Brett Hiebert

Non-invasive endothelial function testing and the risk of adverse outcomes: a systematic review and meta-analysis

OBJECTIVES We performed a systematic review and meta-analysis to understand the role of flow-mediated dilatation (FMD) of the brachial artery (BA) and peripheral arterial tonometry (PAT) in predicting adverse events, including cardiovascular (CV) events and all-cause mortality. BACKGROUND FMD of the BA and PAT are non-invasive measures of endothelial function. Impairment of endothelial function is associated with increased CV events. While FMD is the more widely used and studied technique, PAT offers several advantages. The purpose of this systematic review and meta-analysis is to determine whether brachial FMD and PAT are independent risk factors for future CV events and mortality. METHODS Multiple electronic databases were searched for articles relating FMD or PAT to CV events. Data were extracted on study characteristics, study quality, and study outcomes. Relative risks (RRs) from individual studies were combined and a pooled multivariate RR was calculated. RESULTS Thirty-six studies for FMD were included in the systematic review, of which 32 studies consisting of 15, 191 individuals were meta-analysed. The pooled RR of CV events and all-cause mortality per 1% increase in brachial FMD, adjusting for potential confounders, was 0.90 (0.88-0.92). In contrast, only three studies evaluated the prognostic value of PAT for CV events, and the pooled RR per 0.1 increase in reactive hyperaemia index was 0.85 (0.78-0.93). CONCLUSION Brachial FMD and PAT are independent predictors of CV events and all-cause mortality. Further research to evaluate the prognostic utility of PAT is necessary to compare it with FMD as a non-invasive endothelial function test in clinical practice.

Radiation Dose Reduction in the Cardiac Catheterization Laboratory Utilizing a Novel Protocol

OBJECTIVES This study reports the results a novel radiation reduction protocol (RRP) system for coronary angiography and interventional procedures and the determinants of radiation dose. BACKGROUND The cardiac catheterization laboratory is an important source of radiation and should be kept in good working order with dose-reduction and monitoring capabilities. METHODS All diagnostic coronary angiograms and percutaneous coronary interventions from a single catheterization laboratory were analyzed 2 months before and after RRP implementation. The primary outcome was the relative dose reduction at the interventional reference point. Separate analyses were done for conventional 15 frames/s (FPS) and at reduced 7.5 FPS post-RRP groups. RESULTS A total of 605 patients underwent coronary angiography (309 before RRP and 296 after RRP), with 129 (42%) and 122 (41%) undergoing percutaneous coronary interventions before and after RRP, respectively. With RRP, a 48% dose reduction (1.07 ± 0.05 Gy vs. 0.56 ± 0.03 Gy, p < 0.0001) was obtained, 35% with 15 FPS RRP (0.70 ± 0.05 Gy, p < 0.0001) and 62% with 7.5 FPS RRP (0.41 ± 0.03 Gy, p < 0.001). Similar dose reductions for diagnostic angiograms and percutaneous coronary interventions were noted. There was no change in the number of stents placed or vessels intervened on. Increased dose was associated with male sex, radial approach, increasing body mass index, cine runs, and frame rates. Using a multivariable model, a 48% relative risk with RRP (p < 0.001), 44% with 15 FPS RRP and 68% with 7.5 FPS RRP was obtained. CONCLUSIONS We demonstrate a highly significant 48.5% adjusted radiation dose reduction using a novel algorithm, which needs strong consideration among interventional cardiology practice.

