Non-fatal Adverse Events Research Articles

The Effect of Defining Chronic Obstructive Pulmonary Disease by the Lower Limit of Normal of FEV1/FVC Ratio in Tiotropium Safety and Performance in Respimat Participants.

There is continuing debate about whether to define airflow obstruction by a post-bronchodilator ratio of forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) below 0.70, or by ratio values falling below the age-dependent lower limit of normal (LLN) derived from general population data. To determine whether using the LLN criterion affects the classification and outcomes of patients previously defined as having chronic obstructive pulmonary disease by the fixed FEV1/FVC ratio. We applied the LLN definition to pooled data from the Tiotropium Safety and Performance in Respimat study that used the fixed FEV1/FVC ratio for the clinical diagnosis of chronic obstructive pulmonary disease. A total of 17,072 patients were analyzed; of these, 1,807 (10.6%) patients had a ratio greater than or equal to LLN. Patients with a ratio greater than or equal to LLN had similar risks of death from any cause and fatal major adverse cardiovascular (CV) event as those below LLN. Patients with a ratio below LLN had a significantly lower risk of major adverse CV events (hazard ratio = 0.69; 95% confidence interval [CI] = 0.55-0.86; P = 0.001), and had significantly greater risks of moderate to severe exacerbation (rate ratio = 1.48; 95% CI = 1.36-1.61; P < 0.0001) and severe exacerbation (rate ratio = 2.01; 95% CI = 1.68-2.40; P < 0.0001) when compared with patients greater than or equal to LLN. Study outcomes by treatment arm (5 μg tiotropium Respimat vs. 18 μg HandiHaler) were comparable. Using the LLN to define airflow obstruction would have excluded patients in the Tiotropium Safety and Performance in Respimat study with a higher risk of nonfatal major adverse CV events and a lower risk of exacerbation; study outcomes by treatment arm (2.5 μg/5 μg tiotropium Respimat vs. 18 μg HandiHaler) remained similar. Clinical trial registered with www.clinicaltrials.gov (NCT01126437).

Can machine learning complement traditional medical device surveillance? A case study of dual-chamber implantable cardioverter-defibrillators.

BackgroundMachine learning methods may complement traditional analytic methods for medical device surveillance.Methods and resultsUsing data from the National Cardiovascular Data Registry for implantable cardioverter–defibrillators (ICDs) linked to Medicare administrative claims for longitudinal follow-up, we applied three statistical approaches to safety-signal detection for commonly used dual-chamber ICDs that used two propensity score (PS) models: one specified by subject-matter experts (PS-SME), and the other one by machine learning-based selection (PS-ML). The first approach used PS-SME and cumulative incidence (time-to-event), the second approach used PS-SME and cumulative risk (Data Extraction and Longitudinal Trend Analysis [DELTA]), and the third approach used PS-ML and cumulative risk (embedded feature selection). Safety-signal surveillance was conducted for eleven dual-chamber ICD models implanted at least 2,000 times over 3 years. Between 2006 and 2010, there were 71,948 Medicare fee-for-service beneficiaries who received dual-chamber ICDs. Cumulative device-specific unadjusted 3-year event rates varied for three surveyed safety signals: death from any cause, 12.8%–20.9%; nonfatal ICD-related adverse events, 19.3%–26.3%; and death from any cause or nonfatal ICD-related adverse event, 27.1%–37.6%. Agreement among safety signals detected/not detected between the time-to-event and DELTA approaches was 90.9% (360 of 396, k=0.068), between the time-to-event and embedded feature-selection approaches was 91.7% (363 of 396, k=−0.028), and between the DELTA and embedded feature selection approaches was 88.1% (349 of 396, k=−0.042).ConclusionThree statistical approaches, including one machine learning method, identified important safety signals, but without exact agreement. Ensemble methods may be needed to detect all safety signals for further evaluation during medical device surveillance.

The CECARI Study: Everolimus (Certican®) Initiation and Calcineurin Inhibitor Withdrawal in Maintenance Heart Transplant Recipients with Renal Insufficiency: A Multicenter, Randomized Trial.

In this 3-year, open-label, multicenter study, 57 maintenance heart transplant recipients (>1 year after transplant) with renal insufficiency (eGFR 30–60 mL/min/1.73 m2) were randomized to start everolimus with CNI withdrawal (N = 29) or continue their current CNI-based immunosuppression (N = 28). The primary endpoint, change in measured glomerular filtration rate (mGFR) from baseline to year 3, did not differ significantly between both groups (+7.0 mL/min in the everolimus group versus +1.9 mL/min in the CNI group, p = 0.18). In the on-treatment analysis, the difference did reach statistical significance (+9.4 mL/min in the everolimus group versus +1.9 mL/min in the CNI group, p = 0.047). The composite safety endpoint of all-cause mortality, major adverse cardiovascular events, or treated acute rejection was not different between groups. Nonfatal adverse events occurred in 96.6% of patients in the everolimus group and 57.1% in the CNI group (p < 0.001). Ten patients (34.5%) in the everolimus group discontinued the study drug during follow-up due to adverse events. The poor adherence to the everolimus therapy might have masked a potential benefit of CNI withdrawal on renal function.

