Conflicting relationships have been described between anemia correction using erythropoiesis-stimulating agents (ESAs) and progression of chronic kidney disease (CKD). This study was undertaken to examine the impact of target hemoglobin on progression of kidney disease in the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) trial.
Secondary analysis of a randomized controlled trial
Setting and participants
1432 participants with CKD and anemia
Participants were randomized to target hemoglobin of 13.5 vs 11.3 gm/dL with the use of epoetin-alfa.
Outcomes and measurements
Cox regression was used to estimate hazard ratios for progression of CKD (a composite of doubling of creatinine, initiation of renal replacement therapy (RRT), or death). Interactions between hemoglobin target and select baseline variables (estimated glomerular filtration rate (eGFR), proteinuria, diabetes, heart failure, and smoking history) were also examined.
Participants randomized to higher hemoglobin targets experienced a shorter time to progression of kidney disease in both univariate (HR, 1.25; 95% CI, 1.03–1.52; p=0.02) and multivariable models (HR, 1.22; 95% CI, 1.00–1.48; p=0.05). These differences were attributable to higher rates of RRT and death among participants in the high hemoglobin arm. Hemoglobin target did not interact with eGFR, proteinuria, diabetes, or heart failure (p>0.05 for all). In the multivariable model, hemoglobin target interacted with tobacco use (p=0.04) such that the higher target had a greater risk of CKD progression among participants that currently smoked (HR, 2.50; 95% CI, 1.23–5.09; p=0.01) which was not present among those who did not currently smoke (HR, 1.15; 95% CI 0.93–1.41; p=0.2).
A post-hoc analysis and thus cause- effect cannot be determined.
These results suggest that high hemoglobin target is associated with a greater risk of progression of CKD. This risk may be augmented by concurrent smoking. Further defining the mechanism of injury may provide insight into methods to optimize outcomes in anemia management.
To describe the development of an academic-health services partnership undertaken to improve use of evidence in clinical practice.
Academic health science schools and health service settings share common elements of their missions: to educate, participate in research, and excel in healthcare delivery, but differences in the business models, incentives, and approaches to problem-solving can lead to differences in priorities. Thus, academic and health service settings do not naturally align their leadership structures or work processes. We established a common commitment to accelerate the appropriate use of evidence in clinical practice and created an organizational structure to optimize opportunities for partnering that would leverage shared resources to achieve our goal.
A jointly governed and funded institute integrated existing activities from the academic and service sectors. Additional resources included clinical staff and student training and mentoring, a pilot research grant-funding program, and support to access existing data. Emergent developments include an appreciation for a wider range of investigative methodologies and cross-disciplinary teams with skills to integrate research in daily practice and improve patient outcomes.
By developing an integrated leadership structure and commitment to shared goals, we developed a framework for integrating academic and health service resources, leveraging additional resources, and forming a mutually beneficial partnership to improve clinical outcomes for patients.
academic-service partnership; academic medical center; evidence-based practice (EBP); nursing research; healthcare delivery
Targeting a higher hemoglobin in patients with chronic kidney disease leads to adverse cardiovascular outcomes, yet the reasons remain unclear. Herein, we sought to determine whether changes in erythropoiesis-stimulating agent (ESA) dose and in hemoglobin were predictive of changes in blood pressure (BP) and whether these changes were associated with cardiovascular outcomes.
In this secondary analysis of 1421 Correction of Hemoglobin and Outcomes in Renal Disease (CHOIR) participants, mixed model analyses were used to describe monthly changes in ESA dose and hemoglobin with changes in diastolic BP (DBP) and systolic BP (SBP). Poisson modeling was performed to determine whether changes in hemoglobin and BP were associated with the composite end point of death or cardiovascular outcomes.
Monthly average DBP, but not SBP, was higher in participants in the higher hemoglobin arm. Increases in ESA doses and in hemoglobin were significantly associated with linear increases in DBP, but not consistently with increases in SBP. In models adjusted for demographics and comorbid conditions, increases in ESA dose (>0 U) and larger increases in hemoglobin (>1.0 g/dL/month) were associated with poorer outcomes [event rate ratio per 1000 U weekly dose per month increase 1.05, (1.02–1.08), P = 0.002 and event rate ratio 1.70 (1.02–2.85), P = 0.05, respectively]. However, increasing DBP was not associated with adverse outcomes [event rate ratio 1.01 (0.98–1.03), P = 0.7].
