Impact of neutrophils to lymphocytes ratio on major clinical outcomes in patients with acute coronary syndromes: A systematic review and meta-analysis of the literature.

BACKGROUND: Inflammatory markers are significantly associated with cardiovascular disease. The ratio between neutrophils and lymphocytes (NLR) is a potential new biomarker, which can single out individuals at risk for future cardiovascular events. Among total white blood cell count (WBC) and its subtypes, NLR seems to have the greatest predictive value for death and major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS). We conducted a meta-analysis of the literature to assess the relation between NLR and cardiovascular outcomes in STEMI/NSTEMI patients. METHODS: MEDLINE and EMBASE databases were searched. Two reviewers selected studies and extracted data. Pooled results were reported as odds ratios (ORs) and were presented with the corresponding 95% confidence intervals (CI). RESULTS: Twenty-three studies for a total of >16,000 patients were included. Compared to those with low NLR, high NLR on-admission was associated with a higher overall mortality both in patients with STEMI (OR: 4.60, 95% CI: 2.84-7.45; P < 0.00001) and in patients with NSTEMI (OR: 6.41, 95% CI: 2.65-15.50; P < 0.00001). An increased MACE risk was found in STEMI patients with high NLR (OR: 3.71, 95% CI: 2.67-5.17; P < 0.00001). Post-PCI mortality risk was significantly increased in patients with high NLR (OR: 3.76, 95% CI: 2.64-5.34; P < 0.00001). CONCLUSIONS: In this large meta-analysis on prognostic significance of NLR in ACS we found that on-admission high NLR in patients with STEMI/NSTEMI appeared to affect clinically important outcomes including both in-hospital and long-term mortality and MACE.

Lipoprotein(a) as a Risk Factor for Venous Thromboembolism: A Systematic Review and Meta-analysis of the Literature.

Elevated plasma levels of lipoprotein(a) (Lp(a)) are associated with increased cardiovascular risk in several clinical studies. However, there is a lack of data supporting a positive association between elevated Lp(a) levels and venous thromboembolism (VTE). Thus, we conducted a systematic review of the literature to better clarify its role as a risk factor for VTE. Medline and the Embase (up to May 2015) electronic databases were used to identify potentially eligible studies. Studies measuring Lp(a) values in adult patients with deep vein thrombosis and/or pulmonary embolism and in a population of patients without a VTE were selected. Studies on patients with major venous thromboembolic events occurring at other unusual site, case reports, and case series were excluded. The odds ratios (ORs) of the association between high values of Lp(a) and VTE and the weighted mean difference (WMD) in Lp(a) levels in cases and in controls were calculated using a random-effect model. Results were presented with 95% confidence interval (CI). Fourteen studies for a total of more than 14,000 patients were finally included in our analysis. Lp(a) was slightly but significantly associated with an increased risk of VTE (OR: 1.56, 95% CI: 1.36, 1.79; 10 studies, 13,541 patients). VTE patients had significantly higher Lp(a) values compared with controls (WMD: 14.46 mg/L, 95% CI: 12.14, 16.78; 4 studies, 470 patients). Lp(a) appeared to be significantly associated with increased risk of VTE. However, Lp(a) levels were only slightly increased in VTE patients compared with controls.

Gender Difference in Efficacy and Safety of Nonvitamin K Antagonist Oral Anticoagulants in Patients with Nonvalvular Atrial Fibrillation or Venous Thromboembolism: A Systematic Review and a Meta-Analysis of the Literature.

INTRODUCTION: Limited information exists on gender-related differences in the safety and efficacy of non-vitamin K antagonist oral anticoagulants (NOACs). AIM OF THE STUDY: To assess the safety and efficacy of direct oral anticoagulants (DOACs)/NOACs in men and women pooling data from randomized controlled trials on the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) and on the acute and extended treatment of venous thromboembolism (VTE). METHODS: MEDLINE and EMBASE databases were searched up to June 2014. The efficacy outcome was defined as the prevention of stroke and systemic embolism (AF studies), or as the prevention of recurrent VTE or VTE-related death (VTE studies). The safety outcome was defined as the occurrence of major and/or clinically relevant non-major bleeding. Differences in the efficacy and safety outcomes were expressed as risk ratio (RR) with pertinent 95% confidence intervals (95% CI). RESULTS: A total of 13 studies (> 100,000 patients) were included. DOACs appeared to have a similar efficacy and safety compared with vitamin K antagonists in female and male patients treated for nonvalvular AF and acute VTE. In the extended treatment of VTE NOACs had a RR of bleeding of 4.97 (95% CI 1.06, 23.41) in males and 1.33 (95% CI 0.63, 2.83) in females compared with placebo (subgroup difference chi-square test: 2.25, p = 0.13). CONCLUSIONS: No gender-related difference in the efficacy and safety of NOACs in patients with AF or acute VTE was found. A trend toward an increased risk of bleeding in male patients as compared with female patients was detected in the extended treatment of VTE.

