The Underestimated Role of Platelets in Severe Infection a Narrative Review

Beyond their role in hemostasis, platelets have emerged as key contributors in the immune response; accordingly, the occurrence of thrombocytopenia during sepsis/septic shock is a well-known risk factor of mortality and a marker of disease severity. Recently, some studies elucidated that the response of platelets to infections goes beyond a simple fall in platelets count; indeed, sepsis-induced thrombocytopenia can be associated with—or even anticipated by—several changes, including an altered morphological pattern, receptor expression and aggregation. Of note, alterations in platelet function and morphology can occur even with a normal platelet count and can modify, depending on the nature of the pathogen, the pattern of host response and the severity of the infection. The purpose of this review is to give an overview on the pathophysiological interaction between platelets and pathogens, as well as the clinical consequences of platelet dysregulation. Furthermore, we try to clarify how understanding the nature of platelet dysregulation may help to optimize the therapeutic approach

Exercise Intervention to Improve Functional Capacity in Older Adults After Acute Coronary Syndrome

More than one-half of patients admitted for acute coronary syndrome (ACS) are age $70 years. Mobility limitations and sedentary behavior are common in older ACS patients and contribute to high risk of recurrence and mortality (1). Although older ACS patients may benefit the most from participation in exercise-based cardiac rehabilitation/secondary prevention programs (CR/SP), they are less likely to participate in such programs (2). Whether an early, individualized, and low-cost physical activity (PA) intervention including a few supervised sessions and a home-based program might be feasible and effective for improving functional capacity in this high-risk and undertreated population is unknown. The HULK (Physical Activity Intervention for Patients With Reduced Physical Performance After Acute Coronary Syndrome; NCT03021044) trial is a multicenter, randomized clinical trial. A detailed study outline and statistical plan have been previously published (3). Inclusion criteria were age$70 years, hospitalization for ACS, and Short Physical Performance Battery (SPPB) score between 4 and 9 at the inclusion visit (30 5 days after hospital discharge). The SPPB is a scale that combines gait speed, chair stand, and balance tests. It ranges from 0 (worst) to 12 (best) and has predictive validity for mortality (4). Participants were randomized to usual care and health education (control group) or usual care and PA intervention (intervention group). The control group received a 20-min session and a detailed brochure stressing the importance of PA in cardiovascular health. The PA intervention consisted of four supervised sessions (1, 2, 3, and 4 months after hospital discharge), combined with an individualized home-based PA program. Centerbased sessions included a moderate standardized treadmill-walk, strength, and balance exercises (3). After the practice sessions, patients received a tailored PA home program (3). Weekly energy expenditure from PA was determined by a selfreported 7-day physical activity recall (kcal/week), and objectively measured by wearing an accelerometer (min/week). The primary endpoint was the 6- month SPPB. Secondary endpoints were 1-year SPPB and time engaged in PA. From January 2017 to April 2018, 235 patients were randomized (n ¼ 117, control group; n ¼ 118, intervention group). The median age was 76 (interquartile range [IQR]: 73 to 81) years, and 23% were female. Before the hospitalization, light and moderateintensive PA was performed by 66% and 14% of patients, respectively. Baseline characteristics, as well as baseline SPPB value (Figure 1), did not differ between groups. The adherence rates of the PA intervention group to the 1-, 2-, 3-, and 4-month scheduled supervised sessions were 100%, 89%, 85%, and 72%, respectively. The time engaged in PA progressively and significantly increased in the intervention group (Figure 1). At 6 months, the SPPB score was significantly higher in the intervention group (median: 9 [IQR: 8 to 11] vs. 7 [IQR: 5 to 8]; p < 0.001) (Figure 1). This improvement was supported by a significant increase in SPPB components of walking and chair rise (balance remained unchanged). The number of patients showing an increase of at least 1 point in SPPB score was 86 (74%) in the intervention group versus 46 (40%) in the control group (p < 0.001). The SPPB increase was maintained at the 1-year visit (Figure 1) and independent of sex and educational status. Typical CR/SP includes 3 weekly supervised exercise and educational sessions for 12 weeks. Despite the health benefits associated with these interventions, few eligible patients are referred or complete such programs (1). Our novel PA intervention was designed to address this issue. The attendance rate was high (72% [95% confidence interval: 64% to 80%]). The average weekly energy expenditure from PA in the intervention group increased 3.4 times, and SPPB score showed a mean increment of 2.0 points. This finding is notable given that an SPPB improvement of 1.0 point is generally considered a substantial clinically meaningful change (2). In addition, despite the absence of supervised sessions after the sixth month, the achievements were maintained until 1-year visit. If confirmed in future studies, our PA intervention model might help to mitigate the challenges related to limited health care resources and might increase the number of older adults receiving CR/SP

