Showing papers by "Marc A. Pfeffer published in 2017"
Harvard University1, Novartis2, University of Minnesota3, Fudan University4, National University of Singapore5, National University of Cordoba6, Baylor University Medical Center7, Charité8, Mayo Clinic9, Université de Montréal10, University of Groningen11, University of Lorraine12, Veterans Health Administration13, Medical University of South Carolina14, University of Glasgow15
TL;DR: The PARAGON-HF trial will determine whether sacubitril/valsartan is superior to angiotensin receptor blockade alone in patients with chronic symptomatic HFpEF.
Abstract: Objectives The PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) trial is designed to determine the efficacy and safety of the angiotensin receptor neprilysin inhibitor sacubitril/valsartan compared with valsartan in patients with chronic heart failure and preserved ejection fraction (HFpEF). Background HFpEF is highly prevalent, associated with substantial morbidity and mortality, and in need of effective therapies that improve outcomes. The angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan, which has been shown to benefit patients with heart failure (HF) and reduced ejection fraction, demonstrated favorable physiologic effects in a phase II HFpEF trial. Methods The PARAGON-HF trial is a randomized, double-blind, parallel group, active-controlled, event-driven trial comparing the long-term efficacy and safety of valsartan and sacubitril/valsartan in patients with chronic HFpEF (left ventricular ejection fraction ≥45%), New York Heart Association functional class II to IV symptoms, elevated natriuretic peptides, and evidence of structural heart disease. Before randomization, all patients entered sequential single-blind run-in periods to ensure tolerability of both drugs at half the target doses (i.e., valsartan titrated to 80 mg bid followed by sacubitril/valsartan 49/51 mg [100 mg] bid). The primary outcome is the composite of cardiovascular death and total (first and recurrent) HF hospitalizations. Conclusions PARAGON-HF will determine whether sacubitril/valsartan is superior to angiotensin receptor blockade alone in patients with chronic symptomatic HFpEF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)
222 citations
TL;DR: In a subgroup of TOPCAT participants assigned to spironolactone, the spironOLactone metabolite canrenone was measured to assess adherence to ensure adherence to the drug.
Abstract: In a subgroup of TOPCAT participants assigned to spironolactone, the spironolactone metabolite canrenone was measured to assess adherence. Canrenone levels were undetectable in 30% of participants from Russia, as compared with only 3% from the United States and Canada.
188 citations
TL;DR: Higher levels of natriuretic peptides were independently associated with an increased risk for TOPCAT's primary endpoint of cardiovascular mortality, aborted cardiac arrest, or hospitalization for HF when analyzed either continuously or grouped by terciles.
Abstract: Objectives The aims of this study were to explore the relationship of baseline levels of natriuretic peptides (NPs) with outcomes and to test for an interaction between baseline levels of NPs and the effects spironolactone. Background Plasma NPs are considered to be helpful in the diagnosis of heart failure (HF) with preserved ejection fraction (HFpEF), and elevated levels are associated with adverse outcomes. Levels of NPs higher than certain cutoffs are often used as inclusion criteria in clinical trials of HFpEF to increase the likelihood that patients have HF and to select patients at higher risk for events. Whether treatments have a differential effect on outcomes across the spectrum of NP levels is unclear. Methods The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) trial randomized patients with HFpEF and either prior hospitalization for HF or elevated natriuretic peptide levels (B-type NP [BNP] ≥100 pg/ml or N-terminal proBNP ≥360 pg/ml) to spironolactone or placebo. Baseline BNP (n = 430) or N-terminal proBNP (n = 257) levels were available in 687 patients enrolled from the Americas in the elevated-NP stratum of TOPCAT. Results Higher levels of NPs were independently associated with an increased risk for TOPCAT’s primary endpoint of cardiovascular mortality, aborted cardiac arrest, or hospitalization for HF when analyzed either continuously or grouped by terciles, adjusting for region of enrollment, age, sex, atrial fibrillation, diabetes, renal function, body mass index, and heart rate. There was a significant interaction between the effect of spironolactone and baseline NP terciles for the primary outcome (p = 0.017), with greater benefit of the drug in the lower compared with higher NP terciles. Conclusions Similar to the effects of irbesartan in the I-PRESERVE (Irbesartan in Heart Failure With Preserved Ejection Fraction) trial, a greater benefit of spironolactone was observed in the group with lower levels of NPs and overall risk in TOPCAT. Elevated NPs in HFpEF identify patients at higher risk for events but who may be less responsive to treatment. The mechanism of this apparent interaction between disease severity and response to therapy requires further exploration. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302)
134 citations
University of Oxford1, Clinical Trial Service Unit2, Johns Hopkins University3, University of British Columbia4, The George Institute for Global Health5, Brigham and Women's Hospital6, University of Copenhagen7, Population Health Research Institute8, University College London9, Baylor College of Medicine10, British Heart Foundation11, Auckland City Hospital12, University of Calgary13, University of Melbourne14, Hong Kong University of Science and Technology15, Post Graduate Institute of Medical Education and Research16, Peking Union Medical College17, University Medical Center Groningen18, University of Toronto19, Heidelberg University20, University of Sydney21
TL;DR: The main findings from the conference are summarized and a range of potential solutions are set out to ensure future trials among people with kidney disease are sufficiently robust to provide reliable answers and are not constrained by inappropriate complexities in design or conduct.
