Carmen D'Amore

Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta-analysis of 22 randomized trials.

OBJECTIVES The objectives of this study were to verify whether improvement in 6-min walk distance (6MWD) is associated with clinical outcome in pulmonary arterial hypertension (PAH). BACKGROUND 6MWD is used as an endpoint to assess the benefit of therapies in PAH. However, whether changes in 6MWD correlate with clinical outcome is unknown. METHODS Randomized trials assessing 6MWD in patients with PAH and reporting clinical endpoints were included in a meta-analysis. The meta-analysis was performed to assess the influence of treatment on outcomes. Meta-regression analysis was performed to test the relationship between 6MWD changes and outcomes. RESULTS Twenty-two trials enrolling 3,112 participants were included. Active treatments led to significant reduction of all-cause death (odds ratio [OR]: 0.429; 95% confidence interval [CI]: 0.277 to 0.664; p < 0.01), hospitalization for PAH, and/or lung or heart-lung transplantation (OR: 0.442; 95% CI: 0.309 to 0.632; p < 0.01), initiation of PAH rescue therapy (OR: 0.555; 95% CI: 0.347 to 0.889; p = 0.01), and composite outcome (OR: 0.400; 95% CI: 0.313 to 0.510; p < 0.01). No relationship between 6MWD changes and outcomes was detected. CONCLUSIONS In patients with PAH, improvement in 6MWD does not reflect benefit in clinical outcomes.

Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis.

OBJECTIVES The purpose of this paper was to assess whether statins reduce all-cause mortality and cardiovascular (CV) events in elderly people without established CV disease. BACKGROUND Because of population aging, prevention of CV disease in the elderly is relevant. In elderly patients with previous CV events, the use of statins is recommended by guidelines, whereas the benefits of these drugs in elderly subjects without previous CV events are still debated. METHODS Randomized trials comparing statins versus placebo and reporting all-cause and CV mortality, myocardial infarction (MI), stroke, and new cancer onset in elderly subjects (age ≥ 65 years) without established CV disease were included. RESULTS Eight trials enrolling 24,674 subjects (42.7% females; mean age 73.0 ± 2.9 years; mean follow up 3.5 ± 1.5 years) were included in analyses. Statins, compared with placebo, significantly reduced the risk of MI by 39.4% (relative risk [RR]: 0.606 [95% confidence interval (CI): 0.434 to 0.847]; p = 0.003) and the risk of stroke by 23.8% (RR: 0.762 [95% CI: 0.626 to 0.926]; p = 0.006). In contrast, the risk of all-cause death (RR: 0.941 [95% CI: 0.856 to 1.035]; p = 0.210) and of CV death (RR: 0.907 [95% CI: 0.686 to 1.199]; p = 0.493) were not significantly reduced. New cancer onset did not differ between statin- and placebo-treated subjects (RR: 0.989 [95% CI: 0.851 to 1.151]; p = 0.890). CONCLUSIONS In elderly subjects at high CV risk without established CV disease, statins significantly reduce the incidence of MI and stroke, but do not significantly prolong survival in the short-term.

Cardiovascular effects of dipeptidyl peptidase-4 inhibitors in diabetic patients: A meta-analysis

BACKGROUND Dipeptidyl peptidase-4 inhibitors (DPP-4is) improve glucose control in patients with type 2 diabetes mellitus (DM); however, only few studies were properly designed to evaluate their cardiovascular (CV) effects. The purpose of this study was to assess the impact of DPP-4i treatment on CV morbidity and mortality. METHODS Randomized clinical trials enrolling more than 200 patients, comparing DPP-4 versus placebo or active treatments in patients with DM and reporting at least one event among all-cause and CV mortality, myocardial infarction (MI), stroke and new onset of heart failure (HF) were included in the analysis. RESULTS Ninety-four trials enrolling 85,224 patients (median follow-up=29weeks) were included in the analysis. Compared to control, treatment with DPP-4i did not affect all-cause and CV mortality, as well as stroke, in the short and long terms (< and >=29weeks, respectively). DPP-4i reduced the risk of MI in the short (RR: 0.584 [95% CI: 0.361 to 0.943]; p=0.028), but not in the long term. Additionally, long-term treatment with DPP-4 was associated with a 15.8% increased risk of HF (RR: 1.158 [CI: 1.011 to 1.326]; p=0.034). No heterogeneity among studies or publication bias was detected. CONCLUSIONS DPP4is do not affect all cause- and CV-mortality and stroke in diabetic patients; the reduction in MI observed with short-term treatment does not persist in the long term. Long-term use of DPP-4i in diabetic patients is associated with increased risk of HF.

