer ≤ 2 × or > 2 × the upper limit of normal. VTE and major plus non‐major clinically relevant bleeding were recorded at day 10, day 35, and between days 11 and 35.
Results
The frequency of VTE was 3.5‐fold greater in patients with high D‐dimer concentrations. Multivariate analysis showed that D‐dimer was an independent predictor of the risk of VTE (odds ratio 2.29 95% confidence interval 1.75–2.98), and had a similar association to established risk factors for VTE, for example cancer and advanced age. In the high D‐dimer group, rivaroxaban was non‐inferior to enoxaparin at day 10 and, unlike the low D‐dimer group, superior to placebo at day 35 (P < 0.001) and days 11–35 (P < 0.001). In both groups, bleeding outcomes favored enoxaparin/placebo.
Conclusions
Elevated baseline D‐dimer concentrations may identify acutely ill, hospitalized medical patients at high risk of VTE for whom extended anticoagulant prophylaxis may provide greater benefit than for those with low D‐dimer concentrations.
In patients with atrial fibrillation (AF) who require interruption of dabigatran or warfarin for an elective surgery/procedure, the risks and benefits of perioperative bridging anticoagulation is ...uncertain.We accessed the database from RE-LY, a randomised trial comparing dabigatran with warfarin for stroke prevention in AF, to assess the potential benefits and risks of bridging. In patients who had a first interruption of dabigatran or warfarin for an elective surgery/procedure, we compared the risk for major bleeding (MB), stroke or systemic embolism (SSE) and any thromboembolism (TE) in patients who were bridged or not bridged during the period of seven days before until 30 days after surgery/procedure. We used multivariable Cox regression to adjust for potential confounders.Bridging was used more during warfarin interruption than dabigatran interruption (27.5 % vs 15.4 %; p< 0.001). With dabigatran interruption, bridged patients had more MB (6.5 % vs 1.8 %, p< 0.001) than those not bridged but bridged and not bridged groups did not differ for any TE (1.2 % vs 0.6 %, p=0.16) and SSE (0.5 % vs 0.3 %, p=0.46). With warfarin interruption, bridged patients had more MB (6.8 % vs 1.6 %, p< 0.001) and any TE (1.8 % vs 0.3 %, p=0.007) than those not bridged but bridged and not bridged groups did not differ for SSE (0.5 % vs 0.2 %, p=0.321). In conclusion, in patients who interrupted dabigatran or warfarin for a surgery/ procedure in the RE-LY trial, use of bridging anticoagulation appeared to increase the risk for major bleeding irrespective of dabigatran or warfarin interruption.
Background: The peri‐operative management of patients on oral anticoagulants (OACs) is a common clinical problem. Our aim was to determine the incidence of major bleeding during peri‐operative ...administration of treatment‐dose enoxaparin and the impact of the extensiveness of the procedure on the risk of bleeding.
Methods: We performed a prospective cohort study of 260 patients at 24 North American sites on OACs for atrial fibrillation or a history of deep vein thrombosis (DVT) requiring invasive or surgical procedures whose treating physician felt that bridging therapy was required. Warfarin was withheld, and once‐daily s.c. enoxaparin (1.5 mg kg−1) was given peri‐operatively. Patients were followed for 28 days after OAC was therapeutic.
Results: Major bleeding was observed in nine of 260 patients (3.5%, 95% CI: 1.6–6.5). The bleeding risk varied markedly by extensiveness of procedure: the incidence of major bleeding for invasive procedures, minor surgery and major surgery was 0.7% (95% CI: 0.02–3.7), 0% (95% CI: 0–5.0), and 20.0% (95% CI: 9.1–35.7), respectively. There were five thromboembolic events in total (1.9%, 95% CI: 0.6–4.4). There were four arterial events (2.3%, 95% CI: 0.6–5.7) in 176 patients with atrial fibrillation, and one venous event (1.0%, 95% CI: 0.03–5.7) in 96 patients with prior DVT.
Conclusions: Bridging therapy with once‐daily therapeutic‐dose enoxaparin administered primarily in an outpatient setting has a low incidence of major bleeding for patients undergoing invasive procedures and minor surgery. Further studies are needed to optimize the bridging strategy for patients undergoing major surgery.
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