95 citations
TL;DR: In patients with a recent acute coronary syndrome and type 2 diabetes mellitus, BNP and NT‐proBNP were powerful predictors of cardiovascular outcomes beyond heart failure and death, ie, were also predictive of MI and stroke.
Abstract: BackgroundNatriuretic peptides are recognized as important predictors of cardiovascular events in patients with heart failure, but less is known about their prognostic importance in patients with a...
79 citations
TL;DR: In patients with HF with preserved ejection fraction, both poor and intermediate self-reported PA were associated with higher risk of HF hospitalization and mortality.
Abstract: Background:Physical activity (PA) is inversely associated with adverse cardiovascular outcomes in healthy populations, but the impact of physical activity in patients with heart failure (HF) with p...
77 citations
TL;DR: It is demonstrated that dysglycemia is associated with a higher risk of adverse clinical outcomes, even before the diagnosis of diabetes and institution of glucose lowering therapy in patients with HFpEF as well as HFrEF.
Abstract: The prevalence and consequences of prediabetic dysglycemia and undiagnosed diabetes is unknown in patients with heart failure (HF) and preserved ejection fraction (HFpEF) and has not been compared to heart failure and reduced ejection fraction (HFrEF). We examined the prevalence and outcomes associated with normoglycemia, prediabetic dysglycemia and diabetes (diagnosed and undiagnosed) among individuals with a baseline glycated hemoglobin (hemoglobin A1c, HbA1c) measurement stratified by HFrEF or HFpEF in the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity programme (CHARM). We studied the primary outcome of HF hospitalization or cardiovascular (CV) death, and all-cause death, and estimated hazard ratios (HR) by use of multivariable Cox regression models. HbA1c was measured at baseline in CHARM patients enrolled in the USA and Canada and was available in 1072/3023 (35%) of patients with HFpEF and 1578/4576 (34%) patients with HFrEF. 18 and 16% had normoglycemia (HbA1c 6.4), and 40% had known diabetes (any HbA1c), with corresponding prevalence among HFrEF patients being 26 and 35%. The rates of both clinical outcomes of interest were higher in patients with undiagnosed diabetes and prediabetes, compared to normoglycemic patients, irrespective of HF subtype, and in general higher among HFrEF patients. For the primary composite outcome among HFpEF patients, the HRs were 1.02 (95% CI 0.63–1.65) for prediabetes, HR 1.18 (0.75–1.86) for undiagnosed diabetes and 2.75 (1.83–4.11) for known diabetes, respectively, p value for trend across groups < 0.001. Dysglycemia was also associated with worse outcomes in HFrEF. These findings confirm the remarkably high prevalence of dysglycemia in heart failure irrespective of ejection fraction phenotype, and demonstrate that dysglycemia is associated with a higher risk of adverse clinical outcomes, even before the diagnosis of diabetes and institution of glucose lowering therapy in patients with HFpEF as well as HFrEF.
50 citations
University of Washington1, University of Wisconsin-Madison2, Duke University3, Center for Drug Evaluation and Research4, University of Pittsburgh5, Merck & Co.6, Tufts Medical Center7, National Institutes of Health8, Stanford University9, Florida Atlantic University10, University of Minnesota11, AstraZeneca12, Brigham and Women's Hospital13, University of Pennsylvania14
TL;DR: An expert panel of representatives from academia, industry and government sponsors, and regulatory agencies discussed these challenges and proposed best practices and operating principles for effective functioning of contemporary data monitoring committees.