Influenza Vaccine Effectiveness in the Elderly Based on Administrative Databases: Change in Immunization Habit as a Marker for Bias

Background Administrative databases provide efficient methods to estimate influenza vaccine effectiveness (IVE) against severe outcomes in the elderly but are prone to intractable bias. This study returns to one of the linked population databases by which IVE against hospitalization and death in the elderly was first assessed. We explore IVE across six more recent influenza seasons, including periods before, during, and after peak activity to identify potential markers for bias. Methods and Findings Acute respiratory hospitalization and all-cause mortality were compared between immunized/non-immunized community-dwelling seniors ≥65years through administrative databases in Manitoba, Canada between 2000-01 and 2005-06. IVE was compared during pre-season/influenza/post-season periods through logistic regression with multivariable adjustment (age/sex/income/residence/prior influenza or pneumococcal immunization/medical visits/comorbidity), stratification based on prior influenza immunization history, and propensity scores. Analysis during pre-season periods assessed baseline differences between immunized and unimmunized groups. The study population included ∼140,000 seniors, of whom 50–60% were immunized annually. Adjustment for key covariates and use of propensity scores consistently increased IVE. Estimates were paradoxically higher pre-season and for all-cause mortality vs. acute respiratory hospitalization. Stratified analysis showed that those twice consecutively and currently immunized were always at significantly lower hospitalization/mortality risk with odds ratios (OR) of 0.60 [95%CI0.48–0.75] and 0.58 [0.53–0.64] pre-season and 0.77 [0.69–0.86] and 0.71 [0.66–0.77] during influenza circulation, relative to the consistently unimmunized. Conversely, those forgoing immunization when twice previously immunized were always at significantly higher hospitalization/mortality risk with OR of 1.41 [1.14–1.73] and 2.45 [2.21–2.72] pre-season and 1.21 [1.03–1.43] and 1.78 [1.61–1.96] during influenza circulation. Conclusions The most pronounced IVE estimates were paradoxically observed pre-season, indicating bias tending to over-estimate vaccine protection. Change in immunization habit from that of the prior two years may be a marker for this bias in administrative data sets; however, no analytic technique explored could adjust for its influence. Improved methods to achieve valid interpretation of protection in the elderly are needed.

Variation in the Level of eGFR at Dialysis Initiation across Dialysis Facilities and Geographic Regions

BACKGROUND AND OBJECTIVES The relative influence of facilities and regions on the timing of dialysis initiation remains unknown. The purpose of the study is to determine the variation in eGFR at dialysis initiation across dialysis facilities and geographic regions in Canada after accounting for patient-level factors (case mix). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In total, 33,263 dialysis patients with an eGFR measure at dialysis initiation between January of 2001 and December of 2010 representing 63 dialysis facilities and 14 geographic regions were included in the study. Multilevel models and intraclass correlation coefficients were used to evaluate the variation in timing of dialysis initiation by eGFR at the patient, facility, and geographic levels. RESULTS The proportion initiating dialysis with an eGFR≥10.5 ml/min per 1.73 m(2) was 35.3%, varying from 20.1% to 57.2% across geographic regions and from 10% to 67% across facilities. In an unadjusted, intercept-only linear model, 90.7%, 6.6%, and 2.7% of the explained variability were attributable to patient, facility, and geography, respectively. After adjustment for patient and facility factors, 96.9% of the explained variability was attributable to patient case mix, 3.1% was attributable to the facility, and 0.0% was attributable to the geographic region. These findings were consistent when the eGFR was categorized as a binary variable (≥10.5 ml/min per 1.73 m(2)) or in an analysis limited to patients with >3 months of predialysis care. CONCLUSIONS Patient characteristics accounted for the majority of the explained variation regarding the eGFR at the initiation of dialysis. There was a small amount of variation at the facility level and no variation among geographic regions that was independent of patient- and facility-level factors.

Long-Term Effects of Postoperative Delirium in Patients Undergoing Cardiac Operation: A Systematic Review

Delirium is an acute syndrome that involves fluctuating changes in attention and cognition. Although delirium is the most common neurologic complication after cardiac operation, data about its impact on long-term outcomes are lacking. The purpose of this systematic review was to examine the effect of postoperative delirium (PoD) on long-term outcomes, including morbidity, probability of death, cognitive decline, institutionalization, and health-related quality of life (HRQoL) in patients undergoing cardiac operation. After performing this systematic review we determined that PoD after cardiac operation is associated with an increased risk of probability of death and readmission to the hospital and a decrease in cognitive function, overall function, and HRQoL.

