Reg Anesth Pain Med 2010;35:64-101

NEJM 2010; 363:2499-2510

Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring.

Methods
We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study.

Results
The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin–vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11).

Conclusions
Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation.

Anesthesiology 2008;109:596-604

The American College of Cardiology released a scientific advisory that included a recommendation to delay elective of noncardiac surgery (NCS) for 1 yr after percutaneous coronary intervention (PCI) with a drug-eluting stent (DES).

Methods
This single-center, retrospective study examined the risk for complications of NCS performed within 2 yr after DES placement and examined whether this risk changed based on the time between procedures. The primary endpoint was major adverse cardiac events (MACEs) during the hospitalization for NCS. Bleeding events were analyzed as a secondary endpoint.

Results
From April 22, 2003, to December 31, 2006, a total of 520 patients underwent NCS within 2 yr after PCI with a DES at Mayo Clinic. The majority, 84%, of the DES placed were Cypher stents. The frequency of MACE was not found to be significantly associated with the time between PCI and NCS (rate of MACEs 6.4, 5.7, 5.9, and 3.3% at 0-90, 91-180, 181-365, and 366-730 days after PCI with DES, respectively; P = 0.727 for comparison across groups). Characteristics found to be associated with MACEs in univariate analysis were advanced age (P = 0.031), emergent NCS (P = 0.006), shock at time of PCI (P = 0.035), previous history of myocardial infarction (P = 0.046), and continuation of a thienopyridine (ticlopidine or clopidogrel) into the preoperative period (P = 0.040). The rate of transfusion did not seem to be associated with antiplatelet therapy use.

Conclusions
The risk of MACEs with NCS after DES placement was not significantly associated with time from stenting to surgery, but observed rates of MACEs were lowest after 1 yr.

Best Pract Res Clin Anaesthesiol 2007; 21:241–256

Performing a surgical procedure on a patient undergoing anti-platelet therapy raises a dilemma: is it safer to withdraw the drugs and reduce the haemorrhagic risk, or to maintain them and reduce the risk of myocardial ischaemic events? Based on recent clinical data, this review concludes that the risk of coronary thrombosis on anti-platelet drugs withdrawal is much higher than the risk of surgical bleeding when maintaining them. In secondary prevention, aspirin is a lifelong therapy and should never be stopped. Clopidogrel is mandatory as long as the coronary stents are not fully endothelialized, which takes 6–24 weeks depending on the technique used, but might be required for a longer period

Lancet 2009;373:1849-1860.

Low-dose aspirin is of definite and substantial net benefit for many people who already have occlusive vascular disease. We have assessed the benefits and risks in primary prevention.

Methods
We undertook meta-analyses of serious vascular events (myocardial infarction, stroke, or vascular death) and major bleeds in six primary prevention trials (95,000 individuals at low average risk, 660,000 person-years, 3554 serious vascular events) and 16 secondary prevention trials (17,000 individuals at high average risk, 43,000 person-years, 3306 serious vascular events) that compared long-term aspirin versus control. We report intention-to-treat analyses of first events during the scheduled treatment period.

Findings
In the primary prevention trials, aspirin allocation yielded a 12% proportional reduction in serious vascular events (0.51% aspirin vs 0.57% control per year, p=0.0001), due mainly to a reduction of about a fifth in non-fatal myocardial infarction (0.18%vs 0.23% per year, p<0.0001). The net effect on stroke was not significant (0.20%vs 0.21% per year, p=0.4: haemorrhagic stroke 0.04%vs 0.03%, p=0.05; other stroke 0.16%vs 0.18% per year, p=0.08). Vascular mortality did not differ significantly (0.19%vs 0.19% per year, p=0.7). Aspirin allocation increased major gastrointestinal and extracranial bleeds (0.10%vs 0.07% per year, p<0.0001), and the main risk factors for coronary disease were also risk factors for bleeding. In the secondary prevention trials, aspirin allocation yielded a greater absolute reduction in serious vascular events (6.7%vs 8.2% per year, p<0.0001), with a non-significant increase in haemorrhagic stroke but reductions of about a fifth in total stroke (2.08%vs 2.54% per year, p=0.002) and in coronary events (4.3%vs 5.3% per year, p<0.0001). In both primary and secondary prevention trials, the proportional reductions in the aggregate of all serious vascular events seemed similar for men and women.