Novel oral anticoagulats for the treatment of left ventricle thrombosis: a systematic review and meta-analysis

Abstract Funding Acknowledgements Type of funding sources: None. Background novel oral anticoagulants (NOACs) are not guideline-recommanded treatment for left ventricular thrombus. Purpose: the aim of this meta-analysis is to compare NOACs versus vitamin-K atagonsits (VKAs) efficacy in treating left ventricular thrombus (LVT). Methods: we systematically searched MEDLINE, Cochrane Library, Biomed Central, and Web of Science for trials comparing NOACs versus VKAs in the setting of LVT. Five studies, out of the 74 initially selected after first screening, were included in the meta-analysis. For the development of this meta-analysis, the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were followed. The shortlisted studies were retrieved as full articles and appraised independently by two unblinded reviewers. The Mantel-Haensel method with a random effect model was used for the pooled analysis. The primary outcome was the occurrence of stroke and systemic embolism. Secondary outcome was occurrence of left ventricular thrombosis resolution during treatment. Results: 707 patients were included in the analysis for the primary outcome. Of these, 230 were treated with NOACs and 477 with VKAs. The pooled OR for the primary outcome was 0.71 (95% CI 0.18-2.86, I2 67%), thus showing similar effect in term of ischaemic protection. A total of 698 patients, 228 on NOACs and 470 on VKAs were included in the analysis of the secondary outcome. The pooled OR for the secondary outcome pooled OR 0.97, 95% CI 0.56-1.68, I2 46%. Conclusions and Relevance: NOACs seem to have a similar efficacy profile compare to VKAs and so they should be considered as an alternative treatment for left ventricular thrombosis. Large prospective randomized clinical trials are needed to confirm this exploratory finding. Abstract Figure

Contrast associated acute kidney injury and mortality in older adults with acute coronary syndrome: A pooled analysis of the fraser and hulk studies

Whether contrast-associated acute kidney injury (CA-AKI) is only a bystander or a risk factor for mortality in older patients undergoing percutaneous coronary intervention (PCI) is not well understood. Data from FRASER (NCT02386124) and HULK (NCT03021044) studies have been analysed. All patients enrolled underwent coronary angiography. The occurrence of CA-AKI was defined based on KDIGO criteria. The primary outcome of the study was to test the relation between CA-AKI and 3-month mortality. Overall, 870 older ACS adults were included in the analysis (mean age 78 ± 5 years; 28% females). CA-AKI occurred in 136 (16%) patients. At 3 months, 13 (9.6%) patients with CA-AKI died as compared with 13 (1.8%) without it (p < 0.001). At multivariable analysis, CA-AKI emerged as independent predictor of 3-month mortality (HR 3.51, 95%CI 1.05–7.01). After 3 months, renal function returned to the baseline value in 78 (63%) with CA-AKI. Those without recovered renal function (n = 45, 37%) showed an increased risk of mortality as compared to recovered renal function and no CA-AKI subgroups (HR 2.01, 95%CI 1.55–2.59, p = 0.009 and HR 2.71, 95%CI 1.45–5.89, p < 0.001, respectively). In conclusion, CA-AKI occurs in a not negligible portion of older MI patients undergoing invasive strategy and it is associated with short-term mortality

Physical activity intervention for elderly patients with reduced physical performance after acute coronary syndrome (HULK study): Rationale and design of a randomized clinical trial