Among CHOIR participants, higher hemoglobin targets, increases in ESA dose and in hemoglobin were associated both with increases in DBP and with higher event rates; however, increasing DBP was not associated with adverse outcomes.
anemia; blood pressure; cardiovascular events; chronic kidney disease; erythropoietin dose
Edifoligide, an E2F transcription factor decoy, does not prevent vein graft failure or adverse clinical outcomes at 1-year in patients undergoing coronary artery bypass grafting (CABG). We compared the 5-year clinical outcomes of patients in PREVENT IV treated with edifoligide and placebo and to identify predictors of long-term clinical outcomes.
A total of 3014 patients undergoing CABG with at least 2 planned vein grafts were enrolled. Kaplan-Meier curves were generated to compare the long-term effects of edifoligide and placebo. A Cox proportional hazards model was constructed to identify factors associated with 5-year post-CABG outcomes. The main outcome measure was death, myocardial infarction (MI), repeat revascularization, and rehospitalization through 5 years.
Five-year follow-up was complete in 2865 (95.1%) patients. At 5 years, patients randomized to edifoligide and placebo had similar rates of death (11.7% and 10.7%), MI (2.3% and 3.2%), revascularization (14.1% and 13.9%), and rehospitalization (61.6% and 62.5%). The 5-year composite outcome of death, MI, or revascularization occurred at similar frequency in patients assigned to edifoligide and placebo (26.3% and 25.5%; hazard ratio 1.03 [95% confidence interval 0.89–1.18]; P=0.721). Factors associated with death, MI, or revascularization at 5 years included diabetes, sex, worst graft quality, peri-index CABG MI, and ejection fraction.
Up to a quarter of patients undergoing CABG will have a major cardiac event or repeat revascularization procedure within 5 years of surgery. Edifoligide does not affect outcomes following CABG; however, common identifiable baseline and procedural risk factors are associated with long-term outcomes following CABG.
vein graft failure; coronary artery bypass graft surgery; transcription factor decoy; outcomes
To examine the relationship of depression and survival of patients with chronic heart failure (HF) over a 12-year follow-up period.
The survival associated with depression has been demonstrated in HF patients for up to 7 years. Longer-term impact of depression on survival of these patients remains unknown.
Prospectively conducted observational study examining adult HF patients who were admitted to a cardiology service at Duke University Medical Center between March 1997 and June 2003 and completed the Beck Depression Inventory (BDI) scale. The National Death Index was queried for vital status. Cox proportional hazards modeling was used to determine association of survival and depression.
During a mean follow-up of 1792.33±1372.82 days (median 1600; range 0–4683), 733 of 985 HF participants died of all causes, representing 80% of those with depression (BDI>10) and 73% of those without (p=0.01). Depression was significantly and persistently associated with decreased survival over follow-up (Hazard Ratio [HR] 1.35, 95% Confidence Interval [CI] 1.15–1.57) and was independent of conventional risk factors (HR 1.40, 95% CI 1.16–1.68). Furthermore, survival was inversely associated with depression severity (BDIcontinuous HR 1.02, 95% CI 1.006–1.025, p=0.001).
The impact of co-morbid depression during index hospitalization on significantly increased mortality of HF patients is strong and persists over12 years. These findings suggest that more investigation is needed to understand the trajectory of depression and the mechanisms underlying the impact of depression as well as to identify effective management strategies for depression of patients with HF.
depression; cardiovascular disease; chronic disease; epidemiology
Some prior studies have suggested that the time to cardiac surgery after cardiac catheterization is inversely related to post-operative acute kidney injury (AKI). However, these studies because of small number of patients were unable to adequately account for patient case-mix and included those undergoing either elective or urgent surgery.
