Hard Clinical Outcomes Research Articles

Responses to ARUBA: a systematic review and critical analysis for the design of future arteriovenous malformation trials.

OBJECTIVE The ARUBA study (A Randomized Trial of Unruptured Brain Arteriovenous Malformations [AVMs]) on unruptured brain AVMs has been the object of comments and editorials. In the present study the authors aim to systematically review critiques, discuss design issues, and propose a framework for future trials. METHODS The authors performed a systematic review of the French and English literature on the ARUBA study published between January 2006 and February 2015. The electronic search, including the Cochrane Library, MEDLINE (PubMed and Ovid), CINAHL, and EMBASE databases, was complemented by hand searching and cross-referencing. The comments were categorized as items related to the design, the conduct, and the analysis and interpretation of the trial. RESULTS Thirty-one articles or letters were identified. The pragmatic design, with heterogeneity of patients and lack of standardization of the treatment arm, were frequently stated concerns. The choice of outcome measures was repeatedly criticized. During the trial, low enrollment rates, selection bias, and premature interruption of enrollment were frequent comments. The short follow-up period, the lack of subgroup analyses, the lack of details on the results of the various treatments, and a contentious interpretation of results were noted at the analysis stage. A fundamental problem was the primary hypothesis testing conservative management. The authors believe that other trials are needed. Future trials could be pragmatic, test interventions stratified at the time of randomization, and look for long-term, hard clinical outcomes in a large number of patients. CONCLUSIONS In the authors' view, the ARUBA trial is a turning point in the history of brain AVM management; future trials should aim at integrating trial methodology and clinical care in the presence of uncertainty.

Optimal nutrition in the paediatric ICU.

This article describes the current best available evidence on optimal nutrition in the paediatric intensive care based on different levels of outcome, which can be divided in surrogate and hard clinical outcome parameters. Undernutrition is associated with increased morbidity and mortality, whereas in specific cohorts of critically ill children, such as those with burn injury, obesity is associated with more complications, longer length of stay, and decreased likelihood of survival. There is a relation with adequacy of delivery of enteral nutrition and the amount of protein on length of hospital stay, neurological status, and mortality. Studies relating organ function, other than skin healing after thermal injury, with the nutritional status are scarce. There is also a scarcity of data concerning long-term follow-up and health economics. Until now, there are no randomized controlled trials which have investigated a causal relation between different feeding regimens on the nutritional status and short and long-term outcome. As a result current optimal nutritional strategies are based on small trials with surrogate outcome parameters. Prospective randomized studies are needed with nutritional and/or metabolic interventions to come to an optimal feeding strategy for critically ill children.

The cardiovascular polypill: clinical data and ongoing studies

AbstractCardiovascular risk modification in terms of comprehensive medical therapy (antithrombotic therapy, lipid-lowering therapy, antihypertensive medication) and lifestyle modification (healthy diet, regular exercise, weight loss, smoking cessation) is the cornerstone of secondary prevention. It is now clear that even in those undergoing PCI or bypass surgery, appropriate lifestyle modification and aggressive medical therapy are paramount for optimizing long-term outcomes. However, what has emerged from studies that examined the role of medical therapy in the context of coronary heart disease is that only ∼50% of the patients in these studies are achieving target treatment goals for blood pressure, lipid and glycemic control. Non-adherence is thought to be a very large contributor to this problem; across all health-care categories, non-adherence is estimated to account for $290 billion of annual health-care expenditure in the United States and €1.25 billion in European Union, with poor adherence to CVD medication accounting for 9% of all European CVD events. Socioeconomic factors may have a role in patients' discontinuing their medications, and a major initiative to combat this problem is the increasing focus on the polypill. The idea of combining numerous medications into a single tablet to reduce CV risk was first proposed more than a decade ago. This combined formulation not only significantly enhances patient convenience and adherence but also drives savings for the healthcare systems. Several randomized clinical trials have consistently demonstrated the effects of polypills on CV risk factors and adherence, and major trials are underway to study the effect on hard clinical outcomes.

