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Background: Conflicting results were reported by randomized controlled trials (RCTs) exploring guided therapy (GT) with anti-P2Y12 drugs in patients undergoing percutaneous coronary intervention (PCI). Meta-analyses of RCTs failed to clearly identify what GT strategy, if any, is effective, because they lumped together RCTs with heterogeneous designs, comparing either genotype-GT or platelet function test (PFT)-GT with unguided standard therapy. Some meta-analysis also included RCTs that did not actually explore GT, but tested the effects of switching patients with high on-treatment platelet reactivity (HTPR) to alternative therapies (HTPR-Therapy), rather than comparing GT with unguided standard therapy. We performed 3 distinct systematic reviews with meta-analyses, each exploring only RCTs with homogeneous design. Methods. MEDLINE, Embase and Central databases were searched for RCTs testing genotype-GT, PFT-GT or HTPR-Therapy in PCI-treated patients, through October 1st 2022. Two reviewers extracted the data. Risk ratios (RR) (95% confidence intervals) were calculated. Primary outcomes were major bleedings (MB) and major adverse cardiovascular events (MACE). Results: In 7 genotype-GT RCTs, RR were: MB, 1.06 (0.73?1.54; p=0.76); MACE, 0.64 (0.45?0.91; p=0.01), but significant risk reduction was observed only in RCTs performed in China (0.30, 0.16-0.54; p

Without rescue drugs approved, holistic approach by daily hemodialysis, noninvasive ventilation, anti‐inflammatory medications, fluid assessment by bedside ultrasound, and anxiolytics improved outcomes of a maintenance hemodialysis patient affected by severe COVID‐19.

Background: It is uncertain whether higher doses of anticoagulants than recommended for thromboprophylaxis are necessary in COVID-19 patients hospitalized in general wards. Methods: This is a multicentre, open-label, randomized trial performed in 9 Italian centres, comparing 40 mg b.i.d. versus 40 mg o.d. enoxaparin in COVID-19 patients, between April 30 2020 and April 25 2021. Primary efficacy outcome was in-hospital incidence of venous thromboembolism (VTE): asymptomatic or symptomatic proximal deep vein thrombosis (DVT) diagnosed by serial compression ultrasonography (CUS), and/or symptomatic pulmonary embolism (PE) diagnosed by computed tomography angiography (CTA). Secondary endpoints included each individual component of the primary efficacy outcome and a composite of death, VTE, mechanical ventilation, stroke, myocardial infarction, admission to ICU. Safety outcomes included major bleeding. Results: The study was interrupted prematurely due to slow recruitment. We included 183 (96%) of the 189 enrolled patients in the primary analysis (91 in b.i.d., 92 in o.d.). Primary efficacy outcome occurred in 6 patients (6.5%, 0 DVT, 6 PE) in the o.d. group and 0 in the b.id. group (ARR 6.5, 95% CI: 1.5–11.6). The absence of concomitant DVT and imaging characteristics suggests that most pulmonary artery occlusions were actually caused by local thrombi rather than PE. Statistically nonsignificant differences in secondary and safety endpoints were observed, with two major bleeding events in each arm. Conclusions: No DVT developed in COVID-19 patients hospitalized in general wards, independently of enoxaparin dosing used for thromboprophylaxis. Pulmonary artery occlusions developed only in the o.d. group. Our trial is underpowered and with few events.