Background: Reduced physical performance and impaired mobility are common in elderly patients after acute coronary syndrome (ACS) and they represent independent risk factors for disability, morbidity, hospital readmission and mortality. Regular physical exercise represents a means for improving functional capacity. Nevertheless, its clinical benefit has been less investigated in elderly patients in the early phase after ACS. The HULK trial aims to investigate the clinical benefit of an early, tailored low-cost physical activity intervention in comparison to standard of care in elderly ACS patients with reduced physical performance. Design: HULK is an investigator-initiated, prospective multicenter randomized controlled trial (NCT03021044). After successful management of the ACS acute phase and uneventful first 1 month, elderly (≥70 years) patients showing reduced physical performance are randomized (1:1 ratio) to either standard of care or physical activity intervention. Reduced physical performance is defined as a short physical performance battery (SPPB) score of 4-9. The early, tailored, low-cost physical intervention includes 4 sessions of physical activity with a supervisor and an home-based program of physical exercise. The chosen primary endpoint is the 6-month SPPB value. Secondary endpoints briefly include quality of life, on-treatment platelet reactivity, some laboratory data and clinical adverse events. To demonstrate an increase of at least one SPPB point in the experimental arm, a sample size of 226 patients is needed. Conclusions: The HULK study will test the hypothesis that an early, tailored low-cost physical activity intervention improves physical performance, quality of life, frailty status and outcome in elderly ACS patients with reduced physical performance

Anti-anginal drugs-beliefs and evidence: systematic review covering 50 years of medical treatment.

Chronic stable angina is the most prevalent symptom of ischaemic heart disease and its management is a priority. Current guidelines recommend pharmacological therapy with drugs classified as being first line (beta blockers, calcium channel blockers, short acting nitrates) or second line (long-acting nitrates, ivabradine, nicorandil, ranolazine, and trimetazidine). Second line drugs are indicated for patients who have contraindications to first line agents, do not tolerate them or remain symptomatic. Evidence that one drug is superior to another has been questioned. Between January and March 2018, we performed a systematic review of articles written in English over the past 50 years English-written articles in Medline and Embase following preferred reporting items and the Cochrane collaboration approach. We included double blind randomized studies comparing parallel groups on treatment of angina in patients with stable coronary artery disease, with a sample size of, at least, 100 patients (50 patients per group), with a minimum follow-up of 1 week and an outcome measured on exercise testing, duration of exercise being the preferred outcome. Thirteen studies fulfilled our criteria. Nine studies involved between 100 and 300 patients, (2818 in total) and a further four enrolled greater than 300 patients. Evidence of equivalence was demonstrated for the use of beta-blockers (atenolol), calcium antagonists (amlodipine, nifedipine), and channel inhibitor (ivabradine) in three of these studies. Taken all together, in none of the studies was there evidence that one drug was superior to another in the treatment of angina or to prolong total exercise duration. There is a paucity of data comparing the efficacy of anti-anginal agents. The little available evidence shows that no anti-anginal drug is superior to another and equivalence has been shown only for three classes of drugs. Guidelines draw conclusions not from evidence but from clinical beliefs

Grip strength predicts cardiac adverse events in patients with cardiac disorders: an individual patient pooled meta-analysis

Objective: Grip strength is a well-characterised measure of weakness and of poor muscle performance, but there is a lack of consensus on its prognostic implications in terms of cardiac adverse events in patients with cardiac disorders. Methods: Articles were searched in PubMed, Cochrane Library, BioMed Central and EMBASE. The main inclusion criteria were patients with cardiac disorders (ischaemic heart disease, heart failure (HF), cardiomyopathies, valvulopathies, arrhythmias); evaluation of grip strength by handheld dynamometer; and relation between grip strength and outcomes. The endpoints of the study were cardiac death, all-cause mortality, hospital admission for HF, cerebrovascular accident (CVA) and myocardial infarction (MI). Data of interest were retrieved from the articles and after contact with authors, and then pooled in an individual patient meta-analysis. Univariate and multivariate logistic regression was performed to define predictors of outcomes. Results: Overall, 23 480 patients were included from 7 studies. The mean age was 62.3±6.9 years and 70% were male. The mean follow-up was 2.82±1.7 years. After multivariate analysis grip strength (difference of 5 kg, 5× kg) emerged as an independent predictor of cardiac death (OR 0.84, 95% CI 0.79 to 0.89, p<0.0001), all-cause death (OR 0.87, 95% CI 0.85 to 0.89, p<0.0001) and hospital admission for HF (OR 0.88, 95% CI 0.84 to 0.92, p<0.0001). On the contrary, we did not find any relationship between grip strength and occurrence of MI or CVA. Conclusion: In patients with cardiac disorders, grip strength predicted cardiac death, all-cause death and hospital admission for HF. Trial registration number: CRD42015025280