The Prognostic Value of Normal Stress Cardiac Magnetic Resonance in Patients with Known or Suspected Coronary Artery Disease: A Meta-analysis

Background—Ischemia detection with stress cardiac magnetic resonance (CMR) is typically based on induction of either myocardial perfusion defect or wall motion abnormality. Single-center studies have shown the high value of stress CMR for risk stratification. The aim of this study was to define the prognostic value of stress CMR for prediction of adverse cardiac events in patients with known or suspected coronary artery disease. Methods and Results—Studies published between January 1985 and April 2012 were identified by database search. We included studies using stress CMR to evaluate subjects with known or suspected coronary artery disease and providing primary data on clinical outcomes of nonfatal myocardial infarction or cardiac death with a follow-up time ≥3 months. Total of 14 studies were finally included, recruiting 12 178 patients. The negative predictive value for nonfatal myocardial infarction and cardiac death of normal CMR was 98.12% (95% confidence interval, 97.26–98.83) during a weighted mean follow-up of 25.3 months, resulting in estimated event rate after a negative test equal to 1.88% (95% confidence interval, 1.17–2.74). The corresponding annualized event rate after a negative test was 1.03%. Comparable negative predictive values for major coronary events were obtained in studies considering the absence of inducible perfusion defect compared with those evaluating the absence of inducible wall motion abnormality (98.39% versus 97.31%, respectively; P=0.227 by meta-regression analysis). Conclusions—Stress CMR has a high negative predictive value for adverse cardiac events, and the absence of inducible perfusion defect or wall motion abnormality shows a similar ability to identify low-risk patients with known or suspected coronary artery disease.

Haemodynamics, exercise capacity and clinical events in pulmonary arterial hypertension

The purpose of this study was to clarify whether changes in cardiopulmonary haemodynamics induced by pharmacological therapy correlate with exercise capacity and clinical events in patients with pulmonary arterial hypertension. 16 randomised trials including 2353 patients, followed up for 16.4±10.6 weeks, measuring cardiopulmonary haemodynamics by right heart catheterisation and reporting clinical events were included. Meta-analysis and meta-regression analysis were performed to assess the effects of treatments on clinical events and the relationship between haemodynamic changes (pulmonary artery pressure, pulmonary vascular resistance, cardiac index and right atrial pressure) and clinical events. Treatments significantly reduced all-cause death (OR 0.5, 95% CI 0.3–0.7; p<0.01), hospitalisation for pulmonary arterial hypertension (OR 0.4, 95% CI 0.2–0.7; p<0.01), initiation of rescue therapy (OR 0.3, 95% CI 0.2–0.6; p<0.01) and the composite outcome (OR 0.3, 95% CI 0.3–0.5; p<0.01). No relationship was found between changes of haemodynamic parameters and clinical events, whereas changes of cardiac index and pulmonary vascular resistance significantly correlated with changes in the 6-min walking distance (r = 0.64, p = 0.03; r = -0.55, p = 0.04, respectively). In patients with pulmonary arterial hypertension, improvements of cardiopulmonary haemodynamics observed in randomised clinical trials correlate with exercise capacity changes but do not predict clinical events in a short-term follow-up.

Endothelial dysfunction in type 2 diabetic patients with normal coronary arteries: A digital reactive hyperemia study