The Effect of Erythropoietin-Stimulating Agents on Health-Related Quality of Life in Anemia of Chronic Kidney Disease: A Systematic Review and Meta-analysis

Chronic kidney disease (CKD) is a global health epidemic (1) that is increasing in incidence and prevalence (2, 3). Anemia is common in CKD (4); its treatment with erythropoietin-stimulating agents (ESAs) reduces the need for blood transfusions and has varying effects on morbidity and mortality (57). The optimal hemoglobin targets for treating anemia with ESAs are controversial, with safety concerns around the normalization of hemoglobin levels due to the increased risk for cardiovascular events (812). Clinical practice guidelines recommend hemoglobin targets of 10 to 11 g/L (13, 14), but individualization of hemoglobin targets remains relatively common among clinicians. In 2007, the U.S. Food and Drug Administration placed black box warnings on ESAs (15). Publication of the trial by Pfeffer and colleagues (16), combined with changes in Medicare reimbursement in 20102011, has led to decreased ESA use. Nonetheless, higher hemoglobin targets for some patients (that is, individualization of treatment) continues to be discussed and practiced. Most clinicians believe that treatment of anemia in CKD influences health-related quality of life (HRQOL) and its various domains (17, 18). In particular, younger, healthier patients may benefit from higher hemoglobin targets, and the harm may be concentrated in older individuals with preexisting cardiovascular risk factors. Previous systematic reviews have examined the use of ESAs to improve HRQOL in anemia of CKD (1922). However, these studies have focused only on dialysis recipients (20) or have included only specific HRQOL domains (2022). In addition, findings from recent large randomized trials have not been included (19). We performed an updated systematic review and meta-analysis on the effect of achieving higher hemoglobin targets with ESAs on HRQOL in patients with CKD and those undergoing dialysis. Methods Data Sources and Searches We developed and followed a protocol summarized in a document that included PICO (population, intervention, comparison, outcomes) criteria for search strategy and subgroup analyses (see protocol in the Supplement). We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (23) for reporting of systematic reviews and meta-analyses. Supplement. Study Protocol We identified studies evaluating the treatment of anemia with ESAs in patients with CKD who were receiving or not receiving dialysis. The studies had to report HRQOL measurements according to ESA treatment strategies to achieve 2 hemoglobin targets: a combined placebo or low-hemoglobin target versus a higher hemoglobin target. We included only prospective, randomized trials; placed no limits on sample size, duration of follow-up, type of ESA, or use of iron; and included only studies reported in English. In collaboration with a medical librarian (K.M.), we retrieved information for the study from the following databases: PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov. Our search of these databases ranged from the date of their establishment until 1 November 2015. The search strategy was tailored to each database and used a combination of key terms, such as quality of life, erythropoietin, outcome, health status, and quality-adjusted life-years. Medical Subject Heading terms (Appendix Table 1) were applied in the search strategy. We downloaded all of the received citations into RefWorks, version 2.0 (RefWorks-COS, Bethesda, Maryland). Appendix Table 1. Medical Subject Headings Search Terms Two reviewers (R.G. and B.L.) independently reviewed each citation by title and abstract, and articles were selected for full-text review. Two reviewers (R.G. and F.E.) screened the reference lists of articles selected for full-text review. Full-text articles were finalized for inclusion after consultation with third and fourth reviewers (Y.X and N.T.). All disagreements were resolved by consensus. Data Extraction and Quality Assessment We created a data extraction form to capture relevant information from the included studies. Two reviewers (R.G. and F.E.) independently extracted data; inconsistencies were corrected and resolved by consensus and consultation with third and fourth reviewers (Y.X and N.T.). Two reviewers (R.G. and D.C.) assessed studies for their quality of reporting and risk of bias using the Cochrane Collaborations tool for assessing risk of bias (24). Categories included random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting. Conflict was resolved by a third reviewer (N.T.). Data Synthesis and Analysis The primary measure was the change in baseline and follow-up scores of HRQOL instruments, specifically the Short Form-36 Health Survey (SF-36) (25) and the Kidney Disease Questionnaire (KDQ) (26). The SF-36 has been validated in earlier studies of patients with CKD and consists of 8 domains: physical