Acute upper and lower gastrointestinal bleeding management in older people taking or not taking anticoagulants: a literature review.

Acute upper and lower gastrointestinal (GI) bleeding may be a potentially life-threatening event that requires prompt recognition and an early effective management, being responsible for a considerable number of hospital admissions. Methods. We perform a clinical review to summarize the recent international guidelines, helping the physician in clinical practice. Older people are a vulnerable subgroup of patients more prone to developing GI bleeding because of several comorbidities and polypharmacy, especially related to an increased use of antiplatelet and anticoagulant drugs. In addition, older patients may have higher peri-procedural risk that should be evaluated. The recent introduction of reversal strategies may help the management of GI bleeding in this subgroup of patients. In this review, we aimed to (1) summarize the epidemiology and risk factors for upper and lower GI bleeding, (2) describe treatment options with a focus on pharmacodynamics and pharmacokinetics of different proton pump inhibitors, and (3) provide an overview of the clinical management with flowcharts for risk stratification and treatment. In conclusion, GI is common in older patients and an early effective management may be helpful in the reduction of several complications.

Efficacy and Safety of Combination Therapy with Low-Dose Rivaroxaban in Patients with Cardiovascular Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Objectives: To review the evidence on the effectiveness and safety of low-dose-rivaroxaban 2.5 mg twice daily (LDR) in patients with coronary artery disease (CAD) and/or peripheral artery disease (PAD) taking antiplatelets. Methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs). Efficacy endpoints were cardiovascular events (CVEs), myocardial infarction, stroke, all-cause, and cardiovascular death. Any, major, fatal bleeding, and intracranial hemorrhage (ICH) were safety endpoints. Numbers needed to treat (NNT), and numbers needed to harm (NNH) were also calculated. Results: Seven RCTs were included with 45,836 patients: 34,276 with CAD and 11,560 with PAD. Overall, 4247 CVEs and 3082 bleedings were registered. LDR in association with either any antiplatelet drug or aspirin (ASA) alone reduced the risk of CVEs (hazard ratio [HR] 0.86, 95% confidence interval [95%CI] 0.78-0.94) and ischemic stroke (HR 0.68, 95%CI 0.55-0.84). LDR + ASA increased the risk of major bleeding (HR 1.71, 95%CI 1.38-2.11) but no excess of fatal bleeding or ICH was found. The NNT to prevent one CVE for LDR + ASA was 63 (43-103) and the NNH to cause major bleeding was 107 (77-193). Conclusions: The combination of LDR with either antiplatelet drugs or low-dose aspirin reduces CVEs and ischemic stroke in patients with CAD/PAD. There was an increased risk of major bleeding but no excess of fatal or ICH was found. LDR seems to have a favorable net clinical benefit compared to ASA treatment alone.

Risk of venous thromboembolism in autoimmune diseases: A comprehensive review.

Autoimmune diseases have specific pathophysiologic mechanisms leading to an increased risk of arterial and venous thrombosis. The risk of venous thromboembolism (VTE) varies according to the type and stage of the disease, and to concomitant treatments. In this review, we revise the most common autoimmune disease such as antiphospholipid syndrome, inflammatory myositis, polymyositis and dermatomyositis, rheumatoid arthritis, sarcoidosis, Sjogren syndrome, autoimmune haemolytic anaemia, systemic lupus erythematosus, systemic sclerosis, vasculitis and inflammatory bowel disease. We also provide an overview of pathophysiology responsible for the risk of VTE in each autoimmune disorder, and report current indications to anticoagulant treatment for primary and secondary prevention of VTE.

A Comprehensive Review of Risk Factors for Venous Thromboembolism: From Epidemiology to Pathophysiology.