Long-term secondary prevention of acute myocardial infarction (SEPAT) - guidelines adherence and outcome.

BackgroundA number of registry studies have reported suboptimal adherence to guidelines for cardiovascular prevention during the first year after acute myocardial infarction (AMI). However, only a few studies have addressed long-term secondary prevention after AMI. This study evaluates prevention guideline adherence and outcome of guideline-directed secondary prevention in patients surviving 2 years after AMI.MethodsPatients aged 18–85 years at the time of their index AMI were consecutively identified from hospital discharge records between July 2010 and December 2011 in Gothenburg, Sweden. All patients who agreed to participate in the study (16.2%) were invited for a structured interview, physical examinations and laboratory analysis 2 years after AMI. Guideline-directed secondary preventive goals were defined as optimally controlled blood pressure, serum cholesterol, glucose, regular physical activity, smoking cessation and pharmacological treatment.ResultsThe mean age of the study cohort (n = 200) at the index AMI was 63.0 ± 9.7 years, 79% were men. Only 3.5% of the cohort achieved all six guideline-directed secondary preventive goals 2 years after infarction. LDL < 1.8 mmol/L was achieved in 18.5% of the cohort, regular exercise in 45.5% and systolic blood pressure <140 mmHg in 57.0%. Anti-platelet therapy was used by 97% of the patients, beta-blockers by 83.0%, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers by 76.5% and statins by 88.5%. During follow-up, non-fatal adverse cardiovascular events (cardiac hospitalization, recurrent acute coronary syndrome, angina pectoris, new percutaneous coronary intervention, new onset of atrial fibrillation, post-infarct heart failure, pacemaker implantation, stroke/transient ischemic attack (TIA), cardiac surgery and cardiac arrest) occurred in 47% of the cohort and readmission due to cardiac causes in 30%.ConclusionsOur data showed the failure of secondary prevention in our daily clinical practice and high rate of non-fatal adverse cardiovascular events 2 years after AMI.

Combination inhaled steroid and long-acting beta₂-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease.

The long-acting bronchodilator tiotropium and single-inhaler combination therapy of inhaled corticosteroids and long-acting beta2-agonists (ICS/LABA) are commonly used for maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Combining these treatments, which have different mechanisms of action, may be more effective than administering the individual components. To assess relative effects of the following treatments on markers of exacerbations, symptoms, quality of life and lung function in patients with COPD.• Tiotropium plus LABA/ICS versus tiotropium.• Tiotropium plus LABA/ICS versus LABA/ICS. We searched the Cochrane Airways Group Specialised Register of Trials (April 2015), ClinicalTrials.gov (www.ClinicalTrials.gov), the World Health Organization (WHO) trials portal and reference lists of relevant articles. We included parallel, randomised controlled trials (RCTs) lasting three months or longer conducted to compare ICS and LABA combination therapy in addition to inhaled tiotropium versus tiotropium alone or combination therapy alone. We independently assessed trials for inclusion, then extracted data on trial quality and outcome results. We contacted study authors to ask for additional information. We collected trial information on adverse effects. Tiotropium plus LABA/ICS versus tiotropiumWe included six studies (1902 participants) with low risk of bias that compared tiotropium in addition to inhaled corticosteroid and long-acting beta2-agonist combination therapy versus tiotropium alone. Investigators found no statistically significant differences in mortality between treatments (odds ratio (OR) 1.80, 95% confidence interval (CI) 0.55 to 5.91; two studies; 961 participants), a reduction in all-cause hospitalisations with the use of combined therapy (tiotropium + LABA/ICS) (OR 0.61, 95% CI 0.40 to 0.92; two studies; 961 participants; number needed to treat for an additional beneficial outcome (NNTB) 19.7, 95% CI 10.75 to 123.41). The effect on exacerbations was heterogeneous among trials and was not meta-analysed. Health-related quality of life measured by St. George's Respiratory Questionnaire (SGRQ) showed a statistically significant improvement in total scores with use of tiotropium + LABA/ICS compared with tiotropium alone (mean difference (MD) -3.46, 95% CI -5.05 to -1.87; four studies; 1446 participants). Lung function was significantly different in the combined therapy (tiotropium + LABA/ICS) group, although average benefit with this therapy was small. None of the included studies included exercise tolerance as an outcome.A pooled estimate of these studies did not show a statistically significant difference in adverse events (OR 1.16, 95% CI 0.92 to 1.47; four studies; 1363 participants), serious adverse events (OR 0.86, 95% CI 0.57 to 1.30; four studies; 1758 participants) and pneumonia (Peto OR 1.62, 95% CI 0.54 to 4.82; four studies; 1758 participants). Tiotropium plus LABA/ICS versus LABA/ICSOne of the six studies (60 participants) also compared combined therapy (tiotropium + LABA/ICS) versus LABA/ICS therapy alone. This study was affected by lack of power; therefore results did not allow us to draw conclusions for this comparison. In this update, we found new moderate-quality evidence that combined tiotropium + LABA/ICS therapy compared with tiotropium plus placebo decreases hospital admission. Low-quality evidence suggests an improvement in disease-specific quality of life with combined therapy. However, evidence is insufficient to support the benefit of tiotropium + LABA/ICS for mortality and exacerbations (moderate- and low-quality evidence, respectively). Of note, not all participants enrolled in the included studies would be candidates for triple therapy according to current international guidance.Compared with the use of tiotropium plus placebo, tiotropium + LABA/ICS-based therapy does not increase undesirable effects such as adverse events or serious non-fatal adverse events.