Methods and Results
We examined data on 2441 consecutive patients undergoing elective coronary artery bypass surgery (CABG) after cardiac catheterization. The association of post-CABG AKI (defined as increase in post-CABG serum creatinine ≥ 50% above baseline and/or the need for new dialysis) and time between cardiac catheterization and CABG was evaluated using multivariable logistic regression modeling. AKI occurred in 17.1% of CABG patients. The risk of AKI was highest in patients in whom CABG was performed ≤ 1 day of cardiac catheterization (adjusted mean rates [95% CI] 24.0% [18.0%, 30.9%], 18.4% [14.8%, 22.5%], 17.3% [13.3%, 21.9%], 16.4% [12.6%, 20.8%], and 15.8% [13.7%, 18.0%] for days ≤ 1, 2, 3, 4 and ≥ 5, respectively; p = 0.019 for test of trend). Post-CABG AKI was associated with increased risk of long-term death (HR 1.268, 95% CI 1.093–1.471).
The risk of post-CABG AKI was inversely and modestly related to the time between cardiac catheterization and CABG with highest incidence in those operated ≤ 1 day of cardiac catheterization despite their lower risk profile. Whether delaying elective CABG > 24 hours of exposure to contrast agents (when feasible) has the potential for decreasing post-CABG AKI remains to be evaluated in future studies.
Coronary artery bypass surgery; acute kidney injury; risk; outcomes
Vein graft failure (VGF) is common after coronary artery bypass graft surgery, but its relationship with long-term clinical outcomes is unknown. In this retrospective analysis, we examined the relationship between VGF, assessed by coronary angiography 12 to 18 months after coronary artery bypass graft surgery, and subsequent clinical outcomes.
Methods and Results
Using the Project of Ex Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) trial database, we studied data from 1829 patients who underwent coronary artery bypass graft surgery and had an angiogram performed up to 18 months after surgery. The main outcome measure was death, myocardial infarction, and repeat revascularization through 4 years after angiography. VGF occurred in 787 of 1829 patients (43%). Clinical follow-up was completed in 97% of patients with angiographic follow-up. The composite of death, myocardial infarction, or revascularization occurred more frequently among patients who had any VGF compared with those who had none (adjusted hazard ratio, 1.58; 95% confidence interval, 1.21–2.06; P=0.008). This was due mainly to more frequent revascularization with no differences in death (adjusted hazard ratio, 1.04; 95% confidence interval, 0.71–1.52; P=0.85) or death or myocardial infarction (adjusted hazard ratio, 1.08; 95% confidence interval, 0.77–1.53; P=0.65).
VGF is common after coronary artery bypass graft surgery and is associated with repeat revascularization but not with death and/or myocardial infarction. Further investigations are needed to evaluate therapies and strategies for decreasing VGF to improve outcomes in patients undergoing coronary artery bypass graft surgery.
angiography; coronary artery bypass; graft survival; outcome assessment; veins
Chronic kidney disease is assuming epidemic proportions, and an increasing number of clinical trials are testing treatments developed to improve morbidity and mortality. Surprisingly, however, a large proportion of these trials have had negative or neutral results. When trials unexpectedly demonstrate either no benefit or a detrimental impact of a treatment, especially when that treatment is already used in practice, critics commonly argue that the results were dictated by flawed trial design rather than the intrinsic properties of the treatment. In kidney disease therapeutics, trials commonly rely on observational data and test the hypothesis that these associations may be extrapolated to cause-and-effect. Other key issues in trial design that may affect outcomes include the impact of enrolling relatively healthier subjects, the complexity of recruiting participants with specific characteristics while maintaining generalizability, and the subtleties of event adjudication and quality of life assessments. In this article, general principles of trial design will be discussed and the potential lessons learned from recent trials in nephrology will be critically reviewed.
nephrology; clinical trial; CHOIR; CREATE; HEMO; MDRD
Current understanding of chronic diseases is based on crude clinical characterization, imaging studies, and laboratory testing that has evolved over decades. The Measurement to Understand Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study is a multi-tiered, longitudinal study designed to enable classification of chronic diseases using clinically annotated biospecimen collections, -omic technologies, electronic health records, and standard epidemiological methods. We expect that detailed molecular classification will improve mechanistic understanding of chronic diseases, augmenting discovery and testing of new treatments, and allowing refined selection of prevention and treatment strategies. The MURDOCK Study Community Registry and Biorepository will serve as a bridge for validation of initial exploratory studies, a platform for future prospective studies in targeted populations, and a resource of both data (analytical and clinical) and samples for cross-registry meta-analyses and comparative population studies. Participation of local health care providers and the Cabarrus County/Kannapolis, NC, community will facilitate future medical research and provide the opportunity to educate and inform the public about genomic research, actively engaging them in shaping the future of medical discovery and treatment of chronic diseases. We present the rationale and study design for the MURDOCK Community Registry and Biorepository and baseline characteristics of the first 6000 participants.
