Sepsis is a complex syndrome with a high incidence, increasing by 8.7% annually over the last 20 years. Coagulopathy is a leading factor associated with mortality in patients with sepsis and range ...from slight thrombocytopenia to fatal disorders, such as disseminated intravascular coagulation (DIC). Platelet reactivity increases during sepsis but prospective trials of antiplatelet therapy during sepsis have been disappointing. Thrombocytopenia is a known predictor of worse prognosis during sepsis. The mechanisms underlying thrombocytopenia in sepsis have yet to be fully understood but likely involves decreased platelet production, platelet sequestration and increased consumption. DIC is an acquired thrombohemorrhagic syndrome, resulting in intravascular fibrin formation, microangiopathic thrombosis, and subsequent depletion of coagulation factors and platelets. DIC can be resolved with treatment of the underlying disorder, which is considered the cornerstone in the management of this syndrome. This review presents the current knowledge on the pathophysiology, diagnosis, and treatment of sepsis-associated coagulopathies.
Abstract Introduction The role of thrombolysis in hemodynamically stable patients with acute pulmonary embolism (PE) remains controversial. We performed a meta-analysis of randomized trials to assess ...the effect of thrombolysis in these patients. Materials and Methods We searched MEDLINE and EMBASE for randomized studies comparing thrombolysis and heparin for the initial treatment of hemodynamically stable PE patients. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated. NNH to cause a major bleeding (MB) or an intracranial hemorrhage (ICH) and NNT to avoid one death were also calculated. Results Eleven studies (1833 patients) were included seven with rt-PA, three with tenecteplase and one with urokinase. Patients randomized to thrombolysis had a significant increased risk for MB (5.9% vs 1.9%; OR 2.83, 95% CI 1.68-4.76, I2 18.7%) and an increased risk for ICH (1.74% versus 0.6%; OR 2.36, 95% CI 0.98-5.71, I2 0%) and for fatal bleeding (1.3% versus 0.54%; OR 1.84, 95% CI 0.73-4.61, I2 0%). A not-significant reduction for all-cause death (1.74% vs 2.51%; OR 0.68, 95% CI 0.37-1.26, I2 0%) and a significant reduction for recurrent PE (1.1% vs 2.5%; OR 0.44, 95% CI 0.21-0.92, I2 0%) in favor of thrombolysis compared with heparin was found. NNH to cause a MB or an ICH were 27 and 91 patients, respectively. NNT to avoid one death was 125 patients. Conclusions Due to increased risk for MB and ICH with no evidence of reduction in mortality, thrombolysis should not be used for most normotensive PE patients.
Low-molecular-weight heparins (LMWHs) are the recommended treatment for cancer-associated venous thrombosis (CAT). Recent evidences suggest a role for direct-acting oral anticoagulants (DOACs) in ...this clinical setting.
To evaluate the efficacy and safety of different anticoagulants we performed a network meta-analysis of RCTs including patients with CAT treated with LMWHs, vitamin K antagonists (VKAs) or DOACs. MEDLINE and EMBASE were searched up to February 2018. The primary efficacy and safety outcomes were recurrent VTE and major bleeding, respectively.
Overall, 4720 CAT patients from 12 studies were included: 1430 from 2 studies comparing DOACs with LMWHs, 1212 from 4 studies comparing DOACs with VKAs and 2078 from 6 studies comparing VKAs to LMWHs.
Recurrent VTE occurred in 4.9% of patients receiving DOACs, 9.6% receiving VKAs and 8.4% receiving LMWHs. The network meta-analysis showed a not significant increase of recurrent VTE in patients receiving LMWHs compared to those receiving DOACs (RR 1.3, 95% CI 0.9 to 2.0). The risk of recurrent VTE was higher in patients receiving VKAs compared to LMWHs (RR 1.5, 95% CI 1.0 to 2.0) or DOACs (RR 2.0, 95% CI 1.3 to 3.0) with no heterogeneity.
Major bleeding occurred in 4.9, 4.1 and 4.3% of patients with CAT treated with DOAC, VKA or LMWH, respectively. No significant differences were observed from the direct, indirect and network meta-analyses.
In patients with CAT, DOACs showed a good efficacy and safety profile compared to other anticoagulants and is candidates to be an alternative to LMWHs.
•The clinical benefit of DOACs in patients with cancer and venous thromboembolism (CAT) is debated.•We compared the use of DOACs, VKAs or LMWHs in 4720 patients with CAT.•Risk of recurrent VTE was 50% lower in patients who received DOACs compared VKAs.•Risk of recurrent VTE was 30% lower in patients who received LMWHs compared to VKAs.•Overall rates of major bleedings were similar among the 3 treatment groups.
