Aim: Some studies suggested that metformin could reduce cardiovascular risk to a greater extent than that determined by glucose reduction. Aim of the present meta-analysis is to assess the effects of ...metformin on the incidence of cardiovascular events and mortality. Methods: An extensive search of Medline, EMBASE and the Cochrane Library (any date up to 31 October 2009) was performed for all trials containing the word ‘metformin'. Randomized trials with a duration ≥52 weeks were included. A meta-regression analysis was also performed to identify factors associated with cardiovascular morbidity and mortality in metformin-treated patients. Results: A total of 35 clinical trials were selected including 7171 and 11 301 participants treated with metformin and comparator, respectively, who had 451 and 775 cardiovascular (CV) events, respectively. Overall, metformin was not associated with significant harm or benefit on cardiovascular events (MH-OR 0.940.82-1.07, p = 0.34). A significant benefit was observed in trials versus placebo/no therapy (MH-OR 0.790.64-0.98, p = 0.031), but not in active-comparator trials (MH-OR 1.030.72-1.77, p = 0.89). Meta-regression showed a significant correlation of the effect of metformin on cardiovascular events with trial duration and with minimum and maximum age for inclusion, meaning that the drug appeared to be more beneficial in longer trials enrolling younger patients. It is likely that metformin monotherapy is associated with improved survival (MH-OR: 0.8010.625-1.024, p = 0.076). However, concomitant use with sulphonylureas was associated with reduced survival (MH-OR: 1.4321.068-1.918, p = 0.016). Conclusion: Available evidence seems to exclude any overall harmful effect of metformin on cardiovascular risk, suggesting a possible benefit versus placebo/no treatment. The observed detrimental effect of the combination with sulphonylureas deserves further investigation.
Basal insulin in type 1 diabetes can be provided using either NPH (Neutral Protamine Hagedorn) human insulin or long-acting insulin analogues, which are supposed to warrant a better metabolic control ...with reduced hypoglycaemic risk. Aim of this meta-analysis is the assessment of differences with respect to HbA1c (Glycated hemoglobin), incidence of hypoglycaemia, and weight gain, between NPH human insulin and each long-acting analogue. Of 285 randomized controlled trials with a duration > 12 weeks comparing long-acting insulin analogues (detemir or glargine) with NPH insulin in type 1 diabetic patients identified through Medline search and searches on www.clinicaltrials.gov, 20 met eligibility criteria (enrolling 3693 and 2485 in the long-acting analogues and NPH group respectively). Data on HbA1c and body mass index at endpoint, and incidence of any, nocturnal and severe hypoglycaemia, were extracted and meta-analysed. Long-acting analogues had a small, but significant effect on HbA1c -0.07 (-0.13; -0.01)%; p = 0.026, in comparison with NPH human insulin. When analysing the effect of long-acting analogues on body weight, detemir was associated with a significantly smaller weight gain than human insulin by 0.26 (0.06;0.47) kg/m²; p = 0.012. Long-acting analogues were associated with a reduced risk for nocturnal and severe hypoglycaemia OR (Odd Ratio, 95% Confidence Intervals) 0.69 (0.55; 0.86), and OR 0.73 (0.60; 0.89) respectively; all p < 0.01. The switch from NPH to long-acting analogues as basal insulin replacement in type 1 diabetic patients had a small effect on HbA1c, and also reduced the risk of nocturnal and severe hypoglycaemia.
Abstract Background and Aim The role of Dipeptidyl Peptidase-4 (DPP-4) inhibitors in the treatment of type 2 diabetes is debated; many recent trials, which were not included in previous ...meta-analyses, could add relevant information. Methods and Results All available randomized controlled trials (RCTs), either published or unpublished, performed in type 2 diabetic patients with DPP-4 inhibitors, with a duration >12 weeks were meta-analyzed for HbA1c, BMI, hypoglycemia, and other adverse events. A total of 41 RCTs (9 of which are unpublished) was retrieved and included in the analysis. Gliptins determine a significant improvement of HbA1c in comparison with a placebo (−0.7 −0.8:−0.6), with a low risk of hypoglycemia. DPP-4 inhibitors show a similar efficacy in monotherapy and in combination with other agents. The risk of cardiovascular events and all-cause death with DPP-4 inhibitors is 0.76 0.46–1.28 and 0.78 0.40–1.51, respectively. Conclusions DPP-4 inhibitors reduce HbA1c, although to a lesser extent than sulphonylureas, with no weight gain and no hypoglycemic risk; further data are needed to assess their long-term safety.