SummaryIt is uncertain whether higher doses of anticoagulants than recommended for thromboprophylaxis are necessary in COVID-19 patients hospitalized in general wards. This is a multicentre, open-label, randomized trial performed in 9 Italian centres, comparing 40 mg b.i.d. vs 40 mg o.d. enoxaparin in COVID-19 patients, between April 30, 2020 and April 25, 2021. Primary efficacy outcome was in-hospital incidence of venous thromboembolism (VTE): asymptomatic or symptomatic proximal deep vein thrombosis (DVT) diagnosed by serial compression ultrasonography (CUS), and/or symptomatic pulmonary embolism (PE) diagnosed by computed tomography angiography (CTA). Secondary endpoints included each individual component of the primary efficacy outcome and a composite of death, VTE, mechanical ventilation, stroke, myocardial infarction, admission to ICU. Safety outcomes included major bleeding. The study was interrupted prematurely due to slow recruitment. We included 183 (96%) of the 189 enrolled patients in the primary analysis (91 in b.i.d., 92 in o.d.). Primary efficacy outcome occurred in 6 patients (6·5%, 0 DVT, 6 PE) in the o.d. group and 0 in the b.id. group (ARR 6·5, 95% CI, 1·5-11·6). Absence of concomitant DVT and imaging characteristics suggest that most pulmonary artery occlusions were actually caused by local thrombi rather than PE. Statistically non-significant differences in secondary and safety endpoints were observed, with two major bleeding events in each arm. In conclusion, no DVT developed in COVID-19 patients hospitalized in general wards, independently of enoxaparin dosing used for thromboprophylaxis. Pulmonary artery occlusions developed only in the o.d. group. Our trial is underpowered and with few events.REGISTRATIONClinicalTrials.gov Identifier: NCT04366960Ethics Commettee approvation number75/2020

BACKGROUND: Long-term sequelae of acute pulmonary embolism (PE) include decreased quality of life (QoL). Evidence suggests that adequacy of initial anticoagulant treatment in the acute phase of venous thrombosis has a key impact on late postthrombotic complications. We hypothesize that patients with acute PE treated with edoxaban for acute PE experience have improved QoL compared to those treated with warfarin. METHODS: Patients with PE who participated in the Hokusai-VTE trial were contacted between June 2017 and September 2020 for a single long-term follow-up visit. Main outcomes were the generic and disease-specific QoL measured by the 36-Item Short Form Health Survey (SF-36) and Pulmonary Embolism Quality of Life questionnaire. RESULTS: We included 251 patients from 26 centers in eight countries, of which 129 (51%) had been assigned to edoxaban and 122 (49%) to warfarin. Patient- and thrombus-specific characteristics were similar in both groups. Mean time since randomization in the Hokusai-VTE trial was 7.0 years (standard deviation, 1.0). No relevant or statistical differences were observed in the QoL for patients treated with edoxaban compared to patients treated with warfarin. The mean difference between patients treated with edoxaban and patients with PE treated with warfarin was 0.8 (95% confidence interval [CI]. -1.6 to 3.2) for the SF-36 summary mental score and 1.6 (95% CI, -0.9 to 4.1) for summary physical score. CONCLUSION: Our findings indicate that patients with an index PE treated with edoxaban or warfarin have a similar long-term QoL. Since our study was a follow-up study from a well-controlled clinical trial setting, future studies should be designed in a daily clinical practice setting. We suggest a longitudinal design for investigation of changes in QoL over time. ispartof: RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS vol:5 issue:5 ispartof: location:United States status: published

Background COVID‐19 patients are considered at high risk of venous thromboembolism (VTE). The real nature of pulmonary artery occlusions (PAO) in COVID‐19 has been questioned, suggesting that it is caused also by in situ thrombi, rather than only by emboli (PE) from peripheral thrombi. Methods We searched MEDLINE for studies published until 6 June 2020 that included COVID‐19 patients or non‐COVID‐19 medical patients at VTE risk, treated with heparins, in whom VTE (PE and deep vein thrombosis, DVT) had been reported. Systematic review and results reporting were conducted in accordance with PRISMA guidelines. Data were independently extracted by two observers, and estimates were pooled using random‐effects meta‐analysis. Results We identified 17 studies including 3224 COVID‐19 patients and 7 including 11 985 non‐COVID‐19 patients. Two analyses were performed: in all COVID‐19 patients and only in those (n = 515) who, like non‐COVID‐19 patients, were screened systematically for DVT. The latter analysis revealed that the prevalence of DVT was 15.43% (95%CI, 4.08‐31.77) in COVID‐19 and 4.21% (2.27‐6.68) in non‐COVID‐19 patients (P = .0482). The prevalence of PE was 4.85% (40.33‐13.01) in COVID‐19 patients and 0.22% (0.03‐0.55) in non‐COVID‐19 patients (P = .0128). The percentage of PE among VTE events was 22.15% (5.31‐44.60) in COVID‐19 and 6.39% (3.17‐10.41) in non‐COVID‐19 patients (P = .0482). Differences were even more marked when all COVID‐19 patients were analysed. Conclusions The results of our meta‐analysis highlight a disproportion in the prevalence of PE among all VTE events in COVID 19 patients, likely reflecting PAO by pulmonary thrombi, rather than emboli from peripheral vein thrombi.