Background
European guidelines do not recommend the use of carbamazepine, levetiracetam, phenobarbital, phenytoin, topiramate and valproic acid in patients taking direct oral anticoagulants (DOACs). ...Little is known regarding the clinical relevance of the interaction between DOACs and antiepileptic drugs.
Objectives
To evaluate the incidence of thromboembolic and bleeding events in patients with non-valvular atrial fibrillation (AF) concurrently treated with DOACs and antiepileptic drugs.
Methods
This is a prospective multicentre cohort study of patients with non-valvular AF concurrently treated with DOACs and antiepileptic drugs. The primary outcome was ischaemic stroke/transient ischaemic attack (TIA)/systemic embolism (SE). Secondary outcome was major bleeding (MB). Incidence rates (% patient-year) were evaluated for the study outcomes.
Results
Overall, 91 patients were included. Mean age was 78 ± 9.5 years, 49.5% were female. Mean CHA
2
DS
2
-VASc score was 4.76 ± 1.59 and mean HAS-BLED was 2.67 ± 1.26. Overall, 41, 20, 11, 10 and 9 out of 91 patients were treated with levetiracetam, valproic acid, phenobarbital, carbamazepine and other antiepileptic drugs, respectively. During a median follow-up of 17.5 ± 14.5 months, stroke/TIA/SE occurred in 9 patients (5.7% patient-year) and MB in 3 patients (1.9% patient-year). Ischaemic stroke was fatal in 3 patients (1.9% patient-year) and MB in one patient (0.6% patient-year).
Conclusion
In this cohort, patients with non-valvular AF treated with DOACs and antiepileptic drugs appear to have a relatively high rate of thromboembolic events.
Venous thromboembolism (VTE) is a leading cause of morbidity and mortality worldwide. For decades, low molecular weight heparins (LMWH) and vitamin K-antagonists have been the gold standard of ...anticoagulation for VTE. Recently, direct oral anticoagulants (DOACs) that can be administered in fixed doses, without laboratory monitoring and dose adjustment have revolutionized anticoagulation management in VTE. Here, we report on recent evidence regarding the safety of DOACs compared to traditional anticoagulants in surgical and medical prophylaxis as well as in acute and extended treatments of VTE. Additionally, we provide data on special situations such as elderly, cancer and renal impairment patients. Regarding antithrombotic prophylaxis, data are lacking on DOAC use in general surgical patients, while DOACs appear to be more effective than and as safe as LMWHs in VTE prophylaxis for major orthopedic surgical patients. Whether a medically ill patient may benefit from extended VTE prophylaxis remains unclear. In fact, in these patients, DOACs showed an increased risk of bleeding compared to conventional therapy. In the acute treatment of VTE, DOACs were non-inferior and probably safer than conventional anticoagulation therapy while in the extended VTE treatment DOACs were more effective than placebo or aspirin with a comparable risk of major bleeding. These favorable results were also confirmed in elderly, cancer and renal impairment patients. However, further investigations are needed in order to generalize the safe use of DOACs in these specific subgroups of patients.
Venous thromboembolism (VTE), which includes pulmonary embolism and deep vein thrombosis, is a leading cause of morbidity and mortality worldwide. Based on new evidence, the management and treatment ...of VTE have changed over the years. For several decades, low molecular weight heparin and vitamin K antagonists have been the two cornerstones of anticoagulant therapy for VTE. Recently, the introduction in clinical practice of the new oral anticoagulants has radically changed the management of VTE for their easy use and their better efficacy and safety profile. Here, we report on recent evidence of 10 still controversial clinical questions concerning common diagnostic and therapeutic aspects of VTE.
The efficacy and safety profiles of nonrecommended direct oral anticoagulant (DOAC) doses in patients with nonvalvular atrial fibrillation (NVAF) are still undefined.
We searched for randomized ...controlled trials and observational studies that compared nonrecommended versus recommended doses of DOACs, published up to December 2021. Primary study outcomes were ischemic stroke/transient ischemic attack/systemic embolism (IS/TIA/SE) and major bleeding (MB). All-cause mortality was a secondary outcome. We determined pooled odds ratios (ORs) between groups of patients with a random-effect model. Twenty-three studies with 175,801 patients were included. Nonrecommended doses were associated with a higher risk of IS/TIA/SE and all-cause mortality, but not of MB as compared to recommended doses of DOACs (OR 1.25 95% CI: 1.14-1.38, OR 1.69 95% CI: 1.31-2.18 and OR 1.10 95% CI: 0.93-1.31, respectively). The nonrecommended low dose was associated with an increased risk of IS/TIA/SE and all-cause death (OR 1.21 95% CI: 1.05-1.39 and OR 1.66 95% CI: 1.18-2.35, respectively) but not of MB (OR 1.01 95% CI: 0.83-1.22 as compared to recommended doses. Subgroup analysis of nonrecommended low doses of DOACs showed a nonsignificant increase in IS/TIA/SE in Asians (OR 1.17 95% CI: 0.89-1.54 vs. non-Asian (OR 1.21 95% CI: 1.07-1.36).