BACKGROUND To assess endothelial function (EF) in type 2 diabetic patients with angiographically normal coronaries compared to diabetic patients with obstructive coronary artery disease (CAD) and to non-diabetic patients, with and without CAD. METHODS One hundred eighty-three patients undergoing coronary angiography were divided in: group 1 with diabetes mellitus (DM) and CAD (n = 58); group 2 with DM without CAD (n = 58); group 3 with CAD without DM (n = 31) and group 4 without CAD and DM (n = 36). EF was assessed by reactive hyperemia index (RHI) using a fingertip peripheral arterial tonometry and compared to values obtained in 20 healthy volunteers. RESULTS RHI was significantly lower in patients with DM compared to patients without DM (1.69 ± 0.38 vs 1.84 ± 0.44; p = 0.019). RHI was comparable among groups 1, 2 and 3, each value being significantly lower compared to group 4 (2 ± 0.44; p<0.001 vs group 1; p<0.005 vs group 2; p<0.002 vs group 3). At multivariate analysis DM and CAD were significant predictors of endothelial dysfunction (ED) (OR = 2.29; p = 0.012; OR = 2.76; p = 0.001, respectively), whereas diabetic patients (n = 116) CAD and glycated haemoglobin (HbA1c) were independent significant predictors of ED (OR = 3.05; p = 0.009; OR = 1.96; p = 0.004, respectively). Diabetic patients with ED (n = 67) had higher levels of HbA1c than diabetic patients with normal endothelial function (7.35 ± 0.97 vs 6.87 ± 0.90; p = 0.008) and RHI inversely correlated to HbA1c (p = 0.02; r = -0.210). CONCLUSIONS Diabetic patients with and without CAD show significantly impaired peripheral vascular function compared to non-diabetic patients without CAD. ED in diabetic patients without CAD is comparable to that of patients with CAD but without DM. HbA1c is a weak independent predictor of ED.

Effects of Dipeptidyl Peptidase 4 Inhibitors and Sodium-Glucose Linked coTransporter-2 Inhibitors on cardiovascular events in patients with type 2 diabetes mellitus: A meta-analysis

BACKGROUND Dipeptidyl Peptidase 4 Inhibitors (DPP4-I) and Sodium-Glucose Linked coTransporter-2 Inhibitors (SGLT2-I) improve glycemic control in patients with type 2 diabetes mellitus (DM). However, only few studies were designed to assess the efficacy and safety of these drugs on cardiovascular (CV) events and mortality. The purpose of the current study was to evaluate the effects of DPP4-Is and SGLT2-Is on CV events and mortality by meta-analysis. METHODS Randomized trials enrolling more than 200 patients, comparing DPP-4-Is or SGLT2-Is versus placebo or active treatments in patients with DM, and reporting at least one event among all-cause and CV mortality, stroke, myocardial infarction (MI) and new onset of heart failure (HF), were included. RESULTS 157 randomized trials (114 on DPP4-Is and 43 on SGLT2-Is) enrolling 140,470 patients (107,100 in DPP4-I and 33,370 in SGLT2-I studies) were included in the analysis. Compared to control, treatment with DPP4-Is did not affect all-cause (RR: 1.010; 95% CI: 0.935-1.091) and CV (RR: 0.975; CI: 0.887-1.073) mortality as well as risk of MI (RR: 0.915; CI: 0.835-1.002), stroke (RR: 0.933; CI: 0.820-1.062) and HF (RR: 1.083; CI: 0.973-1.205). Treatment with SGLT2-Is significantly reduced the risk of all-cause death by 28% (RR: 0.718; CI: 0.613-0.840), CV death by 33% (RR: 0.668; CI: 0.544-0.821), MI by 20% (RR: 0.803; CI: 0.668-0.965) and HF by 35% (RR: 0.652; CI: 0.517-0.823) without effect on stroke (RR: 1.158; CI: 0.912-1.469). CONCLUSIONS DPP4-Is show a safe CV profile as they do not affect mortality and CV events, including HF, in patients with type 2 DM. SGLT2-Is are associated with improved CV outcome and survival in DM patients.

Reduction of albumin urinary excretion is associated with reduced cardiovascular events in hypertensive and/or diabetic patients. A meta-regression analysis of 32 randomized trials