Previous meta-analyses reported discordant results on the efficacy and safety of thrombopoietin receptor agonists (TPO-RA) as second-line treatment in patients with immune thrombocytopenia (ITP). We conducted a meta-analysis of primary ITP treatment with the TPO-RA Romiplostim, Eltrombopag and Avatrombopag, including additional studies and relevant endpoints. We searched MEDLINE, EMBASE and CENTRAL for randomized clinical trials (RCTs) and cohort studies on TPO-RA in ITP published until December 31, 2018. The primary endpoints were: risk ratio (RR) of treatment failure and bleeding of WHO grade ≥2; rate of remission after discontinuation of treatment. The principal safety outcome was RR and incidence of thrombotic events and liver damage. From 1044 identified records we selected 16 RCTs and 19 cohort studies. RCTs included 909 patients assigned to TPO-RA and 427 to the control arm. Treatment failure was observed in 21% TPO-RA-treated patients and 47% control arm patients (RR = 0.42, 95% CI 0.33-0.53) in RCTs during a median follow-up of 13 weeks, and in 29% TPO-RA-treated patients in cohort studies, during a median follow-up of 69 weeks. The incidence of remission after TPO discontinuation was 18% (5-36%). RR of WHO grade ≥2 bleeding was 0.58 (0.38-0.86) in TPO-RA-treated patients, compared to control arm patients. Adverse events were rare and not significantly different in the two groups of patients. All-cause mortality was significantly lower with TPO-RA (RR 0.21, 95% CI, 0.06-0.68). In conclusion, TPO-RA are effective and safe in patients with ITP, even in the long term.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30&ndash, 50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23), heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (&beta, &minus, 3.34, 95%CI &minus, 6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy.

Immune thrombocytopenia (ITP) can be associated with lymphoproliferative diseases (LPD) or solid tumors. A systematic review of published literature was conducted to evaluate response to treatment of ITP secondary to malignancy. Primary outcome was overall response (complete response+response) to first-line treatments [steroids alone or in combination with intravenous immunoglobulins (IVIg)]. Among secondary outcomes, overall response to second-line treatments [splenectomy, rituximab or thrombopoietin receptor agonists (TPO-RA)] and death were evaluated. Of the retrieved 238 text articles, 108 were analyzable, for a total of 154 patients: 142 in 105 case reports and 12 in 3 observational studies. Thirty-nine patients had solid tumors, 114 LPD, and 1 both. The median follow up was 19 months (IQR, 9���40). The overall response was 50% (62% in solid tumors, 46% in LPD) after steroids and 47% (67% in solid tumors, 36% in LPD) after steroids+IVIg, which are lower than historical responses observed in primary ITP (���80%). The overall responses to rituximab (used in LPD only), splenectomy and TPO-RA (70%, 73% and 92%, respectively) were similar to those observed in primary ITP. Seven patients (6%) died due to bleeding events. ITP secondary to malignancy appears to be associated with unsatisfactory response to first-line treatments.