Effectiveness, durability, and safety of darunavir/ritonavir in HIV-1-infected patients in routine clinical practice in Italy: a postauthorization noninterventional study.

Current antiretroviral (ARV) therapy for the treatment of human immunodeficiency virus (HIV-1)-infected patients provides long-term control of viral load (VL). Darunavir (DRV) is a nonpeptidomimetic protease inhibitor approved for use with a ritonavir booster (DRV/r). This study evaluated the effectiveness of DRV/r in combination with other ARV agents in routine clinical practice in Italy. In this descriptive observational study, data on utilization of DRV/r, under the conditions described in the marketing authorization, were collected from June 2009 to December 2012. Effectiveness (VL <50 copies/mL), tolerability, and durability in four patient groups (two DRV/r-experienced, one ARV-experienced DRV/r-naïve, and one ARV-naïve) were analyzed. Secondary objectives included immunological response, safety, and persistence/discontinuation rates. In total, 875 of 883 enrolled patients were included in the analysis: of these, 662 (75.7%) completed the follow-up until the end of 2012 and 213 (24.3%) withdrew from the study earlier. Initial DRV dose was 600 mg twice daily (67.1%) or 800 mg once daily (32.9%). Only 16 patients (1.8%) withdrew from the study due to virological failure. Virological response proportions were higher in patients virologically suppressed at study entry versus patients with baseline VL ≥50 copies/mL in each ARV-experienced group, while there was no consistent difference across study groups and baseline VL strata according to baseline CD4+ cell count. CD4+ cell count increased from study entry to last study visit in all the four groups. DRV/r was well tolerated, with few discontinuations due to study-emergent nonfatal adverse events (3.0% overall, including 2.1% drug-related) or deaths (3.0% overall, all non-drug-related); 35.3% of patients reported ≥1 adverse events. These observational data show that DRV/r was effective and well tolerated in the whole patient population described here. The DRV/r-containing regimen provided viral suppression in a high percentage of patients in all groups, with low rates of discontinuation due to virological failure.

Blood pressure lowering efficacy of coenzyme Q10 for primary hypertension.

Blood pressure is a commonly measured risk factor for non-fatal and fatal cardiovascular adverse events such as heart attacks and strokes. Clinical trials have suggested that coenzyme Q10, a non-prescription nutritional supplement, can effectively lower blood pressure (BP). When this review was completed and published in October 2009, it concluded that "due to the possible unreliability of the 3 included studies, it is uncertain whether or not coenzyme Q10 reduces blood pressure in the long-term management of primary hypertension." To determine the blood pressure lowering effect of coenzyme Q10 in primary hypertension. We searched the Hypertension Group Specialised Register (1946 to November 2015), The Cochrane Central Register of Controlled Trials (The Cochrane Library 2015, Issue 10), MEDLINE (1946 to November 2015), MEDLINE In-Process (accessed 10 November 2015), EMBASE (1974 to November 2015), Web of Science (1899 to November 2015), CINAHL (1970 to November 2015), and ClinicalTrials.gov (accessed 10 November 2015). We also searched reference lists of articles for relevant clinical trials in any language. Double blind, randomized, placebo-controlled parallel or cross-over trials evaluating the blood pressure (BP) lowering efficacy of coenzyme Q10 for a duration of at least three weeks, in patients with primary hypertension. The primary author determined trial inclusion, extracted the data and assessed the risk of bias. The second author independently verified trial inclusion and data extraction. In this update of the review, one new randomized, controlled cross-over trial with a total of 30 participants was added, and one trial included in the initial review was excluded. Only two of the three included trials were pooled in the meta-analysis, as one trial was judged to have an unacceptably high risk of bias. In the meta-analysis of two RCTs (50 participants), coenzyme Q10 did not significantly change systolic BP: -3.68 mm Hg (95% confidence interval (CI) -8.86 to 1.49), or diastolic BP: -2.03 mm Hg (95% CI -4.86 to 0.81] ), based on clinic data. This review provides moderate-quality evidence that coenzyme Q10 does not have a clinically significant effect on blood pressure. In one of three trials reporting adverse effects, coenzyme Q10 was well tolerated. Due to the small number of individuals and studies available for analysis, more well-conducted trials are needed.