Disease reclassification; community registry; biorepository
Facing critically low return per dollar invested on clinical research and clinical care, the American biomedical enterprise is in need of a significant transformation. A confluence of high-throughput “omic” technologies and increasing adoption of the electronic health record has fueled excitement for a new paradigm for biomedical research and practice. The ability to simultaneously measure thousands of molecular variables and assess their relationships with clinical data collected during the course of care could enable reclassification of disease not only by gross phenotypic observation but according to underlying molecular mechanism and influence of social determinants.In turn, this reclassification could enable development of targeted therapeutic interventions as well as disease prevention strategies at the individual and population levels.
The MURDOCK Study consists of distinct project “horizons” or stages. Horizon 1 entailed the generation and analysis of molecular data for existing large,clinically well-annotated cohorts in four disease areas. Horizon 1.5 involves creating and maintaining a 50,000-person,community volunteer registry for biomarker signature validation and prospective studies, including integration of environmental and social data. Horizon 2 leverages and prospectively recruits Horizon 1.5 volunteers, and extends the study to additional disease areas of interest. Horizon 3 will expand the study through regional, national,and international partnerships.
The MURDOCK Study embodies a new model of team science investigation and represents a significant resource for translational research. The study team invites inquiries to form new collaborations to exploit the rich resources provided by these biospecimens and associated study data.
Stratified medicine; personalized medicine; biomarkers; disease reclassification; community registry; biorepository
elderly; clopidogrel; glycoprotein IIb/IIIa blockers
The ClinicalTrials.gov trial registry was expanded in 2008 to include a database for reporting summary results. We summarize the structure and contents of the results database, provide an update of relevant policies, and show how the data can be used to gain insight into the state of clinical research.
We analyzed ClinicalTrials.gov data that were publicly available between September 2009 and September 2010.
As of September 27, 2010, ClinicalTrials.gov received approximately 330 new and 2000 revised registrations each week, along with 30 new and 80 revised results submissions. We characterized the 79,413 registry and 2178 results of trial records available as of September 2010. From a sample cohort of results records, 78 of 150 (52%) had associated publications within 2 years after posting. Of results records available publicly, 20% reported more than two primary outcome measures and 5% reported more than five. Of a sample of 100 registry record outcome measures, 61% lacked specificity in describing the metric used in the planned analysis. In a sample of 700 results records, the mean number of different analysis populations per study group was 2.5 (median, 1; range, 1 to 25). Of these trials, 24% reported results for 90% or less of their participants.
ClinicalTrials.gov provides access to study results not otherwise available to the public. Although the database allows examination of various aspects of ongoing and completed clinical trials, its ultimate usefulness depends on the research community to submit accurate, informative data.
Congress has authorized the U.S. Food and Drug Administration (FDA) to provide industry sponsors with a 6-month extension of drug marketing rights under the Pediatric Exclusivity Provision if FDA-requested pediatric drug trials are conducted. The cost and economic return of pediatric exclusivity to industry sponsors has been shown to be highly variable. We sought to determine the cost of performing pediatric exclusivity trials within a single therapeutic area and the subsequent economic return to industry sponsors.
We evaluated 9 orally administered anti-hypertensive drugs submitted to the FDA under the Pediatric Exclusivity Provision from 1997–2004 and obtained key elements of the clinical trial designs and operations. Estimates of the costs of performing the studies were generated and converted into after-tax cash outflow. Market sales were obtained and converted into after-tax inflows based on 6 months of additional patent protection. Net economic return and net return-to-cost ratios were determined for each drug.
Of the 9 anti-hypertensive agents studied, an average of 2 studies per drug was performed, including at least 1 pharmacokinetic study and a safety and efficacy study. The median cost of completing a pharmacokinetic trial was $862,000 (range: $556,000–1.8 million). The median cost of performing safety and efficacy trials for these agents was $4.3 million (range: $2.1 million–12.9 million). The ratio of net economic return to cost was 17 (range: 4–64.7).