The treatment of unprovoked venous thromboembolism (VTE) is anticoagulant therapy for at least 3 months [1]. As VTE recurs frequently and about 20 % of the patients with an unprovoked VTE develop recurrence within the first 2 years [2], extended vitamin K antagonist (VKA) treatment is often considered. The decision to prolong VKA therapy after the initial treatment period is a dilemma, since longer term therapy reduces the risk of recurrent thromboembolism, but increases the risk of bleeding. The last American College of Chest Physicians (ACCP) EvidenceBased Clinical guidelines suggest a strategy to balance the benefits and risks of different durations of anticoagulant therapy; in unprovoked VTE, ACCP guidelines suggest extended anticoagulant therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy if bleeding risk is high. When extended anticoagulant therapy is contraindicated, aspirin might be appealing. In fact the annual risk of major bleeding is only 0.1 % in patients on long-term low-dose aspirin therapy, thus lower than VKA therapy [3]. A large meta-analysis by the Antiplatelet Trialists’ Collaboration shows that antiplatelet therapy significantly reduces the risk of fatal or non-fatal pulmonary embolism (PE) by 25 % [3]. Moreover, a large trial involving patients undergoing surgery for hip fracture shows a 36 % risk reduction in VTE in the aspirin therapy group, [4] suggesting that antiplatelet therapy may be an alternative to prolonged VKA therapy. Two randomized controlled studies were conducted to evaluate the use of ASA for the prevention of venous thromboembolism recurrence: the Aspirin for the Prevention of Recurrent Venous Thromboembolism (Warfarin and Aspirin [WARFASA]) [5] and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) study [6].

Pneumonia is one of the principal causes of morbidity and mortality worldwide, despite the advances in antibiotic therapies and in preventive measures [1]. The intense inflammatory response that was of fundamental importance in the pre-antibiotics era nowadays might be excessive. In fact, it can lead to multiple organ failure, thus causing more harm than benefit [2]. Corticosteroids have a strong antiinflammatory effect; therefore, their use in pneumonia has been studied for a long time. One of the most important trials was recently published by Meijvis [3]. A 4-day course of 5 mg of dexamethasone was compared to placebo, showing a 1-day reduction in hospital stay, but no difference in mortality. A meta-analysis by Nie [4] does not find any significant reduction in pneumonia overall mortality; however, a subgroup analysis shows a significant reduction in mortality in both studies considering patients with severe pneumonias and treating subjects for more than 5 days. Therefore, the authors conclude that adequately powered double-blind randomized controlled trials (RCTs) are warranted to give recommendations for the use of steroids in pneumonia. Summary

Objectives Interstitial lung disease (ILD) is a frequent extra-articular manifestation of RA associated with increased mortality. High-resolution CT (HRCT) is used for diagnosis and follow-up, but its accuracy is counterbalanced by high costs and radiological risk. In the presence of ILD, lung US (LUS) detects vertical artefacts called B-lines. The aims of the present study were to evaluate the accuracy of LUS in the diagnosis of ILD in RA and to validate the use of a pocket-size US device (PS-USD) as a screening tool. Methods LUS was performed with standard equipment by a trained physician through longitudinal scans following anatomical lines: 72 segments were considered (28 anteriorly and 44 posteriorly) and B-lines were counted in each segment. A B-lines score >10 identified a positive examination (presence of ILD). A second LUS session for positive/negative judgment was performed by a short-trained physician using a PS-USD. Results Thirty-nine patients were studied. The sensitivity and specificity of standard LUS vs HRCT were 92% and 56%, respectively. The B-line score was significantly correlated with HRCT score (r = 0.806). A total of 29 patients were studied with a PS-USD. Sensitivity and specificity for PS-USD vs HRCT were 89% and 50%. Conclusion The sensitivity of LUS in the detection of ILD supports its use as a screening test for ILD in RA patients, even in the ambulatory setting with a PS-USD. The strong correlation between echographic and HRCT scores indicates LUS is a valid tool for grading and follow-up of ILD.

The editorial and peer-review processes should guarantee readers as to the reliability of published data. The first step of these processes is to check for errors. The aim of our study was to look for the presence of objective errors in consecutive articles published on three of the most authoritative clinical journals. Two reviewers evaluated the presence of any error in 200 consecutive original articles containing at least two tables, allowing a reanalysis of the data, published between October 2010 and April 2011. Error was considered any action different from what was planned. Errors were listed as: methodological, numerical and slips. They were considered as severe if numbers in the abstract were completely different from numbers reported in the full text. Among the 125 articles included in the study, 102 (82 %, 95 % CI 74–88 %) contained some kind of error, even multiple. Nine articles (7 %, 95 % CI 3–13 %) contained one slip, 92 articles (74 %, 95 % CI 65–81 %) contained at least one numerical error, and 22 articles (18 %, 95 % CI 11–25 %) contained one methodological error. Five articles (4 %, 95 % CI 1–9 %) contained one serious error. None of the errors retrieved (0 %, 95 % CI 0–2 %) would have changed the results of the studies. Most of the articles published in the most important medical journals present mistakes. Our results could be a clue to editorial and peer review systems system weaknesses. A debate within the scientific medical community about these systems, and possible alternative adjustments are needed.