Abstract: Background and Purpose:Data monitoring committees are responsible for safeguarding the interests of study participants and assuring the integrity and credibility of clinical trials. The independenc...
37 citations
TL;DR: Higher concentrations of urine α1m, MCP‐1, and PINP may identify KTRs at higher risk for CVD events and death, and give new insights into mechanisms linking the kidney with CVD.
36 citations
TL;DR: Left ventricular mechanical dyssynchrony has been described in heart failure with preserved ejection fraction (HFpEF), but its prognostic significance is not known.
Abstract: Aims
Left ventricular mechanical dyssynchrony has been described in heart failure with preserved ejection fraction (HFpEF), but its prognostic significance is not known.
Methods and results
Of 3445 patients with HFpEF enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, dyssynchrony analysis was performed on 424 patients (12%) by multiple speckle tracking echocardiography strain-based criteria. The primary dyssynchrony analysis was the standard deviation of the time to peak longitudinal strain (SD T2P LS). Cox proportional hazards models assessed the association of dyssynchrony with the composite outcome of cardiovascular death or heart failure hospitalization. Mean age was 70 ± 10 years, LVEF was 60 ± 8%, and QRS duration was 101 ± 27 ms. Worse dyssynchrony, reflected in SD T2P LS, was associated with wider QRS, prior myocardial infarction, larger LV volume and mass, and worse systolic (lower LVEF and global longitudinal strain) and diastolic (lower e' and higher E/e') function. During a median follow-up of 2.6 (interquartile range 1.5–3.8) years, 107 patients experienced the composite outcome. Worse dyssynchrony was associated with the composite outcome in unadjusted analysis [hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.01–1.07; P = 0.021, per 10 ms increase], but not after adjusting for clinical characteristics, or after further adjustment for LVEF, AF, NYHA class, stroke, heart rate, creatinine, haematocrit, and QRS duration (HR 1.03, 95% CI 0.99–1.06; P = 0.16, per 10 ms increase).
Conclusion
Worse LV mechanical dyssynchrony, assessed by speckle tracking echocardiography, is not an independent predictor of adverse outcomes in HFpEF, suggesting that mechanical dyssynchrony is unlikely to be an important mechanism underlying this syndrome. These findings warrant validation in an independent study specifically designed to assess the prognostic utility of mechanical dyssynchrony in HFpEF.
Trial registration: NCT00094302
32 citations
TL;DR: It is concluded that cystatin C and B2M are strongly associated with cardiovascular events, mortality, and kidney failure in stable kidney transplant recipients.
TL;DR: The treatment of hypertension with antihypertensive agents is particularly effective in preventing heart failure, which makes it the most effective therapy for heart failure.
Rhode Island Hospital1, Brown University2, University of North Carolina at Chapel Hill3, National Institutes of Health4, United States Department of Agriculture5, Brigham and Women's Hospital6, Tufts Medical Center7, Toronto General Hospital8, Ohio State University9, Duke University10, University of Alabama at Birmingham11, London Health Sciences Centre12, University of California, San Diego13
TL;DR: Serum phosphorus level is marginally associated with CVD and more strongly associated with transplant failure and total mortality in long-term KTRs, and a randomized controlled clinical trial in K TRs that assesses the potential impact of phosphorus-lowering therapy on these hard outcomes may be warranted.
TL;DR: Following kidney transplantation, uric acid concentrations are not independently associated with CV events, mortality, or transplant failure, and the strong association between uric Acid concentrations with traditional risk factors and eGFR is a possible explanation.
TL;DR: Baseline resting HR and change in HR over time predict outcomes in patients with HFpEF, as does time-updated HR during follow-up, and frequent outpatient monitoring of HR, possibly with remote technologies, may identify patients withHFpEF who may be at increased risk for rehospitalization or death.