function, physical role, bodily pain, general health, vitality, emotional role, social function, and mental health. Scales were standardized to scores ranging from 0 to 100, with higher scores indicating better health. A clinically meaningful difference in the SF-36 is a 5-point change (27). The KDQ has also been validated in the CKD setting and contains 26 questions, with scores in 5 dimensions: fatigue, depression, relationships with others, frustration, and physical symptoms. All dimensions are scored on a Likert scale between 7 (no problem) and 1 (a severe problem), with higher scores indicating better health. A clinically meaningful difference in KDQ is a 0.5-point change (28). A meta-analysis was performed to determine whether the change in HRQOL between 2 time points differed between hemoglobin target strategies. For this analysis, each of the 8 domains of the SF-36 and the 3 domains of the KDQ were analyzed individually. If the SE of the change was not available, we calculated its estimated value by assuming a normal distribution and independence between the 2 variables (29). Because the degree of heterogeneity between study estimates was expected to differ among the SF-36 and KDQ domains, we decided a priori to report aggregate estimates and corresponding 95% CIs using the HartungKnappSidikJonkman random-effects method (30). For each domain, a Cochran Q test was conducted to assess heterogeneity and an I 2 statistic was calculated to estimate the percentage of total variation resulting from between-study variation (31). We performed subgroup analyses on the SF-36 domains to examine the differences in aggregate estimates and heterogeneity when certain studies were excluded from the analysis. A subgroup analysis included studies that were deemed to have a low risk of bias, as determined by the Cochrane Collaborations tool for assessing risk of bias (24). Other subgroup analyses included nondialysis versus dialysis status, mean age of study participants younger or older than 60 years, publication before or after 2000, study follow-up of less than or greater than 1 year, and studies with reported incomplete follow-up less than 20%. All statistical analyses were performed by using SAS software, version 9.3 (SAS Institute). Role of the Funding Source The primary funding sources were KRESCENT and the Manitoba Health Research Council Establishment award, which had no role in the studys design, conduct, or reporting or in the decision to submit the manuscript for publication. Results A flow diagram outlining the selection strategy is shown in Appendix Figure 1. Our search strategy retrieved 5798 studies, including duplicates, for abstract screening. Of these, 43 studies were selected for full-text review, and 16 met criteria for inclusion in our systematic review. An additional study was identified for inclusion after review of included study references, for a total of 17 studies. Appendix Figure 1. Summary of evidence search and selection. Performed 1 November 2015. Quality of Reporting and Risk of Bias Four studies had a low risk of bias (3235) (Appendix Figure 2). A subgroup analysis including only the studies with low risk of bias was performed for SF-36 domains; no statistically significantly differences were seen between groups (Appendix Table 2). Allocation concealment and blinding were infrequent, which could have influenced the results of a subjective HRQOL assessment. Incomplete outcome data were common and were driven by the initiation of dialysis in predialysis studies, renal transplantation in the dialysis population, and a variety of adverse events that did not significantly differ between treatment groups. Appendix Figure 2. Risk-of-bias assessment of included studies. USREPSG= U.S. Recombinant Human Erythropoietin Predialysis Study Group. Appendix Table 2. Meta-analysis of Studies Using SF-36 With a Low Risk of Bias Characteristics of Selected Studies Of the 17 included studies, 12 were in the nondialysis CKD population, 4 were in the dialysis population, and 1 was in a combined sample. Three studies compared treatment with erythropoietin alfa (EPO) with placebo, 2 studies compared darbepoetin (DPO) with placebo, 1 study compared EPO with DPO, and 11 compared EPO with EPO. The follow-up ranged from 8 weeks to 36 months, with achieved hemoglobin ranging from 7.4 to 12 g/L for the placebo/lower hemoglobin target and 10.2 to 13.6 g/L for the higher hemoglobin target (Appendix Table 3). Thirteen studies measured SF-36 domains (Appendix Table 4) and 4 studies measured KDQ domains (Appendix Table 5). Other HRQOL tools included the Sickness Impact Profile, Functional Assessment of Chronic Illness Therapy, and Linear Analogue Self-Assessment. Heterogeneity for studies using SF-36 was moderate (I 2= 0% to 63.1%; see Figure 1 ). Appendix Table 3. Characteristics of Included Studies Appendix Table 4. Mean Scores on SF-36 Appendix Table 5. HRQOL Tools and Results Figure 1. Forest plot of all reported data o