Statins for the prevention of dementia.

This is an update of a Cochrane review first published in 2001 and then updated in 2009. Vascular risk factors including high cholesterol levels increase the risk of dementia due to Alzheimer's disease and of vascular dementia. Some observational studies have suggested an association between statin use and lowered incidence of dementia. To evaluate the efficacy and safety of statins for the prevention of dementia in people at risk of dementia due to their age and to determine whether the efficacy and safety of statins for this purpose depends on cholesterol level, apolipoprotein E (ApoE) genotype or cognitive level. We searched ALOIS (the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, ClinicalTrials.gov and the World Health Organization (WHO) Portal on 11 November 2015. We included double-blind, randomised, placebo-controlled trials in which statins were administered for at least 12 months to people at risk of dementia. We used standard methodological procedures expected by Cochrane. We included two trials with 26,340 participants aged 40 to 82 years of whom 11,610 were aged 70 or older. All participants had a history of, or risk factors for, vascular disease. The studies used different statins (simvastatin and pravastatin). Mean follow-up was 3.2 years in one study and five years in one study. The risk of bias was low. Only one study reported on the incidence of dementia (20,536 participants, 31 cases in each group; odds ratio (OR) 1.00, 95% confidence interval (CI) 0.61 to 1.65, moderate quality evidence, downgraded due to imprecision). Both studies assessed cognitive function, but at different times using different scales, so we judged the results unsuitable for a meta-analysis. There were no differences between statin and placebo groups on five different cognitive tests (high quality evidence). Rates of treatment discontinuation due to non-fatal adverse events were less than 5% in both studies and there was no difference between statin and placebo groups in the risk of withdrawal due to adverse events (26,340 participants, 2 studies, OR 0.94, 95% CI 0.83 to 1.05). There is good evidence that statins given in late life to people at risk of vascular disease do not prevent cognitive decline or dementia. Biologically, it seems feasible that statins could prevent dementia due to their role in cholesterol reduction and initial evidence from observational studies was very promising. However, indication bias may have been a factor in these studies and the evidence from subsequent RCTs has been negative. There were limitations in the included studies involving the cognitive assessments used and the inclusion of participants at moderate to high vascular risk only.

Health care resource utilization and costs associated with nonfatal major adverse cardiovascular events.

Risk of recurrent cardiovascular events following an initial cardiovascular-related hospitalization remains high despite available interventions. Rates of cardiovascular events as well as associated health care resource utilization and costs are needed to assess the value of treatments. To quantify, in patients with previous hospitalization for acute coronary syndrome (ACS), rates of nonfatal major adverse cardiovascular events (MACE) and secondary coronary events (SCE), as well as health care utilization and costs associated with a first MACE. Administrative data from a large population of commercial managed care and managed Medicare enrollees in the United States were retrospectively analyzed. Patients with an ACS-related hospitalization from 2006 to 2011 were followed for 12 months to assess subsequent MACE and SCE rates. Patients were aged ≥ 18 years at initial ACS hospitalization (the index episode) and had ≥ 12 months of continuous health plan enrollment before and after the end of the index episode. Resource utilization and costs during a first MACE were assessed. Multivariable analyses were used to assess the associations between cardiovascular risk factors and the occurrence of a MACE, as well as the costs incurred during a first MACE. Of 75,231 study patients identified, 3.3% had a MACE and 8.3% had an SCE during the 12-month follow-up. Median time to first MACE and SCE from end of the index episode was 4.6 and 3.7 months, respectively. Mean MACE-related cost incurred during the first MACE was $19,642. Logistic analyses showed that age and diabetes were associated with increased odds of a MACE, while index ACS episodes involving ST-elevation myocardial infarction were associated with reduced odds. Findings from generalized linear models indicated that statin use and age were associated with lower episode-related costs and that MACE occurrence within 3 months of ACS hospitalization was associated with increased episode-related costs. MACEs and SCEs represent a common and costly burden in the year following ACS hospitalization. Our findings may inform future economic assessments of new therapies aimed at prevention of MACEs and SCEs.