REDUCTION IN UNNECESSARY VENTRICULAR PACING FAILS TO AFFECT HARD CLINICAL OUTCOMES: A META-ANALYSIS

BACKGROUND: Several pacing modalities have been introduced to minimize unnecessary right ventricular pacing. We conducted a meta-analysis to assess whether ventricular pacing reduction modalities (VPRM) influence accepted hard clinical outcomes in comparison to standard dual-chamber pacing (DDD). METHODS: An electronic search was performed using Cochrane central database, PubMed, Embase, and Web of Knowledge. References were searched manually. Only randomized controlled trials (RCT) were included. Outcomes of interest were: percentages of ventricular pacing (VP), incident of atrial fibrillation (AF)/atrial tachycardia (AT), all cause mortality (including cardiac death) and cardiovascular (CV)/ heart failure (HF) hospitalizations. Continuous variables were expressed as weighted means. Odds ratios (OR) were reported for dichotomous variables. RESULTS: Five RCTs involving 3470 adult patients were identified. VPRM were employed in 1737 patients (MVP (Medtronic) in 1423 and SafeR (Sorin) in 314 patients). Baseline demographics and clinical characteristics were similar between VPRM and DDD groups (Age: 73 1.9 vs. 73 1.5 years, P1⁄4 1.0; Male gender: 54% vs. 53%, P1⁄40.9 and LVEF: 58 4.4% vs. 57 4.0%, P1⁄40.7). Follow up ranged between 12-36 months. VPRM showed significant reduction in VP in comparison to DDD groups (7% vs. 85%, P<0.001). The incidence of AF/AT was similar between both groups (14% vs. 15%, OR 0.98 (95% confidence interval [CI] 0.61; 1.30), P1⁄40.56). VPRM showed no significant differences in comparison to DDD for all cause mortality or CV/HF hospitalizations (5% vs. 6%, OR 0.86 (95% CI 0.62; 1.19), P1⁄4 0.35; 9% vs. 9%, OR 0.94 (95% CI 0.72; 1.22), P1⁄4 0.64, respectively). CONCLUSION: Novel VPRM significantly reduced VP in comparison to standard DDD. When actively programmed, VPRM did not improve clinical outcomes and were not superior to standard DDD programming in reducing incidence of AF/AT, all cause mortality or CV/HF hospitalizations.

Insulin resistance and vascular dysfunction in chronic kidney disease: mechanisms and therapeutic interventions.

Insulin resistance (IR) is a novel cardiovascular risk factor that has been implicated in the pathogenesis of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Beyond its metabolic effects, insulin can potentially mediate the increased risk for CVD through its vasoactive properties. This review examines key clinical data and potential mechanisms linking IR and cardiovascular risk in CKD. While lifestyle interventions and pharmacotherapies with known insulin-sensitizing properties are promising therapeutic targets to reduce the CVD burden in this population, clinical trial data on the effect of insulin sensitization on vascular function in CKD are either lacking or conflicting and are limited by small sample size and short duration of intervention. Affirming the role of IR in lowering CVD risk in CKD will require prospective randomized controlled studies with sufficient sample size and hard clinical outcomes. Future research efforts should be directed at assessing the efficacy, safety and mechanisms by which novel insulin sensitizers such as bile acid sequestrant, selective and dual peroxisome proliferator-activated receptor modulators and modulators of gut microbiota and uraemic toxins alter vascular function in patients with CKD.