Abstract Background and aims Randomized clinical trials (RCTs) aimed at the assessment of the efficacy of lowering blood glucose in the prevention of diabetic complications have always failed to ...detect a significant effect on cardiovascular events. Aim of this meta-analysis is the assessment of the effects of improvement of glycemic control on the incidence of cardiovascular diseases in patients with type 2 diabetes. Methods The RCTs were included in this meta-analysis if: a) the between-group difference in mean HbA1c during the trial was at least 0.5%, b) they had a planned duration of treatment of at least 3 years, c) if they had a cardiovascular endpoint. Data for analysis were extracted independently by two observers and potential contrasts were resolved by a senior investigator. Results Five studies (17,267 and 15,362 patients in the intensive and conventional therapy groups, respectively) were included. Intensive treatment, which reduced mean HbA1c by 0.9% on average, was associated with a significant reduction of incident cardiovascular events and myocardial infarction (OR 0.89 0.83–0.95 and 0.86 0.78–0.93, respectively), but not of stroke or cardiovascular mortality (OR 0.93 0.81–1.07 and 0.98 0.77–1.23, respectively). In meta-regression analysis, a higher BMI duration of diabetes, and incidence of severe hypoglycaemia were associated with greater risk for cardiovascular death in intensive treatment groups. Conclusion Intensified hypoglycaemic treatment in type 2 diabetic patients leads to a significant reduction of the incidence of myocardial infarction, while it does not affect the incidence of stroke and cardiovascular mortality. Hypoglycemia induced by intensified treatment could be associated with increased cardiovascular mortality.
The aim of this meta-analysis of randomized clinical trials (RCT) was to assess whether pioglitazone is also associated with increased cardiovascular risk, as recently reported for rosiglitazone. RCT ...of pioglitazone were retrieved from Medline (any date up to 31 August 2007; English language only). Unpublished RCT were identified through http://www.clinicaltrials.gov or http://www.fda.gov websites, and results on cardiovascular outcomes were retrieved from investigators and/or sponsors, whenever possible. RCT were included in meta-analysis if pioglitazone was compared with other treatments (placebo, active comparators or no treatment) for at least 4 weeks. Ninety-four trials, 10 of which were unpublished, were retrieved; those included in the analysis, which excluded PROspective PioglitAzone Clinical Trial In MacroVascular Events (PROACTIVE), enrolled 11 268 and 9912 patients in the pioglitazone and comparator groups respectively. Data for analysis, extracted independently by two observers, included all-cause and cardiovascular mortality and incidence of non-fatal coronary events and heart failure. Proportions of outcome measures across treatment groups were compared by odds ratios (ORs) and 95% confidence interval. Pioglitazone was associated with reduced all-cause mortality OR 0.30 (0.14-0.63); p < 0.05, with no relevant effect on non-fatal coronary events. The observed increase in incidence of non-fatal heart failure was not statistically significant OR 1.38 (0.90-2.12). The use of pioglitazone does not appear to be harmful in terms of cardiovascular events and all-cause deaths.
Physiotherapy is usually provided only in the first few months after stroke, while its effectiveness and appropriateness in the chronic phase are uncertain. The authors conducted a systematic review ...and meta-analysis of randomised clinical trials (RCT) to evaluate the efficacy of physiotherapy interventions on motor and functional outcomes late after stroke.
The authors searched published studies where participants were randomised to an active physiotherapy intervention, compared with placebo or no intervention, at least 6 months after stroke. The outcome was a change in mobility and activities of daily living (ADL) independence. The quality of the trials was evaluated using the PEDro scale. Findings were summarised across studies as effect size (ES) or, whenever possible, weighted mean difference (WMD) with 95% CI in random effects models.
Fifteen RCT were included, enrolling 700 participants with follow-up data. The meta-analysis of primary outcomes from the original studies showed a significant effect of the intervention (ES 0.29, 95% CI 0.14 to 0.45). The efficacy of the intervention was particularly evident when short- and long-distance walking were considered as separate outcomes, with WMD of 0.05 m/s (95% CI 0.008 to 0.088) and 20 m (95% CI 3.6 to 36.0), respectively. Also, ADL improvement was greater, though non-significantly, in the intervention group. No significant heterogeneity was found.
A variety of physiotherapy interventions improve functional outcomes, even when applied late after stroke. These findings challenge the concept of a plateau in functional recovery of patients who had experienced stroke and should be valued in planning community rehabilitation services.