Abstract 359: Duke Activity Status Index is Sensitive to Non-Fatal Adverse Cardiac Events when Evaluating Patient Outcome at Late Follow-up

Objective: The Duke Activity Status Index (DASI) questionnaire has become an established measure of cardiac functional capacity and quality of life. However, the relationship between a low DASI score and presence of major adverse cardiac events has not yet been assessed. This study evaluates differences in patient function and occurrence of late cardiac events in patients undergoing coronary artery bypass (CAB). Methods: Patients undergoing CAB between 1994 and 2014 at the Valley Hospital were assessed and propensity matched for surgical approach. The resulting population of 1856 patients was followed for a mean time of 11.2 years ranging from 1 to 20 year. Survival, occurrence of MI, stroke, repeat revascularization and patient function using the DASI questionnaire were assessed. At the latest follow-up, 1363 patients were still alive, of which 776 had completed the DASI questionnaire. Patients who completed the questionnaire (Responders) were compared to those who did not complete the DASI (Non-Responders) on baseline demographic and clinical characteristics. Kaplan-Meier and Cox Proportional Hazards Regression were used to compare late non-fatal events that occurred in patients with a low (&lt;37, N=247), medium (37-52, N=209), or high (&gt;52, N=310) DASI score. Results: Responders had a higher rate of prior MI, increased hypertension, and were significantly older at baseline procedure compared to Non-Responders. Both groups had comparable surgical risk and left ventricle ejection fraction at baseline revascularization. Kaplan-Meier analysis of the Responders showed that patients with a low scoring DASI had significantly greater occurrence of all late events. Cox Regression analysis controlling for all baseline factors showed that patients with a low DASI score had a two-fold increase in late non-fatal events compared to medium and high DASI scoring patients (adjusted hazard ratio: 2.076, 95% C.I. 1.309-3.293, p=0.002) (Figure 1). Conclusions: This study demonstrates that in cardiac surgical patients, a low score on DASI is independently associated with a higher occurrence of late non-fatal cardiac events. This provides further evidence supporting the use of the DASI questionnaire in evaluating patient functioning after cardiac surgery.

Presentation, Treatment and Outcomes of Acute Coronary Syndrome in a Tertiary Care Hospital in Central Nepal

INTRODUCTION: Nepal is facing with increasing rate of coronary artery disease, yet little is known about presentation, treatment and outcome of this disease in our population and our setting. We aimed to document the characteristics in consecutive cases in a tertiary level hospital. MATERIAL AND METHODS: Seventy eight total cases were documented in six months period and evaluated the data on presentation, management, in-hospital mortality and non-fatal adverse cardiovascular event (MACE). RESULTS: Mean (SD) age at presentation was 65 (13) years and did not differ among acute coronary syndrome (ACS) types (STEMI= 23%, Non ST Elevation Myocardial Infarction (NSTEMI)= 28%, UA= 49%). ACS is still a disease prevalent in &gt;50 years of age (88%). Dual antiplatelet agents and statin were used &gt;90% cases and coronary angiography was performed in ~50% cases. Unstable angina patients has significantly higher number of normal coronaries or non- critical stenosis. Percutaneous coronary intervention rates were significantly higher among STEMI admissions (38% vs 22 % vs 13%, P= 0.003). Unadjusted in-hospital mortality rate was 11%, significantly higher than NSTEMI (5%) and UA (5%). Non-fatal major MACE rate including reinfarction, heart failure or cardiogenic shock was also high in STEMI and NSTEMI patients than in unstable angina patients. CONCLUSION: This study represents contemporary practice of ACS care and provides opportunity to improve care for symptom recognition, treatment options and medical therapy.DOI: http://dx.doi.org/10.3126/jucms.v2i4.12036Journal of Universal College of Medical Sciences (2014) Vol.02 No.04 Issue 08Page: 11-14

Culprit vessel only vs immediate complete revascularization in patients with acute ST-segment elevation myocardial infarction: systematic review and meta-analysis.

Although multivessel coronary artery disease has been associated with poor health outcomes in patients with acute ST-segment elevation myocardial infarction (STEMI), the optimal approach to revascularization remains uncertain. The objective of this review was to determine the benefits and harms of culprit vessel only vs immediate complete percutaneous coronary intervention (PCI) in patients with acute STEMI. We searched MEDLINE, EMBASE, the Cochrane Register of Controlled Trials, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) for randomized controlled trials (RCTs). Teams of 2 reviewers, independently and in duplicate, screened titles and abstracts, completed full-text reviews, and abstracted data. We calculated pooled risk ratios (RRs) and associated 95% confidence intervals (CIs) using random-effect models for nonfatal myocardial infarction (MI), revascularization, cardiovascular mortality, all-cause mortality, and adverse events, and used the GRADE approach to rate confidence in estimates of effect. Of 341 patients randomized to complete revascularization and followed to study conclusion, 31 experienced revascularization, as did 80 of 324 randomized to culprit vessel only revascularization (RR: 0.35, 95% CI: 0.24-0.53). Ten patients in the complete revascularization group and 28 patients in the culprit vessel only revascularization group experienced nonfatal MI (RR: 0.35, 95% CI: 0.17-0.72). All-cause mortality and cardiac deaths did not differ between groups (RR: 0.69, 95% CI: 0.40-1.21 for all-cause mortality; RR: 0.48, 95% CI: 0.22-1.04 for cardiac deaths). Pooled data from 3 RCTs suggest that immediate complete revascularization probably reduces revascularization in patients with acute STEMI; although results suggest possible benefits on MI and death, confidence in estimates is low.