Interpretation
In primary prevention without previous disease, aspirin is of uncertain net value as the reduction in occlusive events needs to be weighed against any increase in major bleeds. Further trials are in progress.

Ann Int Med 2008;149:481-490

The optimal duration of anticoagulation for a first episode of unprovoked venous thromboembolism (VTE) is uncertain. Methods for predicting risk for recurrence may identify low-risk patients who are less likely to benefit from prolonged anticoagulation.

Purpose
To synthesize evidence evaluating the value of D-dimer as a predictor of recurrent disease in patients who have stopped anticoagulant therapy after a first unprovoked VTE.

Data sources
The MEDLINE, EMBASE, CINAHL, and Cochrane databases were searched until March 2008 without language restrictions. The strategy was supplemented with manual review of reference lists and contact with content experts.

Study selection
Randomized, controlled trials or prospective cohort studies that measured D-dimer after anticoagulant therapy in patients who received at least 3 months of anticoagulant treatment of unprovoked VTE.

Data extraction
Two authors independently reviewed articles and extracted data.

Data synthesis
Seven studies, totaling 1888 patients with a first unprovoked VTE, were eligible for analysis. During 4500 person-years of follow up, annual rates of recurrent VTE differed statistically significantly: 8.9% (95% CI, 5.8% to 11.9%) in patients with positive D-dimer results and 3.5% (CI, 2.7% to 4.3%) in patients with negative D-dimer results.

Limitation
The duration of anticoagulation, timing of D-dimer testing, and D-dimer assay varied across studies.

Conclusion
In patients who have completed at least 3 months of anticoagulation for a first episode of unprovoked VTE and after approximately 2 years of follow-up, a negative D-dimer result was associated with a 3.5% annual risk for recurrent disease, whereas a positive D-dimer result was associated with an 8.9% annual risk for recurrence. These rates should inform decisions about the balance of risks and benefits of prolonging anticoagulation.

Crit Care Med 2008;36:2973-2979

Sepsis and septic shock represent a systemic inflammatory state with substantial pro-coagulant elements. Unfractionated heparin is a known anticoagulant, which also possesses anti-inflammatory properties. Unfractionated heparin has been shown to increase survival in experimental models of septic shock.

Objective
To evaluate the impact of intravenous therapeutic dose unfractionated heparin in a cohort of patients diagnosed with septic shock.

Design
Retrospective, propensity matched, multicenter, cohort study.

Setting
Regional intensive care units in Winnipeg, Canada between 1989 and 2005.

Patients
Two thousand three hundred fifty-six patients diagnosed with septic shock, of which 722 received intravenous therapeutic dose heparin.

Measurements and Main Results
The primary outcome of study was 28-day mortality, and mortality stratified by severity of illness (Acute Physiologic and Chronic Health Evaluation II quartile). Safety was assessed by comparing rates of gastrointestinal hemorrhage, intracranial hemorrhage, and the need for transfusion. By using a Cox proportional hazards model, systemic heparin therapy was associated with decreased 28-day mortality (307 of 695 [44.2%] vs. 279 of 695 [40.1%]; hazard ratio 0.85 [confidence interval (CI) 95% 0.73-1.00]; p = 0.05). In the highest quartile of severity of illness (Acute Physiologic and Chronic Health Evaluation II score 29-53), heparin administration was associated with a clinically and statistically significant reduction in 28-day mortality [127 of 184 (69.0%) vs. 94 of 168 (56.0%); hazard ratio 0.70 (CI 95% 0.54-0.92); p = 0.01]. The use of intravenous unfractionated heparin was associated with successful liberation from mechanical ventilation [odds ratio of 1.42 (CI 95% 1.13-1.80); p = 0.003], and successful discontinuation of vasopressor/inotropic support [odds ratio of 1.34 (CI 95% 1.06-1.71); p = 0.01]. No significant differences in the rates of major hemorrhage or need for transfusion were identified.