The diagnostic accuracy of tests for latent tuberculosis infection in hemodialysis patients: a systematic review and meta-analysis.

Background Reactivation of latent Mycobacterium tuberculosis infection is an important health concern for patients on hemodialysis because of their immunosuppressed state and in kidney transplant patients receiving immunosuppressive therapy to prevent organ rejection. There are several tests available to determine the presence of latent tuberculosis infection: the tuberculin skin test (TST), QuantiFERON-TB Gold (QFT-G), and T-SPOT.TB. The objective of this study is to evaluate the diagnostic accuracy of these tests in determining latent tuberculosis infection in the hemodialysis population. Methods The study design was a systematic review. We selected studies with adequate information to ascertain test sensitivity or specificity of the TST, QFT-G, and TSPOT.TB with regards to determining latent tuberculosis infection in the hemodialysis population. Results One hundred two articles were selected for full review, and 17 were included in the meta-analysis. The TST had a pooled sensitivity of 31% (26%–36%, 95% confidence interval) and specificity of 63% (60%–65%) across eight studies. The QFT-G test had a pooled sensitivity of 53% (46%–59%) and specificity of 69% (65%–72%) across nine studies. The T-SPOT.TB test had a pooled sensitivity of 50% (42%–59%) and specificity of 67% (61%–73%) across three studies. Conclusion The QFT-G and the T-SPOT.TB tests were more sensitive than the TST for diagnosis of latent tuberculosis infection in patients on hemodialysis while offering a comparable level of specificity. This systematic review calls into question the practice of using the TST to screen in this population, especially in patients considered for kidney transplantation.

The impact of frailty on functional survival in patients 1 year after cardiac surgery

Objective: This study determined whether frailty provides incremental value to the European System for Cardiac Operative Risk Evaluation II in identifying patients at risk of poor 1‐year functional survival. Methods: This prospective study in patients undergoing cardiac surgery defined frailty using 3 common definitions: (1) the Modified Fried Criteria; (2) the Short Physical Performance Battery; and (3) the Clinical Frailty Scale. The primary outcome was functional survival, defined as being alive at 1 year postsurgery with a health‐related quality of life score greater than 60 on the EuroQol‐Visual Analogue Scale. Results: Of the 188 participants, 49.5%, 52.6%, and 31.9% were deemed frail according to the Modified Fried Criteria, Short Physical Performance Battery, and Clinical Frailty Scale, respectively. The median age of our cohort was 71.0 years (29.3% female). The probability of functional survival at 1 year for the entire cohort was 73.9%. After adjusting for the European System for Cardiac Operative Risk Evaluation II, patients deemed frail under the Modified Fried Criteria, Short Physical Performance Battery, and Clinical Frailty Scale had an increased odds ratio for poor functional survival of 3.44, 3.47, and 2.08, respectively. When compared with the European System for Cardiac Operative Risk Evaluation II alone, the Modified Fried Criteria, Short Physical Performance Battery, and Clinical Frailty Scale showed an absolute improvement in the discrimination slope of 6.7%, 6.5%, and 2.4% with a category‐free classification improvement of 59.6%, 59.2%, and 35.1%, respectively. Conclusions: Preoperative frailty was associated with a 2‐ to 3.5‐fold higher risk of poor functional survival 1 year after cardiac surgery. The addition of frailty to the European System for Cardiac Operative Risk Evaluation II provides incremental value in identifying patients at risk of poor functional survival 1 year postsurgery, regardless of frailty definition.