We found that, within a cohort of anti-hypertensive drugs, the Pediatric Exclusivity Provision has generated highly variable, yet lucrative returns to industry sponsors.
clinical trials; hypertension; pediatrics; drugs; cost-benefit analysis
Few data exist to guide antiarrhythmic drug therapy for sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) after acute myocardial infarction (MI). The objective of this analysis was to describe survival of patients with sustained VT/VF post-MI according to antiarrhythmic drug treatment.
Design & Setting
We conducted a retrospective analysis of ST-segment elevation MI patients with sustained VT/VF in GUSTO IIB and III and compared all-cause death in patients receiving amiodarone, lidocaine, or no antiarrhythmic. We used Cox proportional hazards modeling and inverse weighted estimators to adjust for baseline characteristics, beta-blocker use, and propensity to receive antiarrhythmics. Due to non-proportional hazards for death in early follow-up (0–3 hours after sustained VT/VF) compared with later follow-up (>3 hours), we analyzed all-cause mortality using time-specific hazards.
Patients & Interventions
Among 19,190 acute MI patients, 1126 (5.9%) developed sustained VT/VF and met the inclusion criteria. Patients received lidocaine (n=664, 59.0%), amiodarone (n=50, 4.4%), both (n=110, 9.8%), or no antiarrhythmic (n=302, 26.8%).
In the first 3 hours after VT/VF, amiodarone (adjusted HR 0.39, 95% CI 0.21–0.71) and lidocaine (adjusted HR 0.72, 95% CI 0.53–0.96) were associated with a lower hazard of death—likely evidence of survivor bias. Among patients who survived 3 hours, amiodarone was associated with increased mortality at 30 days (adjusted HR 1.71, 95% CI 1.02–2.86) and 6 months (adjusted HR 1.96, 95% CI 1.21–3.16) but lidocaine was not at 30 days (adjusted HR 1.19, 95% CI 0.77–1.82) and 6 months (adjusted HR 1.10, 95% CI 0.73–1.66).
Among patients with acute MI complicated by sustained VT/VF who survive 3 hours, amiodarone, but not lidocaine, is associated with an increased risk of death; reinforcing the need for randomized trials in this population.
ventricular arrhythmia; antiarrhythmic drug therapy; clinical trials; acute coronary syndrome; ventricular tachycardia; ventricular fibrillation
We examined the relation of maximal in-hospital diuretic dose to weight loss, changes in renal function, and mortality in hospitalised heart failure (HF) patients.
In ESCAPE, 395 patients received diuretics in-hospital. Weight was measured at baseline, discharge, and every other day before discharge. Weight loss was defined as the difference between baseline and last in-hospital weight. Mortality was assessed using a log-logistic model with non-zero background.
Median weight loss: 2.8 kg (0.7, 6.1); mean: 3.7 kg (22% of values <0). Weight loss and maximum in-hospital dose were correlated (p = 0.0007). Baseline weight, length of stay, and baseline brain natriuretic peptide were significant predictors of weight loss. After adjusting for these, dose was not a significant predictor of weight loss. A strong relation between dose and mortality was seen (p = 0.003), especially at >300 mg/day. Dose remained a significant predictor of mortality after adjusting for baseline variables that significantly predicted mortality. Correlation between maximal dose and creatinine level change was not significant (r = 0.043; p = 0.412)
High diuretic doses during HF hospitalisation are associated with increased mortality and poor 6-month outcome.
diuretics; heart failure; outcomes
Advances in human health require the efficient and rapid translation of scientific discoveries into effective clinical treatments; this process in turn depends upon observational data gathered from patients, communities, and public-health research that can be used to guide basic scientific investigation. Such bidirectional translational science, however, faces unprecedented challenges due to the rapid pace of scientific and technological development, as well as the difficulties of negotiating increasingly complex regulatory and commercial environments that overlap the research domain. Further, numerous barriers to translational science have emerged among the nation’s academic research centers, including basic structural and cultural impediments to innovation and collaboration, shortages of trained investigators, and inadequate funding.
To address these serious and systemic problems, in 2006, the National Institutes of Health created the Clinical and Translational Science Awards (CTSA) program, which aims to catalyze the transformation of biomedical research at a national level, speeding the discovery and development of therapies, fostering collaboration, engaging communities, and training succeeding generations of clinical and translational researchers. The authors report in detail on the planning process, begun in 2008, that was used to engage stakeholders and to identify, refine, and ultimately implement the CTSA program’s overarching strategic goals. They also discuss the implications and likely impact of this strategic planning process as it is applied among the nation’s academic health centers.