Bringing Back Targets to “IMPROVE” Atherosclerotic Cardiovascular Disease Outcomes

In this issue of Circulation , Bohula et al1 publish an elegant and very clinically relevant analysis from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) of patients who were randomly assigned to either simvastatin or ezetimibe/simvastatin combination following an acute coronary syndrome. This analysis evaluates outcomes based on 1-month on-treatment levels of low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hsCRP).1 Importantly, it was prespecified and not exploratory. Four mutually exclusive groups were compared: those achieving dual targets of LDL-C <70 mg/dL and hsCRP <2.0 mg/L, one of these targets, or neither target. In comparison with those who achieved neither target, those reaching dual targets had a statistically significant 27% lower relative risk for the primary end point of major atherosclerotic cardiovascular disease (ASCVD) events. Article see p 1224 More patients treated with ezetimibe added to simvastatin reached these dual targets than those treated with simvastatin alone. However, the benefit in risk reduction for those meeting both targets was similar by treatment arm. This has important clinical implications because it opens discussion about on-treatment monitoring and personalization of combination lipid therapy. A high-intensity statin was not evaluated in this trial, but could confer similar reductions in LDL-C and hsCRP. In this IMPROVE-IT analysis, successful achievement of dual LDL-C and hsCRP targets was more important than the specific agent(s) used. However, one should have a level of caution here and only extend that concept to drugs with proven efficacy for hard clinical outcomes and safety. Currently, the concept of lower is better should not be extended to other classes of lipid-modifying drugs like cholesterol ester transfer protein inhibitors. In contrast, the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors seem more promising in achieving large reductions in LDL-C, a good safety profile, and a signal for …

Cinacalcet and Clinical Outcomes in Dialysis.

Secondary hyperparathyroidism (SHPT) is a common complication of end-stage renal disease and is one of the most prominent causes of a markedly increased risk of death and cardiovascular disease in this patient population. Cinacalcet hydrochloride is a new option for the treatment of SHPT, and the efficacy and effectiveness to lower parathyroid hormone levels and to improve control of mineral metabolism, even in patients with severe disease, has been well established in many clinical trials and observational studies. Currently, the focus has moved to the impact of cinacalcet on hard clinical outcomes, and two randomized controlled trials, ADVANCE and EVOLVE, have been performed to assess the effects of cinacalcet on cardiovascular calcification and the risk of cardiovascular events and mortality, respectively. Although the primary analysis of both trials did not find significant effects of cinacalcet, the benefit of cinacalcet was suggested in the subanalyses in which the potential problems of the trials were taken into account. These positive results are consistent with experimental studies showing favorable effects of cinacalcet on bone metabolism and vascular calcification, providing plausibility to support the beneficial effects of cinacalcet. Definitive evidence is, however, still lacking, and further efforts should be made to establish the optimal role of cinacalcet in the treatment of SHPT.

Hydrochlorothiazide--Teaching an Old Drug New Tricks.

Hydrochlorothiazide--Teaching an Old Drug New Tricks.

Granulocyte-colony stimulating factor for large anterior ST-elevation myocardial infarction: Rationale and design of the prospective randomized phase III STEM-AMI OUTCOME trial

Granulocyte-colony stimulating factor (G-CSF) has been clinically tested in ST-elevation myocardial infarction (STEMI) with mixed results. Our 3-year follow-up data from STEM-AMI trial documented a sustained benefit of G-CSF on adverse ventricular remodeling after large anterior STEMI, when administered early and at a high-dose in patients with left ventricular (LV) dysfunction. The Aim of the present trial is to establish whether G-CSF improves hard clinical long-term outcomes. The STEM-AMI OUTCOME is a prospective, multicenter, randomized, open-label, phase III trial. It will include 1,530 patients with anterior STEMI undergoing primary percutaneous coronary intervention 2 to 24 hours after symptoms onset and with LV ejection fraction ≤45% after successful reperfusion. Patients will be randomized 1:1 to G-CSF and/or standard treatment. The primary end point is a reduced occurrence of all-cause death, recurrence of myocardial infarction, or hospitalization due to heart failure in G-CSF-treated patients. Left ventricular remodeling will be assessed via cardiac ultrasound and a substudy with cardiac magnetic resonance will be carried out in 120 subjects. Accrual and follow-up periods will last 3 and 2 years, respectively. The STEM-AMI OUTCOME study is designed to be a rigorous controlled phase III trial with adequate statistical power to conclusively assess efficacy of G-CSF treatment in STEMI.