Ninety-day postdischarge outcomes of inpatient elective laparoscopic cholecystectomy

Little information is available about postdischarge adverse events after laparoscopic cholecystectomy. Inpatient and 90-day postdischarge adverse events were identified for Medicare patients discharged in 2009-2010 after undergoing elective laparoscopic cholecystectomy on day 0, 1, or 2 of hospitalization at facilities that performed 20 or more laparoscopic cholecystectomies during the study period. A predictive length of stay (LOS) linear regression model was derived and used to identify patients with prolonged LOS (prLOS) whose risk-adjusted LOS exceeded a 3σ upper limit on a moving average control chart. Rates of inpatient and 90-day fatal and nonfatal adverse events and interrelationships among different outcomes and alternative outcome measures were explored. Of 89,639 study cases, 0.7% died during their index hospitalization, and 1.3% died within 90days of discharge. Of live discharges, 8.0% had prLOS, and 42.1% had coded complication. In the 90days after discharge, 9,416 (10.6%) were readmitted. Patients who were prLOS outliers were more likely to die or be readmitted than nonoutliers (P<.0001; χ(2)). More than 18% of Medicare patients undergoing presumably low-risk elective inpatient laparoscopic cholecystectomy died, had a severe inpatient complication, or were readmitted within 90days of discharge.

Everolimus-based calcineurin-inhibitor sparing regimens for kidney transplant recipients: a systematic review and meta-analysis.

Calcineurin inhibitors (CNI) associated nephrotoxicity remains a risk factor for long-term graft dysfunction after renal transplantation. Everolimus is a mammalian target of rapamycin inhibitor and exhibits synergistic immunosuppressive activity with CNI to permit CNI-reduction. We conducted a systematic review to compare the efficacy of everolimus-based CNI sparing and standard CNI regimens in renal transplantation recipients. We searched PubMed and Web of Science databases to identify relevant randomized controlled trials. Glomerular filtration rate (GFR), biopsy-proven acute rejection (BPAR), death or graft loss and incidence of adverse events were the major estimates of renal function, efficacy, and tolerability of the two regimens. Seven studies providing data for 2,067 patients were included. Six of the seven studies used cyclosporine as the CNI. The patients were divided into two groups: everolimus-based CNI sparing (elimination and minimization) group and standard CNI group. Everolimus-based regimen was associated with increased GFR [P = 0.02; weighted mean difference (WMD) 4.83 mL/min], decreased serum creatinine (P = 0.004; WMD -9.94 μmol/L) and no more death or graft loss [P = 0.72; relative risk (RR) 1.07]. CNI-minimization was not associated with increased BPAR (P = 0.25; RR 0.85) while CNI-elimination was associated with more BPAR Grade 1 (P < 0.00001; RR 4.20). Use of everolimus reduced the risk of CMV infection (P = 0.0002; RR 0.47). There was a higher risk of discontinuation of everolimus (P < 0.00001; RR 1.69) and non-fatal adverse events (P < 0.00001; RR 1.73) in patients on the everolimus based CNI sparing regimens. Everolimus-based CNI sparing regimen could optimize long-term graft function without leading to more death or graft loss. Although CNI elimination was associated with higher risk of BPAR, everolimus use with CNI minimization did not increase the risk of acute rejections. Use of everolimus was associated with reduction in the incidence of CMV infection, but there was a higher risk of discontinuation of this drug and other non-fatal adverse events.