To quantify the frequency and type of new safety information arising from studies performed under the auspices of the Pediatric Exclusivity Program, to describe the dissemination of these findings in the peer-reviewed literature and compare this with the FDA review, and to describe their effect on pediatric labeling.
Cohort study of the 365 trials performed for 153 drugs.
The Pediatric Exclusivity incentive from December 1997 through September 2007.
Food and Drug Administration publicly available records and peer-reviewed literature retrievable by Medline search.
New safety findings obtained from the trials completed for exclusivity.
Main Outcome Measures
Concordance of the information highlighted in the peer-reviewed article abstracts with the information in the FDA labeling and drug reviews.
There were 137 labeling changes; we evaluated 129 of these (the 8 selective serotonin reuptake inhibitors were excluded from review). Thirty-three products (26%) had pediatric safety information added to the labeling. Of these, 12 products had neuropsychiatric safety findings, and 21 had other important safety findings. Only 16/33 (48%) of these trials were reported in the peer-reviewed literature; however, 7/16 of these publications focused on findings substantively different from those highlighted in the FDA reviews and labeling changes.
Medication adverse events in children often differ from those in adults, particularly those that are neuropsychiatric in nature. Labeling changes for pediatric use demonstrate that pediatric drug studies provide valuable and unique safety data that can guide the use of these drugs in children. Unfortunately, most these articles are not published, and almost half of the published articles focus their attention away from the crucial safety data.
There is conflicting information about whether sex-differences modulate short-term mortality following acute coronary syndromes (ACS).
To investigate the relationship between sex and 30-day mortality in ACS, and determine whether this relationship is modified by clinical syndrome or coronary anatomy using a large database across the spectrum of ACS and adjusting for potentially confounding clinical covariates.
Design Setting and Participants
Data from 11 ACS trials from 1993 to 2006 were pooled. Of 136,247 patients, 38,048 (28%) were women; 102,004 (26% women) STEMI, 14,466 (29% women) NSTEMI and 19,777 (40% women) unstable angina (UA).
Main Outcome Measure
Thirty-day mortality following ACS.
Mortality at 30 days was 9.6% in women and 5.3% in men (odds ratio [OR] 1.91, 95% confidence interval [CI] 1.83–2.00). After multivariable adjustment, mortality was not significantly different between women and men (adjusted OR 1.06, 95% CI 0.99–1.15). Importantly, a significant sex by type of ACS interaction was demonstrated (P<0.001). In STEMI, 30-day mortality was higher among women (adjusted OR 1.15, 95% CI 1.06–1.24), whereas NSTEMI (adjusted OR 0.77, 95% CI 0.63–0.95), and UA mortality was lower among women (adjusted OR 0.55, 95% CI 0.43–0.70). In a cohort of 35,128 patients with angiographic data, women more often had non-obstructive (15% vs. 8%,) and less often had 2-vessel (25% vs. 28%) and 3-vessel (23% vs. 26%) coronary disease regardless of ACS type. After additional adjustment for angiographic disease severity, 30-day mortality among women was not significantly different than men, regardless of ACS type. The relationship between sex and 30-day mortality was similar across the levels of angiographic disease severity (p-value for interaction =0.70),
Sex-based differences exist in 30-day mortality among ACS patients and vary depending on clinical presentation. However, these differences are markedly attenuated following adjustment for clinical differences and angiographic data.
Trials of anemia correction in chronic kidney disease have found either no benefit or detrimental outcomes of higher targets. We did a secondary analysis of patients with chronic kidney disease enrolled in the Correction of Hemoglobin in the Outcomes in Renal Insufficiency trial to measure the potential for competing benefit and harm from achieved hemoglobin and epoetin dose trials. In the 4 month analysis, significantly more patients in the high-hemoglobin compared to the low-hemoglobin arm were unable to achieve target hemoglobin and required high-dose epoetin-α. In unadjusted analyses, the inability to achieve a target hemoglobin and high-dose epoetin-α were each significantly associated with increased risk of a primary endpoint (death, myocardial infarction, congestive heart failure or stroke). In adjusted models, high-dose epoetin-α was associated with a significant increased hazard of a primary endpoint but the risk associated with randomization to the high hemoglobin arm did not suggest a possible mediating effect of higher target via dose. Similar results were seen in the 9 month analysis. Our study demonstrates that patients achieving their target had better outcomes than those who did not; and among subjects who achieved their randomized target, no increased risk associated with the higher hemoglobin goal was detected. Prospective studies are needed to confirm this relationship and determine safe dosing algorithms for patients unable to achieve target hemoglobin.