Abstract: Objectives The aim of this study was to examine the relationship between baseline heart rate (HR), change in HR from a preceding visit, and time-updated HR with subsequent outcomes in patients with heart failure with preserved ejection fraction (HFpEF) in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial. Background Higher resting HR and increase in HR over time in patients with heart failure are associated with adverse outcomes. Whether these relationships between HR and prognosis are also observed in patients with HFpEF requires further assessment. Methods In 1,767 patients enrolled in the TOPCAT trial from the Americas, the associations between baseline resting HR and change in HR from the preceding visit and clinical outcomes were examined using Cox proportional hazards models, along with the association between HR at each visit and outcome. Results Both baseline HR (adjusted hazard ratio: 1.08; 95% confidence interval: 1.04 to 1.12) and change in HR from the preceding visit (adjusted hazard ratio: 1.09; 95% confidence interval: 1.05 to 1.14; p Conclusions Baseline resting HR and change in HR over time predict outcomes in patients with HFpEF, as does time-updated HR during follow-up. These data suggest that frequent outpatient monitoring of HR, possibly with remote technologies, may identify patients with HFpEF who may be at increased risk for rehospitalization or death.
TL;DR: Assessment of the efficacy and safety of lixisenatide, a glucagon-like peptide-1 receptor agonist, with respect to cardiovascular morbidity and mortality in patients with a recent coronary event and type 2 diabetes mellitus enrolled in the ELIXA trial.
Abstract: Patients with a recent coronary event are at high risk of further cardiovascular events, including hospitalization for heart failure (HFH).1,2 Knowledge of the pathophysiological changes preceding HFH provides insight into the temporal course of the progression of HF and may help identify those at imminent risk of this event. B-type natriuretic peptide (BNP) and NT-proBNP (N-terminal prohormone BNP) change rapidly in relation to changes in filling pressures and wall stress, making them useful for monitoring clinical status and response to treatment and clinical status in HF.3 Because there are limited data on temporal changes in natriuretic peptides (NPs) preceding HFH, we examined concentrations of NPs preceding HFH in patients with a recent coronary event and type 2 diabetes mellitus enrolled in the ELIXA trial [Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010 (Lixisenatide); NCT01147250].
The design and primary findings of ELIXA have been published.4 A total of 6068 patients with type 2 diabetes mellitus and an acute coronary syndrome (index event) occurring within 180 days of randomization were enrolled. The trial was designed to assess the efficacy and safety of lixisenatide, a glucagon-like peptide-1 receptor agonist, with respect to cardiovascular morbidity and mortality.5 Sampling of BNP and NT-proBNP occurred at baseline and at weeks 24, 76, and 108 after randomization, yielding 19 585 samples. Samples were collected and analyzed at a core laboratory (Covance Central Laboratory Services, Meyrin, Switzerland). ELIXA was approved by appropriate institutional or central review boards. All participants provided …
National Institutes of Health1, National and Kapodistrian University of Athens2, Medicines and Healthcare Products Regulatory Agency3, Charité4, University of Göttingen5, European Medicines Agency6, Merck & Co.7, Bristol-Myers Squibb8, Norwegian Medicines Agency9, Novartis10, Amgen11, GlaxoSmithKline12, Pfizer13, Hospital Universitario La Paz14, University of Glasgow15, University of Brescia16, Bayer HealthCare Pharmaceuticals17, Brigham and Women's Hospital18, University of London19, Vita-Salute San Raffaele University20, Campbell University21, University of Gothenburg22, University of Lorraine23, University of Groningen24
TL;DR: The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two‐day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline.
Abstract: Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two-day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run-in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way.
Brigham and Women's Hospital1, Northwestern University2, Baker IDI Heart and Diabetes Institute3, Washington University in St. Louis4, Copenhagen University Hospital5, St. John's University6, University of São Paulo7, Tufts University8, University Medical Center Groningen9, University of Erlangen-Nuremberg10, University of Glasgow11
TL;DR: Most ESRD cases occurred in individuals without intercurrent CV events who had lower eGFRs than individuals with intercurrentCV events, but similar post-ESRD mortality, underscoring the need for kidney-specific therapies in addition to treatment of CV risk factors to lower E SRD incidence in diabetes.
TL;DR: Several completed or ongoing trials illustrate the feasibility of using registry-based controlled trials to answer important questions relevant to daily clinical practice and how trials might be simplified while maintaining randomisation to preserve scientific integrity and unbiased efficacy assessments.