BACKGROUND The association between renal dysfunction and risk of cardiovascular (CV) events and mortality has been reported in several studies. However, it is unclear whether reduction in urinary albumin excretion (UAE) is associated with reduced risk of clinical events. Therefore, we sought to investigate, in a meta-regression analysis of randomized studies enrolling hypertensive and/or diabetic patients, whether changes in UAE are associated with changes in CV outcomes and all-cause mortality. METHODS MEDLINE, ISI Web of Science, Cochrane Database and Scopus were searched for randomized trials enrolling more than 200 diabetic and/or hypertensive patients, reporting UAE at baseline and at end of follow-up and CV events [CV death, myocardial infarction (MI), and stroke], as well all-cause mortality. RESULTS Thirty-two trials enrolling 80,812 participants were included in analyses. Meta-regression analysis showed that each 10% reduction of UAE was significantly associated with 13% reduction of MI (Regression Coefficient [RC]:0.0055; 95% Confidence Interval [CI]:0.0014 to 0.0095; p=0.010), with 29% reduction of stroke (RC:0.0124; CI:0.0030 to 0.0218; p=0.013) and with 14% reduction of the composite outcome (CV death, MI, stroke)(RC:0.0059; CI:0.0027 to 0.0090; p=0.001), whereas not significantly associated with all-cause (RC:0.0028; CI:-0.0047 to 0.0103; p=0.486) and CV mortality (RC:0.0028; CI:-0.0047 to 0.0103; p=0.447). Results were mostly confirmed by sensitivity analysis. No heterogeneity or publication bias was detected. CONCLUSIONS Reduction in UAE is associated with reduced risk of MI and stroke in diabetic and/or hypertensive patients. These findings suggest that UAE changes may represent a valuable intermediate end-point for CV risk evaluation in clinical practice.

Effects of ranolazine in symptomatic patients with stable coronary artery disease. A systematic review and meta-analysis.

BACKGROUND Ranolazine (R), as add-on therapy in symptomatic patients with chronic stable coronary artery disease (CAD), has been tested in randomized clinical studies. Aim of the study was to assess in a meta-analysis the effects of R on angina, nitroglycerin consumption, functional capacity, electrocardiographic signs of ischemia and hemodynamic parameters in patients with chronic CAD. METHODS Randomized trials assessing the effects of R compared to control on exercise duration, time to onset of angina, time to 1mm ST-segment depression, weekly nitroglycerin consumption and weekly angina frequency were included in the analysis. The effects of R compared to control on heart rate and blood pressure were also analyzed. RESULTS Six trials enrolling 9223 patients were included in the analysis. At trough and peak levels, R compared to control significantly improved exercise duration, time to onset of angina and time to 1mm ST-segment depression. Additionally, R compared to control significantly reduced weekly angina frequency and weekly nitroglycerin consumption. Finally, R compared to control did not significantly reduce supine systolic and diastolic blood pressure as well as heart rate, standing heart rate and diastolic blood pressure, whereas it modestly reduced standing systolic blood pressure. At sensitivity analysis, results were not influenced by concomitant background therapy. CONCLUSIONS In symptomatic patients with chronic CAD, R, added to conventional therapy, effectively reduces angina frequency and sublingual nitroglycerin consumption while prolonging exercise duration as well as time to onset of ischemia and to onset of angina with no substantial effects on blood pressure and heart rate.

Reduction of C-reactive protein is not associated with reduced cardiovascular risk and mortality in patients treated with statins. A meta-analysis of 22 randomized trials

BACKGROUND The association between C-reactive protein (CRP) levels and risk of cardiovascular (CV) events has been reported in several studies. However, it is unclear whether a reduction in CRP is associated with a reduction in risk of clinical events. Therefore we sought to investigate, in a meta-regression analysis of randomized studies enrolling patients treated by statins, whether changes in CRP are associated with changes in risk of CV events or overall survival. METHODS Randomized trials enrolling patients treated by statins, reporting CRP at baseline and at end of follow-up, CV events [myocardial infarction (MI) and stroke], CV and all-cause mortality were selected. RESULTS Twenty-two trials enrolling 54,213 participants were included in the analysis. Meta-analysis showed that active treatment significantly reduced risk of all-cause death by 8%, myocardial infarction by 11%, stroke by 10.3% and the composite outcome (including CV death, MI and stroke) by 8%, whereas risks of CV mortality was not significantly reduced. Meta-regression analysis revealed that reduction in CRP levels was significantly associated only with the reduction of MI, whereas no relationship was identified between changes in CRP and risk of stroke, CV and all-cause mortality, and the composite outcome. CONCLUSIONS These findings demonstrate that statin-induced changes in CRP do not correlate with major CV events apart from the risk of MI nor with overall survival in high-risk patients. These data suggest that although CRP may be a surrogate marker for coronary risk, it should not be used for predicting the effectiveness of statin therapy.