anemia; chronic kidney disease; epoetin-α; dose; epidemiology and outcomes
The CHOIR trial in anemic patients with chronic kidney disease compared epoetin-alfa treatment with low (11.3 g/l) and high (13.5 g/l) hemoglobin targets on the composite end point of death, hospitalization for heart failure, stroke, and myocardial infarction. However, other anemia management trials in patients with chronic kidney disease found there was increased risk when hemoglobin is targeted above 13 g/dl. In this secondary analysis of the CHOIR trial, we compared outcomes among the subgroups of patients with diabetes and heart failure to describe the comparative relationship of treatment to these two different hemoglobin goals. By Cox regression analysis, there was no increased risk associated with the higher hemoglobin target among patients with heart failure. In patients without heart failure, however, the hazard ratio (1.86) associated with the higher target was significant. Comparing survival curves in an unadjusted model, patients with diabetes did not have a greater hazard associated with the higher target. Subjects without diabetes had a significantly greater hazard in the high as compared to the low target, but the interaction between diabetes and the target was not significant. We suggest that the increased risks associated with higher hemoglobin targets are not clinically apparent among subgroups with greater mortality risk. These differential outcomes underscore the need for dedicated trials in these subpopulations.
anemia; diabetes mellitus; heart failure; kidney
On the basis of our experience in drug and device development, we have identified six broad categories of issues that profoundly affect the probability for successful translation of basic scientific discoveries into effective therapies. Within each category, we propose a series of questions that form the beginnings of a self-guided global risk assessment tool. Although this preliminary tool will require validation and adjustment, we offer it to stimulate a discussion about more rigorous methods for selecting and conducting translational projects.
To investigate whether the beneficial and harmful effects of platelet glycoprotein IIb/IIIa receptor blockers in non‐ST elevation acute coronary syndromes (NSTE‐ACS) depend on age.
A meta‐analysis of six trials of platelet glycoprotein IIb/IIIa receptor blockers in patients with NSTE‐ACS (PRISM, PRISM‐PLUS, PARAGON‐A, PURSUIT, PARAGON‐B, GUSTO IV‐ACS; n = 31 402) was performed. We applied multivariable logistic regression analyses to evaluate the drug effects on death or non‐fatal myocardial infarction at 30 days, and on major bleeding, by age subgroups (<60, 60–69, 70–79, ⩾80 years). We quantified the reduction of death or myocardial infarction as the number needed to treat (NNT), and the increase of major bleeding as the number needed to harm (NNH).
Subgroups had 11 155 (35%), 9727 (31%), 8468 (27%) and 2049 (7%) patients, respectively. The relative benefit of platelet glycoprotein IIb/IIIa receptor blockers did not differ significantly (p = 0.5) between age subgroups (OR (95% CI) for death or myocardial infarction: 0.86 (0.74 to 0.99), 0.90 (0.80 to 1.02), 0.97 (0.86 to 1.10), 0.90 (0.73 to 1.16); overall 0.91 (0.86 to 0.99). ORs for major bleeding were 1.9 (1.3 to 2.8), 1.9 (1.4 to 2.7), 1.6 (1.2 to 2.1) and 2.5 (1.5–4.1). Overall NNT was 105, and overall NNH was 90. The oldest patients had larger absolute increases in major bleeding, but also had the largest absolute reductions of death or myocardial infarction. Patients ⩾80 years had half of the NNT and a third of the NNH of patients <60 years.
In patients with NSTE‐ACS, the relative reduction of death or non‐fatal myocardial infarction with platelet glycoprotein IIb/IIIa receptor blockers was independent of patient age. Larger absolute outcome reductions were seen in older patients, but with a higher risk of major bleeding. Close monitoring of these patients is warranted.