Effect of Neutral-pH, Low-Glucose Degradation Product Peritoneal Dialysis Solutions on Residual Renal Function, Urine Volume, and Ultrafiltration: A Systematic Review and Meta-Analysis.

Neutral-pH, low-glucose degradation products solutions were developed in an attempt to lessen the adverse effects of conventional peritoneal dialysis solutions. A systematic review was performed evaluating the effect of these solutions on residual renal function, urine volume, peritoneal ultrafiltration, and peritoneal small-solute transport (dialysate to plasma creatinine ratio) over time. Multiple electronic databases were searched from January of 1995 to January of 2013. Randomized trials reporting on any of four prespecified outcomes were selected by consensus among multiple reviewers. Eleven trials of 643 patients were included. Trials were generally of poor quality. The meta-analysis was performed using a random effects model. The use of neutral-pH, low-glucose degradation products solutions resulted in better preserved residual renal function at various study durations, including >1 year (combined analysis: 11 studies; 643 patients; standardized mean difference =0.17 ml/min; 95% confidence interval, 0.01 to 0.32), and greater urine volumes (eight studies; 598 patients; mean difference =128 ml/d; 95% confidence interval, 58 to 198). There was no significant difference in peritoneal ultrafiltration (seven studies; 571 patients; mean difference =-110; 95% confidence interval, -312 to 91) or dialysate to plasma creatinine ratio (six studies; 432 patients; mean difference =0.03; 95% confidence interval, 0.00 to 0.06). The use of neutral-pH, low-glucose degradation products solutions results in better preservation of residual renal function and greater urine volumes. The effect on residual renal function occurred early and persisted beyond 12 months. Additional studies are required to evaluate the use of neutral-pH, low-glucose degradation products solutions on hard clinical outcomes.

Longer-term Outcomes of Darbepoetin Alfa Versus Epoetin Alfa in Patients With ESRD Initiating Hemodialysis: A Quasi-experimental Cohort Study

Adequately powered studies directly comparing hard clinical outcomes of darbepoetin alfa (DPO) versus epoetin alfa (EPO) in patients undergoing dialysis are lacking. Observational, registry-based, retrospective cohort study; we mimicked a cluster-randomized trial by comparing mortality and cardiovascular events in US patients initiating hemodialysis therapy in facilities (almost) exclusively using DPO versus EPO. Nonchain US hemodialysis facilities; each facility switching from EPO to DPO (2003-2010) was matched for location, profit status, and facility type with one EPO facility. Patients subsequently initiating hemodialysis therapy in these facilities were assigned their facility-level exposure. DPO versus EPO. All-cause mortality, cardiovascular mortality; composite of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke. Unadjusted and adjusted HRs from Cox proportional hazards regression models. Of 508 dialysis facilities that switched to DPO, 492 were matched with a similar EPO facility; 19,932 (DPO: 9,465 [47.5%]; EPO: 10,467 [52.5%]) incident hemodialysis patients were followed up for 21,918 person-years during which 5,550 deaths occurred. Almost all baseline characteristics were tightly balanced. The demographics-adjusted mortality HR for DPO (vs EPO) was 1.06 (95% CI, 1.00-1.13) and was materially unchanged after adjustment for all other baseline characteristics (HR, 1.05; 95% CI, 0.99-1.12). Cardiovascular mortality did not differ between groups (HR, 1.05; 95% CI, 0.94-1.16). Nonfatal outcomes were evaluated among 9,455 patients with fee-for-service Medicare: 4,542 (48.0%) in DPO and 4,913 (52.0%) in EPO facilities. During 10,457 and 10,363 person-years, 248 and 372 events were recorded, respectively, for strokes and MIs. We found no differences in adjusted stroke or MI rates or their composite with cardiovascular death (HR, 1.10; 95% CI, 0.96-1.25). Nonrandom treatment assignment, potential residual confounding. In incident hemodialysis patients, mortality and cardiovascular event rates did not differ between patients treated at facilities predominantly using DPO versus EPO.