Conclusion
Early administration of intravenous therapeutic dose unfractionated heparin may be associated with decreased mortality when administered to patients diagnosed with septic shock, especially in patients with higher severity of illness. Prospective randomized trials are needed to further define the role of this agent in sepsis and septic shock.

Circulation 2007; 115:813-818

Dual antiplatelet therapy with aspirin and a thienopyridine has been shown to reduce cardiac events after coronary stenting. However, many patients and healthcare providers prematurely discontinue dual antiplatelet therapy, which greatly increases the risk of stent thrombosis, myocardial infarction, and death. This advisory stresses the importance of 12 months of dual antiplatelet therapy after placement of a drug-eluting stent and educating the patient and healthcare providers about hazards of premature discontinuation. It also recommends postponing elective surgery for 1 year, and if surgery cannot be deferred, considering the continuation of aspirin during the perioperative period in high-risk patients with drug-eluting stents.

Critical Care Medicine 2006;34:2898-2911

Thrombocytopenia is a common occurrence in critical illness, reported in up to 41% of patients. Systematic evaluation of thrombocytopenia in critical care is essential to accurate identification and management of the cause. Although sepsis and hemodilution are more common etiologies of thrombocytopenia in critical illness, heparin-induced thrombocytopenia (HIT) is one potential etiology that warrants consideration.

Objective
This review will summarize the pathogenesis and clinical consequences of HIT, describe the diagnostic process, and review currently available treatment options.

Data Source
MEDLINE/PubMed search of all relevant primary and review articles.

Data Synthesis and Conclusions
HIT is a clinicopathologic syndrome characterized by thrombocytopenia (=50% from baseline) that typically occurs between days 5 and 14 after initiation of heparin. This temporal profile suggests a possible diagnosis of HIT, which can be supported (or refuted) with a strong positive (or negative) laboratory test for HIT antibodies. When considering the diagnosis of HIT, critical care professionals should monitor platelet counts in patients who are at risk for HIT and carefully evaluate for, a) temporal features of the thrombocytopenia in relation to heparin exposure; b) severity of thrombocytopenia; c) clinical evidence for thrombosis; and d) alternative etiologies of thrombocytopenia. Due to its prothrombotic nature, early recognition of HIT and prompt substitution of heparin with a direct thrombin inhibitor (e.g., argatroban or lepirudin) or the heparinoid danaparoid (where available) reduces the risk of thromboembolic events, some of which may be life-threatening.

Critical Care 2006, 10:222

Many critically ill patients develop hemostatic abnormalities, ranging from isolated thrombocytopenia or prolonged global clotting tests to complex defects, such as disseminated intravascular coagulation. There are many causes for a deranged coagulation in critically ill patients and each of these underlying disorders may require specific therapeutic or supportive management. In recent years, new insights into the pathogenesis and clinical management of many coagulation defects in critically ill patients have been accumulated and this knowledge is helpful in determining the optimal diagnostic and therapeutic strategy.

Critical Care 2006, 10:150

Antithrombotic prophylaxis in critically ill patients frequently fails. Venous thromboembolism is associated with adverse clinical outcomes, including a prolonged intensive care unit stay and death. A potential mechanism by which critically ill patients may be predisposed to antithrombotic failure is the inability to achieve ‘prophylactic’ anticoagulant drug levels as a result of impaired absorption. For example, previous studies have shown that patients on inotropes have reduced serum levels of low molecular weight heparin, presumably on the basis of reduced absorption from the subcutaneous injection site. In the previous issue of the journal, Rommers and colleagues examined whether subcutaneous edema reduces absorption of a low molecular weight heparin; although small, and thus underpowered, the authors failed to find any relationship between the level of low molecular weight heparin and the presence of edema. These findings provide reassurance that subcutaneously administered medications may be used in critically ill patients with edema.