Non-vitamin K oral anticoagulants in patients with pulmonary embolism: a systematic review and meta-analysis of the literature.

Limited information exists on the safety and efficacy of non-vitamin K oral anticoagulants (NOACs) in patients with pulmonary embolism (PE). The aim of this study is to evaluate the difference in the safety and efficacy of the NOACs in comparison to the standard treatment in patients presenting with deep vein thrombosis (DVT) and with PE using data from randomized controlled trials. MEDLINE and EMBASE databases were searched. Differences in the efficacy (recurrent VTE or death-related VTE) and in the safety (major bleeding) outcome were expressed as risk ratio (RR) with 95% confidence intervals (95% CI). Heterogeneity among the studies was assessed. Six studies (27,023 patients) were included. NOACs appeared to have a similar efficacy and safety compared to VKAs in patients presenting with PE and with DVT with a non-significant heterogeneity between the groups (efficacy: RR 0.90, 95% CI 0.72, 1.13 in PE patients and 0.93, 95% CI 0.75, 1.16 in DVT patients; χ2 0.04, p = 0.84; safety: RR 0.49, 95% CI 0.26, 0.95 in PE patients and 0.74 95% CI 0.51, 1.06 in DVT; χ2 1.10, p = 0.29). Our results suggest that the efficacy and safety of the NOACs compared to VKAs is similar between patients with PE and DVT.

Is diabetes a hypercoagulable state? A critical appraisal.

Diabetes mellitus (DM), a chronic disease with an increasing incidence and prevalence worldwide, is an established risk factor for arterial cardiovascular, cerebrovascular and peripheral vascular diseases including acute myocardial infarction, stroke and peripheral artery disease. On the other hand, its role as independent risk factor for venous thromboembolism (VTE) and for cardioembolic stroke or systemic embolism (SE) in patients with atrial fibrillation (AF) is more conflicting. Venous and arterial thromboses have traditionally been regarded as separate diseases, but recent studies have documented an association between these vascular complications. Cardiovascular risk factors may contribute to unprovoked VTE, and VTE may be an early symptomatic event in patients at high cardiovascular risk, including diabetic patients. Compelling evidences suggest that DM is associated with a higher risk of development and progression of AF. Furthermore, in AF patients with a coexisting DM the risk of cardioembolic stroke/SE appeared increased. Thus, DM has been included as one of the items of the CHADS2 score and of the subsequent CHA2DS2-VASc score that have been developed to assess the arterial tromboembolic risk of AF patients. Such a high incidence of thromboembolic events observed in these clinical subsets may be attributable to the DM-related prothrombotic state due to a number of changes in primary and secondary hemostasis. Although of potential clinical interest, unfortunately, to date, no study has properly evaluated the effects of drugs used to control blood glucose levels on the risk of venous thromboembolism and arterial cardioembolic events in patients with DM.

Efficacy and safety of direct oral anticoagulants in patients undergoing cardioversion for atrial fibrillation: A systematic review and meta-analysis of the literature.