LEFT VENTRICULAR THROMBUS FORMATION IN PATIENTS WITH ACUTE REPERFUSED ST-ELEVATION MYOCARDIAL INFARCTION: INSIGHTS FROM CARDIAC MAGNETIC RESONANCE

Data on the exact incidence and predictors of left ventricular (LV) thrombus formation after primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) are scarce. Moreover, data on the prognostic significance of LV thrombi on hard clinical outcome measures are

Qigong for Hypertension

The purpose of this review was to evaluate the efficacy and safety of qigong for hypertension.A systematic literature search was performed in 7 databases from their respective inceptions until April 2014, including the Cochrane Library, EMBASE, PubMed, Chinese Scientific Journal Database, Chinese Biomedical Literature Database, Wanfang database, and Chinese National Knowledge Infrastructure. Randomized controlled trials of qigong as either monotherapy or adjunctive therapy with antihypertensive drugs versus no intervention, exercise, or antihypertensive drugs for hypertension were identified. The risk of bias was assessed using the tool described in Cochrane Handbook for Systematic Review of Interventions, version 5.1.0.Twenty trials containing 2349 hypertensive patients were included in the meta-analysis. The risk of bias was generally high. Compared with no intervention, qigong significantly reduced systolic blood pressure (SBP) (weighted mean difference [WMD] = −17.40 mm Hg, 95% confidence interval [CI] −21.06 to −13.74, P < 0.00001) and diastolic blood pressure (DBP) (WMD = −10.15 mm Hg, 95% CI −13.99 to −6.30, P < 0.00001). Qigong was inferior to exercise in decreasing SBP (WMD = 6.51 mm Hg, 95% CI 2.81 to 10.21, P = 0.0006), but no significant difference between the effects of qigong and exercise on DBP (WMD = 0.67 mm Hg, 95% CI −1.39 to 2.73, P = 0.52) was identified. Compared with antihypertensive drugs, qigong produced a clinically meaningful but not statistically significant reduction in SBP (WMD = −7.91 mm Hg, 95% CI −16.81 to 1.00, P = 0.08), but appeared to be more effective in lowering DBP (WMD = −6.08 mm Hg, 95% CI −9.58 to −2.58, P = 0.0007). Qigong plus antihypertensive drugs significantly lowered both SBP (WMD = −11.99 mm Hg, 95% CI −15.59 to −8.39, P < 0.00001) and DBP (WMD = −5.28 mm Hg, 95% CI, −8.13 to −2.42, P = 0.0003) compared with antihypertensive drugs alone. No serious adverse events were reported.The meta-analysis suggests that qigong is an effective therapy for hypertension. However, more rigorously designed randomized controlled trials with long-term follow-up focusing on hard clinical outcomes are required to confirm the results.

Celiac disease and bone fractures: a systematic review and meta-analysis.

Celiac disease, an autoimmune disease induced by dietary gluten, is associated with metabolic bone disorders, such as low bone mineral density. However, it is unclear whether this translates into an association between celiac disease and such hard clinical outcomes as bone fractures. To systematically review and pool the evidence for the relationship of celiac disease with prevalence and incidence of bone fractures. We systematically searched Pubmed, Scopus, Web of Science, and Cochrane Library in January 2014 for studies of celiac disease and bone fractures. Observational studies of any design, in which bone fracture outcomes were compared in individuals with and without celiac disease were included. Two investigators independently extracted results from eligible studies. In the meta-analyses of case-control and cross-sectional studies, bone fractures were almost twice as common in individuals with a clinically diagnosed celiac disease as in those without the disease. In the meta-analyses of prospective studies, celiac disease at baseline was associated with a 30% increase (95% confidence interval [CI]: 1.14, 1.50) in the risk of any fracture and a 69% increase in the risk of hip fracture (95% CI: 1.10, 2.59). The two studies of unrecognized celiac disease (elevated circulating concentrations of celiac disease-specific autoantibodies but no celiac disease diagnosis) had contradicting findings. Our findings suggest that clinically diagnosed celiac disease and bone fractures co-occur and that celiac disease was associated with an increased risk of hip fractures as well as fractures in general. Further research would be needed to determine whether unrecognized celiac disease is associated with the risk of bone fractures.