Cost-effectiveness of metformin plus vildagliptin compared with metformin plus sulphonylurea for the treatment of patients with type 2 diabetes mellitus: a Portuguese healthcare system perspective

Objective:To evaluate the cost-effectiveness of vildagliptin plus metformin vs generic sulphonylurea plus metformin in patients with type 2 diabetes mellitus, not controlled with metformin, from a Portuguese healthcare system perspective.Methods:A cost-effectiveness model was constructed using risk equations from the UK Prospective Diabetes Study Outcomes Model with a 10,000-patient cohort and a lifetime horizon. The model predicted microvascular and macrovascular complications and mortality in yearly cycles. Patients entered the model as metformin monotherapy failures and switched to alternative treatments (metformin plus basal-bolus insulin and subsequently metformin plus intensive insulin) when glycated hemoglobin A1c >7.5% was reached. Baseline patient characteristics and clinical variables were derived from a Portuguese epidemiological study. Cost estimates were based on direct medical costs only. One-way and probabilistic sensitivity analyses were conducted to test the robustness of the model.Results:There were fewer non-fatal diabetes-related adverse events (AEs) in patients treated with metformin plus vildagliptin compared with patients treated with metformin plus sulphonylurea (6752 vs 6815). Addition of vildagliptin compared with sulphonylurea led to increased drug acquisition costs but reduced costs of AEs, managing morbidities, and monitoring patients. Treatment with metformin plus vildagliptin yielded a mean per-patient gain of 0.1279 quality-adjusted life years (QALYs) and a mean per-patient increase in total cost of €1161, giving an incremental cost-effectiveness ratio (ICER) of €9072 per QALY. Univariate analyses showed that ICER values were robust and ranged from €4195 to €16,052 per QALY when different parameters were varied.Limitations:The model excluded several diabetes-related morbidities, such as peripheral neuropathy and ulceration, and did not model second events. Patients were presumed to enter the model with no diabetes-related complications.Conclusion:Treatment with metformin plus vildagliptin compared with metformin plus sulphonylurea is expected to result in a lower incidence of diabetes-related AEs and to be a cost-effective treatment strategy.

Skin Autofluorescence, 5-Year Mortality, and Cardiovascular Events in Peripheral Arterial Disease

The hunt for predictive biomarkers in diseases of the cardio-, cerebro-, and peripheral vascular systems is an ongoing effort and one whose importance cannot be overstated. The identification of subjects most at risk for death or major adverse cardiovascular events may provide a means to stratify diagnostic and therapeutic interventions based on validated predictive algorithms. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , de Vos et al1 report that in 252 eligible subjects with documented peripheral arterial disease (PAD) studied at a single center, the measurement of skin autofluorescence (SAF) was independently associated with all-cause mortality and fatal or nonfatal major adverse cardiovascular events after a follow-up period of 5 years. Importantly, the authors excluded subjects with hemodialysis, kidney transplantation, recent myocardial infarction, or recent stroke and report that even after adjustment for cardiovascular risk factors and the use of lipid-lowering drugs, increased SAF remained associated with increased risk for death and major adverse cardiovascular events. A previous report from these authors compared subjects with PAD versus control PAD-free subjects and showed that increased SAF was significantly associated with PAD in a manner independent of traditional cardiovascular risk factors, although such risk factors were associated with further increases in SAF.2 See accompanying article on page 933 The AGE reader was used as a biological marker of advanced glycation endproducts (AGEs) in the skin and is usually tested in the forearm. AGEs are the products of nonenzymatic glycation and oxidation of proteins and lipids. AGEs are increased not only in diabetes mellitus but also in natural aging, oxidative stress, and inflammatory conditions, and in renal failure.3 AGEs form on lysine and arginine residues and are heterogeneous; some AGEs are associated with crosslinking (such as pentosidine), and some AGEs do not fluoresce, such as the carboxy methyl …

First-line beta-blockers versus other antihypertensive medications for chronic type B aortic dissection.

Thoracic aortic dissection (TAD) is a severe and often lethal complication in people with hypertension. Current practice in the treatment of chronic type B aortic dissections is the use of beta-blockers as first-line therapy to decrease aortic wall stress. Other antihypertensive medications, such as calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), have been suggested for the medical therapy of type B TAD. To assess the effects of first-line beta-blockers compared with other first-line antihypertensive drug classes for treating chronic type B TAD. We searched the Database of Abstracts of Reviews of Effects (DARE) for related reviews. We searched the Hypertension Group Specialised Register (1946 to 26 January 2014), the Cochrane Central Register of Controlled Trials (2014, Issue 1), MEDLINE (1946 to 24 January 2014), MEDLINE In-Process, EMBASE (1974 to 24 January 2014) and ClinicalTrials.gov (to 26 January 2014). We considered randomized controlled trials (RCTs) comparing different antihypertensive medications in the treatment of chronic type B TAD to be eligible for inclusion. Total mortality rate was the primary outcome of this review. Secondary outcomes included total non-fatal adverse events relating to TADs and number of people not requiring surgical treatment. Two review authors (KC, PL) independently reviewed titles and abstracts and decided on studies to include based on the inclusion criteria. We resolved discrepancies between the two review authors by discussion. After a thorough review of the search results, we identified no studies that met the inclusion criteria. We did not find any RCTs that compared first-line beta-blockers with other first-line antihypertensive medications for the treatment of chronic type B TAD. Therefore, there is no RCT evidence to support the current guidelines recommending the use of beta-blockers. RCTs are required to assess the benefits and harms of beta-blockers and other antihypertensive medications as first-line treatment of chronic type B TAD.