BACKGROUND: DOACs are increasingly used in patients with NVAF. Information on efficacy and safety of these compounds in patients undergoing electrical or pharmacological cardioversion is limited. Thus, we performed a systematic review and a meta-analysis of the literature to address this issue. METHODS: Randomized controlled trials comparing the efficacy and safety of DOACs and VKAs in patients with NVAF were systematically searched in Medline, Web of Science, Scopus, Cochrane, and EMBASE databases (up to September 2014). Pooled relative risk (RR) and the corresponding 95% confidence interval (CI) were calculated for each outcome. RESULTS: Four randomized controlled trials (3635 patients), for a total of 4517 cardioversions (2869 with DOACs and 1648 with VKAs), were included in the analysis. DOACs and VKAs appeared equally effective in the prevention of stroke/systemic embolism (0.41% vs 0.61%; RR: 0.73, 95% CI: 0.31, 1.72; P=0.48) and of post-cardiovascular death (0.52% vs 0.81%; RR: 0.73, 95% CI: 0.27, 2.03; P=0.55), with a similar risk of major bleeding complications (0.81% vs 0.60%; RR: 1.23, 95% CI: 0.55, 2.71). Heterogeneity among studies was generally absent. Furthermore, the Weighted Mean Incidence (WMI) of complications appeared very low in patients randomized to DOACs (WMI: 0.6% and 0.9% for stroke/systemic embolism and major bleeding, respectively). CONCLUSION: Our results suggest that DOACs are at least as effective and safe as VKAs in patients with NVAF undergoing to an electrical or pharmacological cardioversion. Thus, DOACs may be considered a valid and practical alternative to VKAs.

How to predict short- and long-term mortality in patients with pulmonary embolism?

Pulmonary embolism (PE) is a common disease with a considerable short- and long-term risk of death. An adequate evaluation of the prognosis in patients with PE may guide decision making in terms of the intensity of the initial treatment during the acute phase, duration of treatment, and intensity of follow-up control visits in the long term. Patients with shock or persistent hypotension are at high risk of early mortality and may benefit from immediate reperfusion. Several tools are available to define the short-term prognosis of hemodynamically stable patients. The Pulmonary Embolism Severity Index (PESI) score, simplified PESI score, and N-terminal pro-B-type natriuretic peptide levels are particularly useful for identifying patients at low risk of early complications who might be safely treated at home. However, the identification of patients who are hemodynamically stable at diagnosis but are at a high risk of early complications is more challenging. The current guidelines recommended a multiparametric prognostic algorithm based on the clinical status and comorbidities. Unfortunately, only a few studies have evaluated the role of risk factors potentially affecting the long-term prognosis of these patients. The available studies suggest a potential role of the PESI score and troponin levels evaluated at the time of an index event. However, further studies are warranted to confirm these preliminary findings and to identify other long-term prognostic factors in this setting.  

The role of inherited thrombophilia in patients with isolated pulmonary embolism: a systematic review and a meta-analysis of the literature.

INTRODUCTION: Venous thromboembolism (VTE) is a common vascular disease that results in deep venous thrombosis (DVT) and pulmonary embolism (PE). Factor V Leiden mutation (FVL) and G20210A prothrombin mutation (PTM) are associated with an increased risk of VTE. Recent studies have reported a lower prevalence of FVL in patients with isolated PE than in patients with DVT with or without PE, suggesting the possibility that the prevalence of FVL in patients with isolated PE may be not significantly different from that of the general population. To address this issue, we performed a systematic review and a meta-analysis of published studies that assessed the prevalence of FVL and/or PTM in patients with isolated PE and in controls without VTE. METHODS: MEDLINE and EMBASE databases were searched up to October 2013. Pooled odds Ratios (OR) and 95% confidence intervals (CIs) were calculated using a random-effects model. Statistical heterogeneity was evaluated using the Cochran Q and I(2) statistics. RESULTS: Eighteen studies totalling more than 11,000 patients were included. FVL was found significantly more often in patients presenting isolated PE than in controls (OR 2.06; 95% CI 1.66, 2.56; p <0.0001). The prevalence of PTM was also significantly different in patients presenting with isolated PE than in controls (OR 2.64, 95% CI 1.92, 3.63; p<0.0001). Heterogeneity among studies was low. CONCLUSION: FVL and PTM are both associated with isolated PE. However, the association magnitude between PE and FVL mutation appeared to be lower compared to that observed in the general population of VTE patients.

Evaluation of right ventricular function in patients with a previous episode of pulmonary embolism using tissue Doppler imaging.