Venous thromboembolism (VTE) is the third most common cause of death worldwide. The incidence of VTE varies according to different countries, ranging from 1-2 per 1000 person-years in Western Countries, while it is lower in Eastern Countries (<1 per 1000 person-years). Many risk factors have been identified in patients developing VTE, but the relative contribution of each risk factor to thrombotic risk, as well as pathogenetic mechanisms, have not been fully described. Herewith, we provide a comprehensive review of the most common risk factors for VTE, including male sex, diabetes, obesity, smoking, Factor V Leiden, Prothrombin G20210A Gene Mutation, Plasminogen Activator Inhibitor-1, oral contraceptives and hormonal replacement, long-haul flight, residual venous thrombosis, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, trauma and fractures, pregnancy, immobilization, antiphospholipid syndrome, surgery and cancer. Regarding the latter, the incidence of VTE seems highest in pancreatic, liver and non-small cells lung cancer (>70 per 1000 person-years) and lowest in breast, melanoma and prostate cancer (<20 per 1000 person-years). In this comprehensive review, we summarized the prevalence of different risk factors for VTE and the potential molecular mechanisms/pathogenetic mediators leading to VTE.

Real-world safety and efficacy of direct oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of 605 771 patients.

AIMS: To analyse the safety and efficacy of direct oral anticoagulants (DOACs) in real-world studies including atrial fibrillation (AF) patients. METHODS AND RESULTS: Systematic review and meta-analysis of observational studies including AF patients on DOACs. Primary endpoints: any, major, gastrointestinal (GI), intracranial haemorrhage (ICH), and haemorrhagic stroke (HS). Secondary endpoints: ischaemic stroke (IS), systemic embolism (SE), myocardial infarction (MI), and all-cause of death. A set of pair-wise meta-analyses using a random effect model and a random effect network meta-analysis under a Bayesian framework were performed. Prospero registration number: CRD42019137111. We included 21 studies with 605 771 AF patients. Apixaban was associated with lower major and GI bleeding compared with Rivaroxaban [hazard ratio (HR) 2.0, 95% confidence interval (CI) 1.6-2.5] and Dabigatran (HR 1.6, 95% CI 1.3-2.1). The latter drug performed better than Rivaroxaban (HR 1.2, 95% CI 1.0-1.5). Dabigatran and Apixaban had a similar association with HS, but Apixaban performed better than Rivaroxaban (HR 1.8, 95% CI 1.1-3.0). Apixaban had a similar association with Rivaroxaban and Dabigatran for ICH, the latter drug performing better than Rivaroxaban (HR 1.3, 95% CI 1.0-1.7). Rankograms showed that Apixaban was likely to be the first-choice treatment in relation to any (65%) major (100%) and GI bleeding (100%) followed by Dabigatran (46%, 100%, 99%, respectively). Dabigatran and Apixaban had similar rank as first choice for ICH (44% and 55%) and HS (52% and 48%). DOACs showed similar association with IS/SE, MI, all-cause of death. CONCLUSIONS: Analysis of real-world studies shows significant differences for safety among DOACs.

Long-Term Risk of Major Adverse Cardiac Events in Atrial Fibrillation Patients on Direct Oral Anticoagulants.

OBJECTIVE: To determine the association between direct oral anticoagulant (DOAC) use and risk of major adverse cardiac events (MACEs) in patients with atrial fibrillation (AF). PATIENTS AND METHODS: This study is a single-center prospective observational cohort study including 2366 outpatients with non-valvular AF on treatment with DOACs or vitamin K antagonists (VKAs) from February 2008 for patients on VKA and September 2013 for patients on novel oral anticoagulants. The primary endpoint was the incidence of MACE including fatal and non-fatal myocardial infarction (MI), cardiac revascularization, and cardiovascular death. RESULTS: The mean age was 75.1±9.0 years; 44.7% were women. During a mean follow-up of 33.3±21.9 months (6567 patients/years) 133 MACEs occurred (2.03%/year): 79 MI/cardiac revascularization and 54 cardiovascular deaths. Of these, 101 were on VKAs (2.42%/year) and 32 on DOACs (1.34%/year; log-rank test P=.040). This difference was evident also considering MI alone (1.53%/year and 0.63%/year in the VKA and DOAC group, respectively, log-rank test P=.009). At multivariable Cox proportional hazard regression analysis, use of DOACs was associated with a lower risk of MACE (hazard ratio, 0.636; 95% CI, 0.417 to 0.970; P=.036) and MI (hazard ratio, 0.497; 95% CI, 0.276 to 0.896; p=.020). Sensitivity analysis showed that this association was consistent in younger patients (<75 years), in patients with anemia, and in those without chronic obstructive pulmonary disease and heart failure. We also found that both dabigatran and apixaban/rivaroxaban were associated with a lower rate of MACE, with similar efficacy between full and low doses. CONCLUSION: DOACs are associated with a lower risk of MACE in patients with AF independently from dosage.