BackgroundThe renin-angiotensin-aldosterone system (RAAS) playsan important role in pathophysiology of heart failure (HF).RAAS blockade with angiotensin converting (ACE)inhibitor slows the progression of HF and improves thesurvival [1]. However, ACE inhibitors do not block themineralocorticoid receptors, which are usually overexpressed in patients with heart failure, and promote car-diac fibrosis in experimental models [2]. The latter hasbeen confirmed by clinical trials that show a reduction inmortality and hospitalization of patients with severe heartfailure in New York Heart Association class III–IV(NYHA III–IV) treated with spironolactone [3], or inpatients after a myocardial infarction complicated by areduced systolic function treated with eplerenone [4].Thus, it is reasonable to suppose that the use of aldoste-rone antagonists might also delay the progression of heartfailure in patients with mild failure symptoms (NYHA II).SummaryThe Eplerenone in Mild Patients Hospitalization and Sur-vival Study in Heart Failure (EMPHASIS-HF) trial [5]randomized 2,737 patients aged more than 55 years withNYHA II heart failure and an ejection fraction of not morethan 35%, to receive either eplerenone (up to 50 mg daily)or placebo, in addition to recommended therapy. The pri-mary outcome was a composite of death from cardiovas-cular causes or a first hospitalization for heart failure. Deathand hospitalization for any cause were secondary outcomes.The trial was planned to last 48 months, but it wasstopped prematurely, after a median follow-up period of21 months, because of an overwhelming benefit in theeplerenone group. The primary outcome occurred in 18.3%of patients in the eplerenone group as compared with25.9% in the placebo group (hazard ratio, 0.63, 95% con-fidence interval (CI), 0.54–0.74, P\0.001). A total of12.5% of patients receiving eplerenone and 15.5% of thosereceiving placebo died (hazard ratio, 0.76, 95% CI,0.62–0.93, P = 0.008); hospitalizations for heart failureand any other cause were also reduced with eplerenone.Among adverse events, only hyperkalemia showed a sig-nificant difference between the two groups: serum potas-sium level exceeding 5.5 mmol per litre occurred in 11.8%of patients in the eplerenone group and in 7.2% of those inthe placebo group (P\0.001). The estimated number ofpatients who would need to be treated to prevent one pri-mary outcome per year was 19 (95% CI 15–27), and theestimated number needed to treat to postpone one death peryear, was 51 (95% CI 32–180).Strength of the study– It addresses a relevant clinical issue (it’s the first trialconducted among the patients in class NYHA II).– Rationale of the study: there is a strong pathophysio-logic background for the utility of aldosterone antag-onists in heart failure patients, and the previous studyalready confirms this observation [3, 4]

In patients with hip fracture, anemia may result as a direct consequence of the injury or surgery. Red blood cell transfusions are commonly administered to surgical patients in response to operative hemorrhage, and to treat anemia. However, the impact of transfusions on mortality and morbidity in patients with hip fracture is still unclear. A large observational study finds no beneficial effect of transfusion on mortality regardless of the presence of preexisting cardiovascular disease [1]. Other studies suggest that anemia decreases physical performance and postoperative rehabilitation in patients with hip fracture, and red blood cell transfusions improve short-term functional outcomes [2, 3]. To date, there are few randomized clinical trials (RCT) assessing the clinical impact of different transfusion thresholds. A large study involving patients in intensive care units shows that a restrictive strategy of redcell transfusion is at least as effective as and possibly superior to a liberal transfusion strategy in critically ill patients [4]. However, there are no RCTs evaluating the safety of withholding transfusion until symptoms of anemia develop in patients with hip fracture. Furthermore, the safety of symptomatic transfusion in patients with cardiovascular disease and the impact of a lower transfusion threshold on functional recovery after surgical hip repair have not been studied. Summary