Compared with recommended doses, nonrecommended low doses of DOACs increase the risk of ischemic events without decreasing the risk of bleeding. For Asians, the efficacy of DOACs seemed preserved despite the nonrecommended low-dose prescription. Clinicians should carefully adhere to recommended DOAC prescription advice in managing NVAF patients.
Limited data are available on the use of direct oral anticoagulants (DOACs) in patients with cancer and atrial fibrillation (AF).
Consecutive patients with non-valvular AF treated with DOACs were ...enrolled in a prospective cohort with the aim of evaluating thromboembolic (ischemic stroke or transient ischemic attack or systemic embolism) and major bleeding (MB) events according to presence and type of cancer. The risk of study outcomes over time was compared using Kaplan-Meier method and log-rank test or Cox proportional hazards regression.
2304 patients with non-valvular AF receiving DOACs were enrolled and 16 excluded: 2288 analysed of whom 289 (12.6%) had cancer. Gastrointestinal (21%), genitourinary (15%), prostate (15%), haematological (14%), breast (13%), and lung (8%) were the more frequent sites of cancer.
After a mean follow-up of 451 days, thromboembolic events occurred in 2.1% and 0.8% patient-year of cancer and non-cancer patients (adjusted-HR 2.58, 95% CI 1.08–6.16, p = 0.033). The rate of MB was 6.6% and 3.0% patient-year in cancer and non-cancer patients (adjusted-HR 2.02, 95% CI 1.25–3.27, p = 0.004). The differences in bleeding were mainly accounted for by bleeding at gastrointestinal and genitourinary sites. No significant differences were found concerning the rates of non-cancer-related mortality, fatal bleeding or fatal thrombotic events.
In this study, the higher bleeding risk found in cancer compared to non-cancer patients was mainly due to an excess of bleeding at gastrointestinal and at genitourinary sites. Larger studies on the optimal management of cancer patients with AF are needed.
•The study includes 2288 prospectively followed patients with non-valvular AF receiving DOACs.•Major bleeding and thromboembolic events are two fold higher in cancer compared to non cancer AF patients receiving DOACs.•The HR was 2.02 (95% CI 1.25–3.27) for major bleedings and 2.58 (95% CI 1.08–6.16) for thromboembolic events.•In cancer patients an excess of bleeding at gastrointestinal and at genitourinary sites was found.•Further evidence is needed on the optimal anticoagulant strategies of AF patients with cancer.
Background
Clinical guidelines advise similar anticoagulant treatment for symptomatic and incidental cancer‐associated venous thromboembolism (VTE). We investigated clinical features and outcomes of ...cancer patients with incidental or symptomatic VTE randomized in the Caravaggio study.
Objectives
We performed a predefined sub‐analysis of the Caravaggio study in order to investigate the clinical features and outcomes of incidental and symptomatic VTE in patients with cancer. The relative efficacy and safety of apixaban and dalteparin in patients with incidental and symptomatic VTE was also assessed.
Methods
The Caravaggio study compared apixaban to dalteparin for the 6‐month treatment of cancer‐associated VTE. The primary efficacy and safety outcomes were recurrent VTE and major bleeding.
Results
Two hundred thirty patients (20%) had incidental and 925 (80%) symptomatic VTE. Pulmonary embolism with or without deep vein thrombosis as index event, colorectal cancer, Eastern Cooperative Oncology Group (ECOG) score of 0, and locally advanced or metastatic cancer were more frequent in patients with incidental VTE. Deep vein thrombosis as index event, hematological cancer, and ECOG score of 2 were more frequent in patients with symptomatic VTE. Ten patients (4.3%) with incidental and 68 (7.4%) with symptomatic VTE had recurrent VTE (hazard ratio HR 0.57, 95% confidence interval CI 0.29–1.10). Major bleeding occurred in 12 (5.2%) patients with incidental VTE and in 33 (3.6%) patients with symptomatic VTE (HR 1.43, 95% CI 0.74–2.77). When comparing apixaban to dalteparin in patients with symptomatic and incidental VTE, the HR for recurrence was 0.73 (95% CI 0.45–1.19) and 0.41 (95% CI 0.11–1.56), respectively, and the HR for major bleeding 0.93 (95% CI 0.47–1.83) and 0.96 (95% CI 0.31–2.96), respectively.
Conclusions
Compared to cancer patients with symptomatic VTE, those with incidental VTE have different clinical features at presentation, with a numerically lower incidence of recurrent VTE and a numerically higher incidence of major bleeding.
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