New echocardiographic techniques including tricuspid annular plane systolic excursion (TAPSE) and pulsed tissue Doppler imaging (TDI) of the right ventricular wall have been assessed to better define right ventricular dysfunction (RVD) during the acute phase of pulmonary embolism (PE) in patients without significant tricuspidal insufficiency. Their application in patients with a previous history of PE may provide a better estimation of the incidence and clinical significance of long-term functional impairment of the right ventricle. In a case-control study, we compared the prevalence of RVD in a cohort of consecutive patients with previous PE and in age and sex-matched controls without PE. Exclusion criteria were moderate-severe left heart failure, moderate-severe mitral valve regurgitation, severe tricuspid insufficiency, or other causes of chronic pulmonary hypertension. Systolic and diastolic right ventricular functions were evaluated by measuring TAPSE and TDI of the right ventricular wall. Twenty-five patients with a previous first episode of PE and 25 controls were enrolled. Mean value of TAPSE was similar between patients with previous PE and controls (2.58 ± 0.33 and 2.53 ± 0.35 cm, P = ns). In patients with PE, the mean value of E″/A″ was significantly lower than in controls (0.89 ± 0.24 vs. 1.30 ± 0.39, P < 0.001), with 14 out of 25 cases having diastolic dysfunction as compared to only 3 out of 25 controls (P < 0.002). A high proportion of patients with previous PE have echocardiographic signs of RV diastolic dysfunction 6 months after the acute phase, even in the absence of symptoms, and in the presence of normal pulmonary pressures.

Neutrophils and clinical outcomes in patients with acute coronary syndromes and/or cardiac revascularisation. A systematic review on more than 34,000 subjects.

Some studies have suggested that high levels of total white blood cell (WBC) count and C-reactive protein (CRP) may be considered as independent prognostic factors in patients with acute coronary syndromes (ACS) and/or after cardiac revascularisation by percutaneous coronary intervention or coronary artery bypass grafting surgery. Evidence on the role of neutrophils in cardiovascular disease is less compelling. Therefore, we conducted a systematic review of the literature with the aim of identifying all the available evidence to clarify the role of neutrophils (absolute or relative count, neutrophil/lymphocyte ratio) as a prognostic risk factor in patients with ACS and/or cardiac revascularisation. All published studies evaluating the role of neutrophils as a risk factor for clinical outcomes were assessed using the MEDLINE and EMBASE databases. Study selection, data extraction and validity assessment was performed independently by two reviewers. Twenty-one studies (17 of which had positive results) for a total of more than 34,000 patients were included. Ten of 13 studies in ACS patients found that neutrophils measured on-admission are related to mortality rate and/or to major adverse clinical events. A predictive value of neutrophils after cardiac revascularisation procedures was reported in seven out of eight studies. Most of the studies showed that neutrophils were independent predictors of cardiovascular outcomes when analysed concomitantly with other markers of inflammation (WBC, CRP). The findings of our systematic review highlight the potential application of this inexpensive and readily available inflammatory marker for risk stratification in patients with ACS and/or cardiac revascularisation.

Use of statins and recurrence of atrial fibrillation after catheter ablation or electrical cardioversion. A systematic review and meta-analysis.

Statins have important pleiotropic effects and have been shown to reduce vascular inflammation. Some evidence suggests that statins may have a role in the primary prevention of atrial fibrillation (AF), whereas little is know on the role of statins in patients with existing AF. We performed a meta-analysis of the literature to assess the effect of statins on the recurrence of AF after electrical cardioversion or ablation. MEDLINE and EMBASE databases were searched up to January 2010. Relative risks (RR) and 95% confidence intervals (CIs) were then calculated and pooled using a random-effects model. Statistical heterogeneity was evaluated through the use of I² statistics. Sixteen studies were included in our systematic review. Statins did not reduce the risk of AF recurrence after ablation (four studies including 750 patients; RR, 1.04; 95% CI, 0.85-1.28, p=0.71; I² = 34%). Conversely, the use of statins was associated with a significantly reduced risk of AF recurrence after electrical cardioversion (12 studies including 1790 patients; RR, 0.78; 95% CI, 0.67-0.90, p=0.0003; I² = 34%). This reduction was not statistically significant when the analysis was restricted to randomised controlled trials (RCTs) only (five studies, 458 patients, RR, 0.76; 95% CI, 0.48-1.20). In conclusion, statins may lower the risk of AF recurrence after electrical cardioversion, but not ablation. However, this finding should be considered with caution, and larger RCTs are warranted to confirm our preliminary results.

Safety of thrombolysis in cerebral venous thrombosis. A systematic review of the literature.