Atrial fibrillation pattern, left atrial diameter and risk of cardiovascular events and mortality. A prospective multicenter cohort study.

BACKGROUND: There are conflicting evidence on the association between atrial fibrillation (AF) pattern, such as persistent/permanent (Pers/Perm) and paroxysmal (PAF) AF and risk of ischemic events. We investigated if left atrial diameter (LAd) may affect the risk of cardiovascular outcomes according to AF pattern. METHODS: Prospective multicenter observational including 1,252 non-valvular AF patients (533 PAF and 719 Pers/Perm AF). Study endpoints were cardiovascular events (CVEs), major adverse cardiac events (MACE) and CV death. LA anteroposterior diameter (LAd) was obtained by transthoracic echocardiography. RESULTS: Pers/Perm AF patients had a higher proportion of LAd above median than PAF (≥44 mm, 59.5% vs 37.5% respectively, P < .001). In a mean follow-up of 42.2 ± 31.0 months (4,315 patients/year) 179 CVEs (incidence rate [IR] 4.2%/year), 133 MACE (IR 3.1%/year), and 97 CV deaths (IR 2.2%/year) occurred. Compared to patients with LAd below median, those with LAd above the median had a higher rate of CVEs (log-rank test, P < .001), MACE (log-rank test P < .001), and CV death (log-rank test P < .001). Multivariable Cox regression analysis showed that LAd above the median was associated with CVEs, (HR 1.569, 95% CI 1.129-2.180, P = .007) MACE (HR 1.858, 95% CI 1.257-2.745, P = .002) and CV death (HR 2.106, 95% CI 1.308-3.390, P = .002). The association between LAd and outcomes was evident both in PAF and Pers/Perm AF patients. No association between AF pattern and outcomes was found. CONCLUSION: LAd is a simple parameter that can be obtained in virtually all AF patients and can provide prognostic information on the risk of CVEs, MACE and CV death regardless of AF pattern.

Inositol and Non-Alcoholic Fatty Liver Disease: A Systematic Review on Deficiencies and Supplementation.

Liver lipid accumulation is a hallmark of non-alcoholic fatty liver disease (NAFLD), broadly associated with insulin resistance. Inositols (INS) are ubiquitous polyols implied in many physiological functions. They are produced endogenously, are present in many foods and in dietary supplements. Alterations in INS metabolism seems to play a role in diseases involving insulin resistance such as diabetes and polycystic ovary syndrome. Given its role in other metabolic syndromes, the hypothesis of an INS role as a supplement in NAFLD is intriguing. We performed a systematic review of the literature to find preclinical and clinical evidence of INS supplementation efficacy in NAFLD patients. We retrieved 10 studies on animal models assessing Myoinosiol or Pinitol deficiency or supplementation and one human randomized controlled trial (RCT). Overall, INS deficiency was associated with increased fatty liver in animals. Conversely, INS supplementation in animal models of fatty liver reduced hepatic triglycerides and cholesterol accumulation and maintained a normal ultrastructural liver histopathology. In the one included RCT, Pinitol supplementation obtained similar results. Pinitol significantly reduced liver fat, post-prandial triglycerides, AST levels, lipid peroxidation increasing glutathione peroxidase activity. These results, despite being limited, indicate the need for further evaluation of INS in NAFLD in larger clinical trials.

Features of severe COVID-19: A systematic review and meta-analysis.