Vocal Cord Paralysis After Thoracic Aortic Surgery: Incidence and Impact on Clinical Outcomes

BACKGROUND Vocal cord paralysis (VCP) is a serious complication associated with thoracic aortic surgery; however, there is a paucity of literature regarding the incidence and impact of VCP on postoperative outcomes. We sought to determine the incidence of VCP and its impact on clinical outcomes in patients who underwent thoracic aortic repair at our center. METHODS A retrospective chart review was conducted on all patients who underwent thoracic aortic surgery between January 2009 and September 2012. RESULTS A total of 259 patients underwent a thoracic aortic procedure during the study period. Vocal cord paralysis was diagnosed in 12 (5%) patients, a median of 6 [3 to 21] days after extubation. The incidence was 1%, 0%, 20%, and 25% in those undergoing an open ascending, hemiarch, total arch, or descending aortic procedure, respectively. Patients with VCP had an increased incidence of pneumonia (58% vs 17%, p = 0.003), readmission to the intensive care unit for respiratory failure (17% vs 2%, p = 0.047), and longer hospital length of stay (18 [11 to 43] days versus 9 [6 to 15] days, p = 0.002). A propensity-matched analysis confirmed a higher incidence of pneumonia (58% vs 17%, p = 0.020) and longer hospital length of stay (18 [11 to 43] vs 10 [7 to 14] days, p = 0.015) in patients suffering VCP. CONCLUSIONS Vocal cord paralysis is a common complication in patients undergoing open surgery of the aortic arch and descending aorta, and is associated with significant morbidity. Further research may be warranted to determine if early fiberoptic examination and consideration of a vocal cord medialization procedure may mitigate the morbidity associated with VCP.

Elevated Urinary Matrix Metalloproteinase-7 Detects Underlying Renal Allograft Inflammation and Injury.

Background The urinary CXC chemokine ligand (CXCL)10 detects renal transplant inflammation noninvasively, but has limited sensitivity and specificity. In this study, we performed urinary proteomic analysis to identify novel biomarkers that may improve the diagnostic performance of urinary CXCL10 for detecting alloimmune inflammation in renal transplant patients. Methods In preliminary studies, adult renal transplant patients with normal histology (n = 5), interstitial fibrosis and tubular atrophy (n = 6), subclinical (n = 6) and clinical rejection (n = 6), underwent in-depth urine protein compositional analysis with LC-MS/MS, and matrix metalloproteinase-7 (MMP7) were identified as a potential candidate for the diagnosis of renal allograft inflammation. Urine MMP7 performance was then studied in a larger, prospective adult renal transplant population (n = 148 urines from n = 133 patients) with matched surveillance/indication biopsies. The diagnostic performance of urinary MMP7 and CXCL10 in combination was next evaluated using concordance (C-) statistics, net reclassification improvement and integrated discrimination improvement indices, to determine whether it was better than CXCL10 alone. Results Urinary MMP7:creatinine (Cr) was lower in normal transplants compared to those with inflammation: glomerulonephritis (P = 0.009), viral nephropathies (P = 0.002), interstitial fibrosis and tubular atrophy and inflammation (P = 0.04), borderline (P = 0.08), subclinical (P = 0.01) and clinical rejection (P = 0.0006), and acute tubular necrosis (P < 0.0001). Urinary MMP7:Cr and CXCL10:Cr significantly distinguished noninflamed from inflamed biopsies (area under the curve, 0.74 and 0.70, respectively). The addition of urinary MMP7:Cr to CXCL10:Cr improved the diagnostic performance for subclinical and clinical inflammation/injury by integrated discrimination improvement (P = 0.002) and net reclassification improvement (P = 0.006) analyses. Conclusions Urinary MMP7:Cr improves the overall diagnostic performance of urinary CXCL10:Cr for distinguishing normal histology from subclinical and clinical inflammation/injury, but not subclinical inflammation alone.