Several small series have suggested the efficacy of thrombolysis in patients with cerebral vein thrombosis (CVT). However, since no randomised controlled trials have compared the use of thrombolysis with anticoagulant treatment in these patients, the risk to benefit ratio of this approach remains uncertain. The aim of this study is therefore to assess the safety of thrombolysis in CVT estimating mortality and major bleeding complications. MEDLINE and EMBASE databases were searched up to June 2010. Two reviewers performed study selection independently. Studies providing data on mortality and/or on the incidence of major bleeding complications were potentially eligible for the study. Two reviewers independently extracted data on study and population characteristics, type, dose and administration route of thrombolytic treatment; use and dose of concomitant heparin. Weighted mean proportion of the mortality rate and of the rate of major and non-major bleeding complications were calculated. Fifteen studies for a total of 156 patients were included. Twelve patients died after thrombolysis (weighted mean 9.2%; 95% CI 4.3, 15.7%) and 15 patients had a major bleeding complication (weighted mean 9.8%; 95% CI 5.3, 15.6%). Twelve haemorrhages were intracranial (weighted mean 7.6%; 95% CI 3.5, 13.1%), and seven of these patients died (58.3%; 95% CI 32.0, 80.7%). Our results suggest that thrombolysis is associated with a non-negligible incidence of major bleeding complications, including intracranial bleeding potentially affecting patients outcome. Future studies are necessary to evaluate the safety of thrombolysis in comparison to more conservative strategies.

5 flourouracil-induced apical ballooning syndrome: a case report.

The apical ballooning syndrome (ABS) is a recently described stress-mediated acute cardiac syndrome characterized by transient wall-motion abnormalities involving the apex and midventricle with hyperkinesis of the basal left ventricular (LV) segments without obstructive epicardial coronary disease. Cardiotoxicity is not an uncommon adverse effect of chemotherapeutic agents. However, there are no reports of ABS secondary to chemotherapeutic agents. We describe the case of a woman who developed the syndrome after chemotherapy for metastatic cancer. A 79-year-old woman presented with typical ischemic chest pain, elevated cardiac enzymes with significant ST-segment abnormalities on her electrocardiogram. She underwent recent chemotherapy with fluorouracil for metastatic colorectal cancer. Echocardiography revealed a wall-motion abnormality involving the apical and periapical segments which appeared akinetic. Coronary angiography revealed no obstructive coronary lesions. The patient was stabilized with medical therapy. Four weeks later she remained completely asymptomatic. Echocardiogram revealed a normal ejection fraction and a resolution of the apical akinesis. Pathogenetic mechanisms of cardiac complications in cancer patients undergoing chemotherapy include coronary vasospasm, endothelial damage and consequent thrombus formation. In our patient, both supraphysiologic levels of plasma catecholamines and stress related neuropeptides caused by cancer diagnosis as well as chemotherapy may have contributed the development of ABS.

Incidence of chronic pulmonary hypertension in patients with previous pulmonary embolism.

INTRODUCTION: The true incidence of chronic thromboembolic pulmonary hypertension (CTPH) remains a matter of debate. Symptomatic CTPH is probably more common than previously reported, whereas the occurrence of asymptomatic CTPH has not been defined since very limited evidence on the incidence of asymptomatic CTPH diagnosed with echocardiography Doppler are currently available. We therefore carried out a prospective cohort study to assess the incidence of CTPH diagnosed with echocardiography Doppler in consecutive patients with a first episode of PE. METHODS: Consecutive patients with a first episode of PE were evaluated with Doppler transthoracic echocardiography within 6 to 12 months after the index event. Pulmonary hypertension was defined as a systolic pulmonary artery pressure > or =40 mmHg at rest in the presence of residual perfusion defects at perfusion scintigraphy. Presence of symptoms related to pulmonary hypertension was evaluated with a standardized questionnaire. RESULTS: Ninety-one patients (mean age 61.9+/-15.7 years; range 22-89; 39 men) were enrolled. Eight patients (8.8%; 95% CI 4.5,16.4) had CTPH: of these, 4 (4.4%; 95% CI 2.0, 9.3) were symptomatic. CONCLUSIONS: Asymptomatic CTPH is not an uncommon finding after PE. Larger prospective trials with a longer follow up should assess the prognostic significance of asymptomatic CPTH.