BACKGROUND: To systematically review clinical and biochemical characteristics associated with the severity of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease (COVID-19). MATERIALS AND METHODS: Systematic review of observational studies from PubMed, ISI Web of Science, SCOPUS and Cochrane databases including people affected by COVID-19 and reporting data according to the severity of the disease. Data were combined with odds ratio (OR) and metanalysed. Severe COVID-19 was defined by acute respiratory distress syndrome, intensive care unit admission and death. RESULTS: We included 12 studies with 2794 patients, of whom 596 (21.33%) had severe disease. A slightly higher age was found in severe vs non-severe disease. We found that prevalent cerebrovascular disease (odds ratio [OR] 3.66, 95% confidence interval [CI] 1.73-7.72), chronic obstructive pulmonary disease (OR: 2.39, 95% CI 1.10-5.19), prevalent cardiovascular disease (OR: 2.84, 95% CI 1.59-5.10), diabetes (OR: 2.78, 95% CI 2.09-3.72), hypertension (OR: 2.24, 95% CI 1.63-3.08), smoking (OR: 1.54, 95% CI 1.07-2.22) and male sex (OR: 1.22, 95% CI 1.01-1.49) were associated with severe disease. Furthermore, increased procalcitonin (OR: 8.21, 95% CI 4.48-15.07), increased D-Dimer (OR: 5.67, 95% CI 1.45-22.16) and thrombocytopenia (OR: 3.61, 95% CI 2.62-4.97) predicted severe infection. CONCLUSION: Characteristics associated with the severity of SARS-CoV-2 infection may allow an early identification and management of patients with poor outcomes.

Statins and Major Adverse Limb Events in Patients with Peripheral Artery Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Statins are guidelines recommended in patients with peripheral artery disease (PAD) for the prevention of cardiovascular (CV) events. Comprehensive meta-data on the impact of statins on major adverse limb events (MALE) in PAD patients are lacking. We examined the association of statin use with MALE in patients with PAD. METHODS: We performed a systematic review (registered at PROSPERO: number CRD42019137111) and metanalysis of studies retrieved from PubMed (via MEDLINE) and Cochrane (CENTRAL) databases addressing the impact of statin on MALE including amputation and graft occlusion/revascularization. Secondary endpoints were all-cause death, composite CV endpoints, CV death, and stroke. RESULTS: We included 51 studies with 138,060 PAD patients, of whom 48,459 (35.1%) were treated with statins. The analysis included 2 randomized controlled trials, 20 prospective, and 29 retrospective studies. Overall, 11,396 MALE events, 21,624 deaths, 4,852 composite CV endpoints, 4,609 CV deaths, and 860 strokes were used for the analysis. Statins reduced MALE incidence by 30% (pooled hazard ratio [HR]: 0.702; 95% confidence interval [CI]: 0.605-0.815) and amputations by 35% (HR: 0.654; 95% CI: 0.522-0.819), all-cause mortality by 39% (pooled HR: 0.608, 95% CI: 0.543-0.680), CV death by 41% (HR: 0.594; 95% CI: 0.455-0.777), composite CV endpoints by 34% (pooled HR: 0.662; 95% CI: 0.591-0.741) and ischemic stroke by 28% (pooled HR: 0.718; 95% CI: 0.620-0.831). CONCLUSION: Statins reduce the incidence of MALE, all-cause, and CV mortality in patients with PAD. In PAD, a high proportion of MALE events and deaths could be prevented by implementing a statin prescription in this patient population.

Incidence of bleeding in patients with atrial fibrillation and advanced liver fibrosis on treatment with vitamin K or non-vitamin K antagonist oral anticoagulants.