CHA2DS2-VASc score predicts atrial fibrillation recurrence after cardioversion: systematic review and individual patient pooled meta-analysis

BackgroundDespite progresses in the treatment of the thromboembolic risk related to atrial fibrillation (AF), the management of recurrences remains a challenge.HypothesisTo assess if congestive heart failure or left ventricular systolic dysfunction (CHA2DS2‐VASc) score is predictive of early arrhythmia recurrence after AF cardioversion.MethodsSystematic review and individual patient pooled meta‐analysis following Preferred Reporting Items for Systematic reviews and Meta‐Analyses guidelines. Inclusion criteria: observational trials in patients with AF undergoing cardioversion, available data on recurrence of AF and available data on CHA2DS2‐VASc score. Clinical studies of interest were retrieved by PubMed, Cochrane Library, and Biomed Central. Seven authors were contacted for joining the patient level meta‐analysis, and three shared data regarding anthropometric measurements, risk factors, major comorbidities, and CHA2DS2‐VASc score. The primary outcome was the recurrence of AF after cardioversion in patients free from antiarrhythmic prophylaxis. Univariate and multivariate logistic regression was performed.ResultsOverall, we collect data of 2889 patients: 61% were male, 50% with hypertension, 12% with diabetes, and 23% with history of ischemic heart disease. The median CHA2DS2‐VASc score was 2.. At the multivariate analysis, chronic kidney disease (odds ratio [OR] 1.94; 95% confidence interval [CI] 1.12‐3.27; P = 0.01), peripheral artery disease (OR 1.65; 95% CI 1.23‐2.19; P P  2 (OR 1.37; 95% CI 1.1‐1.68; P = 0.002) were independent predictors of early recurrence of AF.ConclusionsCHA2DS2‐VASc score predicts early recurrence of AF in the first 30 days after electrical or pharmacological cardioversion.N

Short Physical Performance Battery and all-cause mortality: systematic review and meta-analysis

Background: The Short Physical Performance Battery (SPPB) is a well-established tool to assess lower extremity physical performance status. Its predictive ability for all-cause mortality has been sparsely reported, but with conflicting results in different subsets of participants. The aim of this study was to perform a meta-analysis investigating the relationship between SPPB score and all-cause mortality.Methods: Articles were searched in MEDLINE, the Cochrane Library, Google Scholar, and BioMed Central between July and September 2015 and updated in January 2016. Inclusion criteria were observational studies; > 50 participants; stratification of population according to SPPB value; data on all-cause mortality; English language publications. Twenty-four articles were selected from available evidence. Data of interest (i.e., clinical characteristics, information after stratification of the sample into four SPPB groups [0-3, 4-6, 7-9, 10-12]) were retrieved from the articles and/or obtained by the study authors. The odds ratio (OR) and/or hazard ratio (HR) was obtained for all-cause mortality according to SPPB category (with SPPB scores 10-12 considered as reference) with adjustment for age, sex, and body mass index.Results: Standardized data were obtained for 17 studies (n = 16,534, mean age 76 +/- 3 years). As compared to SPPB scores 10-12, values of 0-3 (OR 3.25, 95% CI 2.86-3.79), 4-6 (OR 2.14, 95% CI 1.92-2.39), and 7-9 (OR 1.50, 95% CI 1. 32-1.71) were each associated with an increased risk of all-cause mortality. The association between poor performance on SPPB and all-cause mortality remained highly consistent independent of follow-up length, subsets of participants, geographic area, and age of the population. Random effects meta-regression showed that OR for all-cause mortality with SPPB values 7-9 was higher in the younger population, diabetics, and men.Conclusions: An SPPB score lower than 10 is predictive of all-cause mortality. The systematic implementation of the SPPB in clinical practice settings may provide useful prognostic information about the risk of all-cause mortality. Moreover, the SPPB could be used as a surrogate endpoint of all-cause mortality in trials needing to quantify benefit and health improvements of specific treatments or rehabilitation programs

Moving forward from statistical to clinical considerations regarding complete revascularization

This commentary refers to ‘Conclusions of complete revascularization meta-analysis are challenged by state-of-the-art methods’ by A. Jobs et al., 2020;41:2223–2224