Recent evidence suggests that carpal tunnel syndrome (CTS) and brachial biceps tendon rupture (BBTR) represent red flags for ATTR cardiac amyloidosis (ATTR‐CA). The prevalence of upper limb ...tenosynovial complications in conditions entering differential diagnosis with CA, such as HCM or Anderson–Fabry disease (AFD), and hence their predictive accuracy in this setting, still remains unresolved. Objective: To investigate the prevalence of CTS and BBTR in a consecutive cohort of ATTR‐CA patients, compared with patients with HCM or AFD and with individuals without cardiac disease history. Participants: Consecutive patients with a diagnosis of ATTR‐CA, HCM and AFD were evaluated. A control group of consecutive patients was recruited among subjects hospitalized for noncardiac reasons and no cardiac disease history. The presence of BBTR, CTS or prior surgery related to these conditions was ascertained. Results: 342 patients were prospectively enrolled, including 168 ATTR‐CA (141 ATTRwt, 27 ATTRm), 81 with HCM/AFD (N = 72 and 9, respectively) and 93 controls. CTS was present in 75% ATTR‐CA patients, compared with 13% and 10% of HCM/AFD and controls (P = 0.0001 for both comparisons). Bilateral CTS was present in 60% of ATTR‐CA patients, while it was rare (2%) in the other groups. BBTR was present in 44% of ATTR‐CA patients, 8% of controls and 1% in HCM/AFD. Conclusions: CTS and BBTR are fivefold more prevalent in ATTR‐CA patients compared with cardiac patients with other hypertrophic phenotypes. Positive predictive accuracy for ATTR‐CA is highest when involvement is bilateral. Upper limb assessment of patients with HCM phenotypes is a simple and effective way to raise suspicion of ATTR‐CA.
Aims We evaluated the early (1 month) and late (2 years) death rate and syncopal relapses of patients referred for syncope to 11 general hospitals emergency departments. Patients were enrolled in the ...Evaluation of Guidelines in SYncope Study 2 (EGSYS 2) study. The guidelines of the European Society of Cardiology were strictly followed in the management of patients. Methods and results Out of the 465 patients enrolled in the EGSYS 2 study, 398 (86%) underwent a complete follow-up. We excluded 18 patients with non-syncopal attacks. Among the remaining 380 patients, death of any cause occurred in 35 (9.2%). The mean follow-up was 614 ± 73 days. Six deaths (17% of total) occurred during the first month of follow-up. Patients who died were older, had a higher incidence of structural heart disease and/or abnormal ECG, had injuries related to syncope and higher EGSYS score. Syncope recurred in 63 (16.5%) patients. Syncopal relapses occurred in only one patient during the first month of follow-up. The incidence of syncopal recurrences was unrelated to the mechanism of syncope. No clinical differences were found between patients with or without syncopal recurrence and in patients with EGSYS score < or ≥3. Conclusion A peak of cardiovascular mortality but not of syncopal recurrences was observed in patients attending to the emergency department for syncope within the first month. Late unfavourable outcomes were caused by associated cardiovascular diseases rather than by the mechanism of syncope. The causes of syncope did not determine the recurrence rate.
High platelet reactivity (HPR) on clopidogrel is an established thrombotic risk factor after percutaneous coronary intervention (PCI). The introduction of more potent antiplatelet drugs has partially ...surpassed this issue. However, in the setting of concomitant atrial fibrillation (AF) and PCI clopidogrel is still the most adopted P2Y
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inhibitor. In the present study all consecutive patients with history of AF discharged from our cardiology ward with dual (DAT) or triple (TAT) antithrombotic therapy after a PCI from April 2018 to March 2021 were enrolled in an observational registry. For all subjects, blood serum samples were collected and tested for platelet reactivity by arachidonic acid and ADP (VerifyNow system) and genotyping of the CYP2C19*2 loss-of-function polymorphism. We recorded at 3 and 12-months follow-up: (1) major adverse cardiac and cerebrovascular events (MACCE), (2) major hemorrhagic or clinically relevant non-major bleeding and (3) all-cause mortality. A total of 147 patients were included (91, 62% on TAT). In 93.4% of patients, clopidogrel was chosen as P2Y
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inhibitor. P2Y
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dependent HPR resulted an independent predictor of MACCE both at 3 and 12 months (HR 2.93, 95% C.I. 1.03 to 7.56, p = 0.027 and HR 1.67, 95% C.I. 1.20 to 2.34, p = 0.003, respectively). At 3-months follow-up the presence of CYP2C19*2 polymorphism was independently associated with MACCE (HR 5.21, 95% C.I. 1.03 to 26.28, p = 0.045). In conclusion, in a real-world unselected population on TAT or DAT, the entity of platelet inhibition on P2Y
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inhibitor is a potent predictor of thrombotic risk, suggesting the clinical utility of this laboratory evaluation for a tailored antithrombotic therapy in this high-risk clinical scenario.
Graphical abstract
The present analysis was performed in patients with AF undergoing PCI on dual or triple antithrombotic therapy. At 1 year follow-up MACCE incidence was consistent, and it was not different in different antithrombotic pattern groups. P2Y
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dependent HPR was a potent independent predictor of MACCE both at 3- and 12-months follow-up. In the first 3 months after stenting the carriage of CYP2C19*2 allele was similarly associated with MACCE. Abbreviation: DAT, dual antithrombotic therapy; HPR, high platelet reactivity; MACCE, major adverse cardiac and cerebrovascular events; PRU, P2Y
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reactive unit; TAT, triple antithrombotic therapy. Created with BioRender.com.
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