Ezetimibe: rescued by randomization (clinical and mendelian).

Since its market launch in the early 2000s, ezetimibe has had a stormy history of acceptance and use by the clinical community. Ezetimibe’s initial approval by regulatory bodies was based primarily on its low side effect profile together with its ability to consistently reduce low-density lipoprotein (LDL) cholesterol by ≈20% either as monotherapy or as an additive to statin therapy. Notably, approval was granted despite the absence from ezetimibe’s portfolio of studies, demonstrating reductions in hard clinical cardiovascular outcomes, such as myocardial infarction or stroke. By 2006, ezetimibe accounted for >15% of all prescriptions for lipid-lowering medications in the United States,1 reflecting that era’s stout faith in the reliability of LDL cholesterol as a surrogate marker for clinical end points, together with practitioners’ positive real-world experiences with ezetimibe’s biochemical efficacy and good tolerability. It was tacitly anticipated that the pending cardiovascular outcome studies would be positive, eventually vindicating the early confidence that clinicians placed in the drug. However, the waters grew rough for ezetimibe in 2008. First, the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial conducted for 24 months in 720 patients with familial hypercholesterolemia showed that combined therapy with ezetimibe and simvastatin did not significantly change carotid intima–media thickness when compared with simvastatin alone, despite decreased levels of LDL cholesterol.2 Next, the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial conducted for 52 months in 1873 elderly nondiabetic patients with aortic stenosis showed that ezetimibe plus simvastatin did not reduce the composite outcome of combined aortic valve events and ischemic events.3 To add insult to injury, the 2009 Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol-6-HDL and LDL Treatment Strategies in Atherosclerosis (ARBITER 6-HALTS) study demonstrated that when combined with a statin, extended-release niacin caused a significant …

Rational and design of a stepped-wedge cluster randomized trial evaluating quality improvement initiative for reducing cardiovascular events among patients with acute coronary syndromes in resource-constrained hospitals in China

Acute coronary syndromes (ACSs) are a major cause of morbidity and mortality, yet effective ACS treatments are frequently underused in clinical practice. Randomized trials including the CPACS-2 study suggest that quality improvement initiatives can increase the use of effective treatments, but whether such programs can impact hard clinical outcomes has never been demonstrated in a well-powered randomized controlled trial. The CPACS-3 study is a stepped-wedge cluster-randomized trial conducted in 104 remote level 2 hospitals without PCI facilities in China. All hospitalized ACS patients will be recruited consecutively over a 30-month period to an anticipated total study population of more than 25,000 patients. After a 6-month baseline period, hospitals will be randomized to 1 of 4 groups, and a 6-component quality improvement intervention will be implemented sequentially in each group every 6months. These components include the following: establishment of a quality improvement team, implementation of a clinical pathway, training of physicians and nurses, hospital performance audit and feedback, online technical support, and patient education. All patients will be followed up for 6months postdischarge. The primary outcome will be the incidence of in-hospital major adverse cardiovascular events comprising all-cause mortality, myocardial infarction or reinfarction, and nonfatal stroke. The CPACS-3 study will be the first large randomized trial with sufficient power to assess the effects of a multifaceted quality of care improvement initiative on hard clinical outcomes, in patients with ACS.

Surfactant protein D, Club cell protein 16, Pulmonary and activation-regulated chemokine, C-reactive protein, and Fibrinogen biomarker variation in chronic obstructive lung disease.