Skin Autofluorescence Is Associated With 5-Year Mortality and Cardiovascular Events in Patients With Peripheral Artery Disease

Advanced glycation end products play a pivotal role in atherosclerosis. Recently, we showed that tissue advanced glycation end products deposition, noninvasively assessed by skin autofluorescence (SAF), is increased in patients with peripheral artery disease. The aim of the present study was to establish whether SAF is associated with all-cause mortality and with fatal or nonfatal major adverse cardiovascular events (MACE) in patients with peripheral artery disease. We performed a single-center prospective cohort study of 252 patients with peripheral artery disease (mean age, 66±11 years), recruited from the outpatient clinic (October 2007 to June 2008) who were followed until June 2013. SAF was measured with the AGE Reader. The primary end point was all-cause mortality, and the secondary end point was fatal or nonfatal MACE, defined as cardiovascular death and nonfatal myocardial infarction or stroke. During a median follow-up of 5.1 (interquartile range, 5.0-5.3) years, 62 (25%) patients died. Fatal or nonfatal MACE occurred in 62 (25%) patients. A higher SAF was associated with increased risk for all-cause mortality (hazard ratio per unit increase, 2.01; 95% confidence interval, 1.40-2.88; P=0.0002) and fatal or nonfatal MACE (hazard ratio, 1.82; 95% confidence interval, 1.28-2.60; P=0.001), also after adjustment for cardiovascular risk factors and the use of lipid-lowering drugs (hazard ratio, 1.63; 95% confidence interval, 1.13-2.34; P=0.009 and hazard ratio, 1.50; 95% confidence interval, 1.04-2.17; P=0.03, for all-cause mortality and fatal and nonfatal MACE, respectively). SAF as a measure of advanced glycation end products deposition is independently associated with all-cause mortality and fatal or nonfatal MACE in patients with peripheral artery disease after a 5-year follow-up.

Type D Personality is Unrelated to Major Adverse Cardiovascular Events in Patients with Coronary Artery Disease Treated by Intracoronary Stenting

Previous research in cardiac patients suggested that type D personality, defined as a combination of negative affectivity (NA) and social inhibition (SI), was associated with adverse outcome. The objective of this prospective study was to examine the independent prognostic value of type D in patients with coronary artery disease (CAD). A total of 465 patients completed the Type D Scale (DS14) questionnaire before undergoing stent implantation and were followed up for 5years. In a Cox regression model adjusted for selected confounders, we found a trend towards NA for the prediction of nonfatal major adverse cardiovascular event (MACE, hazard ratio (HR) = 1.07, 95% confidence intervals (CIs) = 0.99-1.14, p = 0.074), while, in contrast, SI was a significant and independent predictor of better outcome (HR = 0.92, 95% CI = 0.86-0.99, p = 0.027). In a cohort of CAD patients, the type D pattern was not linked to adverse outcome, whereas SI was negatively associated with MACE.

Prognostic role of aldosterone in patients with acute coronary syndrome

Different studies have shown a correlation between aldosterone, atherosclerosis and ischemia in the past decade. Evidence exists for the relationship between high levels of aldosterone and augmented risk of cardiovascular diseases, such as hypertension, cardiac failure, coronary artery disease and stroke. The objective of this study was to determine the prognostic role of aldosterone in patients with myocardial infarction. The study population included 96 consecutive patients admitted to our department for ST-elevated and non-ST-elevated myocardial infarction from June 2009 to March 2012. Plasma aldosterone levels were measured at admission to hospital in all patients. A 2-year prospective follow-up was performed, and fatal events and non-fatal events, such as reinfarction, congestive heart failure and arrhythmias, were recorded. Aldosterone levels at admission were associated with incidence of congestive heart failure (P = 0.02), ventricular arrhythmias (P = 0.01) and all complications (P = 0.003) after 1-month follow-up. Moreover, high aldosterone levels gave important information in the medium term (24 ± 6 months). Specifically, aldosterone was a predictive variable of reinfarction (P < 0.0001), congestive heart failure (P < 0.0001) and adverse events (P = 0.0002). The logistic regression analysis confirmed these results and showed that aldosterone may be predictive of adverse events at medium-term follow-up (odds ratio 1.1, 95% confidence interval 1.03-1.15, P = 0.02). These data show a strong and significant correlation between plasma aldosterone levels at admission for myocardial infarction and fatal and nonfatal adverse events. Aldosterone appears to be a main marker of adverse clinical outcome, in accordance with the literature. These data suggest the need to identify whether antialdosteronic drug treatment, applied acutely in patients with aldosterone elevation, can influence favorably the prognosis of patients with myocardial infarction.