OBJECTIVES: To investigate the incidence of bleeding events in atrial fibrillation (AF) patients treated with vitamin K (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) screened for the presence of liver fibrosis (LF). BACKGROUND: Previous studies provided conflicting results on bleeding risk in AF patients with liver disease on VKAs, and no data on NOACs in this setting are available. METHODS: Post-hoc analysis of a prospective, observational multicentre study including 2330 AF outpatients treated with VKAs (n = 1297) or NOACs (n = 1033). Liver damage was quantified by the FIB-4 score (>3.25), a validated marker of LF. The primary endpoint was the incidence of any bleeding, according to ISTH classification. RESULTS: A high FIB-4 was present in 129 (5.5%) patients: 77 (5.9%) on VKA and 52 (5.0%) on NOACs (p = 0.344). During follow-up, 357 (15.3%) patients experienced a bleeding: 261 (80 major and 180 minor) with VKAs (7.2%/year), and 96 (40 major and 56 minor) with NOACs (6.4%/year). In VKA-treated patients, but not in those on NOACs, FIB-4 >3.25 was associated with higher major bleeding (14.3% vs. 5.6%, log-rank test p < 0.001). Multivariable Cox regression model showed that FIB-4 was associated with major bleeding only in VKA-treated patients (HR: 3.075, 95% CI 1.626-5.818, p = 0.001). On multivariable analysis, FIB-4 was not significantly associated with CVEs neither in VKA or NOAC-treated patients. CONCLUSION: We found a significant association between LF and major bleedings in AF patients treated with VKA, which was not evident in patients on NOACs.

Temporal trends of time in therapeutic range and incidence of cardiovascular events in patients with non-valvular atrial fibrillation.

BACKGROUND: Optimal time in therapeutic range (TTR) of vitamin K antagonists (VKAs) is crucial for cardiovascular events (CVEs) prevention in non-valvular atrial fibrillation (NVAF). The relationship between temporal changes of TTR and the incidence of CVEs has been poorly investigated. We investigated 1) temporal trends of TTR in a long-term follow-up of NVAF patients; 2) the incidence of CVEs according to changes of TTR. METHODS: Prospective observational study including 1341 NVAF outpatients (mean age 73.5 years, 42.5% male) starting VKAs. Patients were divided into 4 groups: Group 0: Optimal TTR, consistently ≥70% (n = 241); Group 1: Temporally worsening TTR, from above to below 70% (n = 263); Group 2: Temporally improving TTR, from below to above 70% (n = 270); Group 3: Suboptimal TTR, consistently <70% (n = 567). RESULTS: In a mean follow-up of 37.7 months (4214.2 patient-years), 108 CVEs occurred (2.6%/year). Survival analysis showed a graded increased risk of CVEs in relation to temporal changes in TTR, with the worst outcomes in Groups 1 and 3 (log-rank test p = 0.013). Multivariable Cox proportional hazards regression analysis showed that Group 1 vs. 0 (HR: 2.096; 95%CI 1.061-4.139, p = 0.033), Group 3 vs. 0 (HR: 2.292; 95%CI 1.205-4.361, p = 0.011), CHA2DS2VASc score (HR:1.316; 95%CI 1.153-1.501, p < 0.001) and PPIs (HR:0.453; 95%CI 0.285-0.721, p = 0.001) were independently associated with CVEs. CONCLUSION: A decrease of TTR <70% over time is observed in almost 20% of NVAF patients. Patients with worsening TTR temporally (ie. from initially above 70% to below 70%) have similar risk of CVEs of patients with consistently suboptimal anticoagulation.

Data on incidence of bleeding in patients with atrial fibrillation and advanced liver fibrosis on treatment with vitamin K or non-vitamin K antagonist oral anticoagulants.

This article contains the data showing the different characteristics of atrial fibrillation (AF) patients treated with vitamin K (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) screened for the presence of liver fibrosis (LF) and followed to record the occurrence of bleeding and cardiovascular events (CVEs). A detailed description of major and minor bleedings is provided according to anticoagulant treatment (VKAs vs. NOACs) and to the presence of LF. Data here reported also show a higher incidence rate of CVEs in VKA-treated patients, but not in those on NOACs. The data are supplemental to our original research article titled "Incidence of bleeding in patients with atrial fibrillation and advanced liver fibrosis on treatment with vitamin K or non-vitamin K antagonists oral anticoagulants" (Pastori et al., 2018) [1].