Chronic obstructive pulmonary disease (COPD) is a multifaceted condition that cannot be fully described by the severity of airway obstruction. The limitations of spirometry and clinical history have prompted researchers to investigate a multitude of surrogate biomarkers of disease for the assessment of patients, prediction of risk, and guidance of treatment. The aim of this review is to provide a comprehensive summary of observations for a selection of recently investigated pulmonary inflammatory biomarkers (Surfactant protein D (SP-D), Club cell protein 16 (CC-16), and Pulmonary and activation-regulated chemokine (PARC/CCL-18)) and systemic inflammatory biomarkers (C-reactive protein (CRP) and fibrinogen) with COPD. The relevance of these biomarkers for COPD is discussed in terms of their biological plausibility, their independent association to disease and hard clinical outcomes, their modification by interventions, and whether changes in clinical outcomes are reflected by changes in the biomarker.

Tip-toeing toward the finish line.

Tip-toeing toward the finish line.

Utility of traditional circulating and imaging-based cardiac biomarkers in patients with predialysis CKD.

Cardiac biomarkers, such as cardiac troponin T (cTnT), brain natriuretic peptide (BNP), and N-terminal-pro-BNP (NT-pro-BNP), are commonly used to diagnose acute coronary syndrome and congestive heart failure exacerbation in symptomatic patients. Levels of these biomarkers are frequently chronically elevated in asymptomatic patients with ESRD who are receiving maintenance dialysis. Other imaging biomarkers commonly encountered in nephrologists' clinical practice, such as coronary artery calcium measured by computed tomography, left ventricular hypertrophy, and carotid intima-media thickness, are also frequently abnormal in asymptomatic patients with ESRD. This article critically reviews the limited observational data on associations between cTnT, BNP, NT-pro-BNP, coronary artery calcium, left ventricular hypertrophy, and carotid intima-media thickness with cardiovascular events and death in non-dialysis-dependent patients with CKD. Although sufficient evidence suggests that these biomarkers may be used for prognostication, the diagnostic utility of cTnT, BNP, and NT-pro-BNP remain challenging in patients with CKD. Decreased renal clearance may affect the plasma levels of these biomarkers, and upper reference limits were originally derived in patients without CKD. Until better data are available, higher cutoffs, or a rise in level compared with previous values, have been proposed to help distinguish acute myocardial infarction from chronic elevations of cTnT in symptomatic patients with CKD. Additionally, it is not known whether these biomarkers are modifiable and amenable to interventions that could change hard clinical outcomes in patients with CKD not yet undergoing long-term dialysis.

Remote preconditioning and major clinical complications following adult cardiovascular surgery: Systematic review and meta-analysis

BackgroundA number of ‘proof-of-concept’ trials suggest that remote ischaemic preconditioning (RIPC) reduces surrogate markers of end-organ injury in patients undergoing major cardiovascular surgery. To date, few studies have involved hard clinical outcomes as primary end-points. MethodsRandomised clinical trials of RIPC in major adult cardiovascular surgery were identified by a systematic review of electronic abstract databases, conference proceedings and article reference lists. Clinical end-points were extracted from trial reports. In addition, trial principal investigators provided unpublished clinical outcome data. ResultsIn total, 23 trials of RIPC in 2200 patients undergoing major adult cardiovascular surgery were identified. RIPC did not have a significant effect on clinical end-points (death, peri-operative myocardial infarction (MI), renal failure, stroke, mesenteric ischaemia, hospital or critical care length of stay). ConclusionPooled data from pilot trials cannot confirm that RIPC has any significant effect on clinically relevant end-points. Heterogeneity in study inclusion and exclusion criteria and in the type of preconditioning stimulus limits the potential for extrapolation at present. An effort must be made to clarify the optimal preconditioning stimulus. Following this, large-scale trials in a range of patient populations are required to ascertain the role of this simple, cost-effective intervention in routine practice.