Abstract: Controlled trials provide the most valid determination of the efficacy and safety of an intervention, but large cardiovascular clinical trials have become extremely costly and complex, making it difficult to study many important clinical questions. A critical question, and the main objective of this review, is how trials might be simplified while maintaining randomisation to preserve scientific integrity and unbiased efficacy assessments. Experience with alternative approaches is accumulating, specifically with registry-based randomised controlled trials that make use of data already collected. This approach addresses bias concerns while still capitalising on the benefits and efficiencies of a registry. Several completed or ongoing trials illustrate the feasibility of using registry-based controlled trials to answer important questions relevant to daily clinical practice. Randomised trials within healthcare organisation databases may also represent streamlined solutions for some types of investigations, although data quality (endpoint assessment) is likely to be a greater concern in those settings. These approaches are not without challenges, and issues pertaining to informed consent, blinding, data quality and regulatory standards remain to be fully explored. Collaboration among stakeholders is necessary to achieve standards for data management and analysis, to validate large data sources for use in randomised trials, and to re-evaluate ethical standards to encourage research while also ensuring that patients are protected. The rapidly evolving efforts to streamline cardiovascular clinical trials have the potential to lead to major advances in promoting better care and outcomes for patients with cardiovascular disease.
TL;DR: This paper proposes a simple, robust procedure based on a mixture population concept and provides a clinically meaningful group contrast summary for a well-defined target population and uses the data from a recent meta-analysis for evaluating statin therapies with respect to the incidence of fatal stroke events to illustrate the issues associated with the standard meta- analysis procedures.
Abstract: Meta-analysis techniques, if applied appropriately, can provide a summary of the totality of evidence regarding an overall difference between a new treatment and a control group using data from multiple comparative clinical studies The standard meta-analysis procedures, however, may not give a meaningful between-group difference summary measure or identify a meaningful patient population of interest, especially when the fixed-effect model assumption is not met Moreover, a single between-group comparison measure without a reference value obtained from patients in the control arm would likely not be informative enough for clinical decision making In this paper, we propose a simple, robust procedure based on a mixture population concept and provide a clinically meaningful group contrast summary for a well-defined target population We use the data from a recent meta-analysis for evaluating statin therapies with respect to the incidence of fatal stroke events to illustrate the issues associated with the standard meta-analysis procedures as well as the advantages of our simple proposal
TL;DR: Higher BNP is associated with mortality and cardiovascular and kidney outcomes in stable kidney transplant recipients and Elevated BNP and hs-cTnI identify candidates for targeted risk reduction.
Abstract: Background Approximately 200 000 kidney transplant recipients are living in the United States; they are at increased risk for cardiovascular and other adverse outcomes. Biomarkers predicting these outcomes are needed. Using specimens collected during the Folic Acid for Vascular Outcome Reduction in Transplantation trial, we determined whether plasma levels of B-type natriuretic peptide (BNP) and cardiac troponin I are associated with adverse outcomes in stable kidney transplant recipients. Methods Five hundred ten subjects were selected randomly from the 4110 Folic Acid for Vascular Outcome Reduction in Transplantation participants. This cohort was then enriched for all additional subjects with adverse outcomes (death, dialysis-dependent kidney failure (DDKF), and cardiovascular outcomes) for a total of 1131 participants studied. Quartiles of BNP and high-sensitivity cardiac troponin I (hs-cTnI) were included in adjusted models. Combinations of normal and elevated hs-cTnI (>26.2 ng/L) and BNP (>100 pg/mL) were also studied. Results Median concentrations (interquartile ranges) were 5.6 (3.3-10.5) ng/L for hs-cTnI and 39 (15, 94) pg/mL for BNP. Hazard ratios for each adverse outcome were higher with higher quartiles of BNP after adjustment and remained statistically significant after adding hs-cTnI to the model. The highest quartile hazard ratio for DDKF was 2.47 (95% confidence interval [95% CI], 1.21-5.05). Simultaneous elevations of BNP and hs-cTnI over clinical cutoffs were strongly associated with adverse outcomes with hazard ratios 8.8 (95% CI, 3.4-23.1) for DDKF and 6.3 (95% CI, 2.7-15.0) for cardiovascular outcomes. Conclusions Higher BNP is associated with mortality and cardiovascular and kidney outcomes in stable kidney transplant recipients. Elevated BNP and hs-cTnI identify candidates for targeted risk reduction.
TL;DR: In this paper, the authors performed a post hoc analysis of 4,038 participants in TREAT and used mixed effects linear regression models to determine the trajectory of parameters of interest prior to end-stage renal disease (ESRD).
Abstract: Background: The pathogenesis of chronic kidney disease associated anemia is multifactorial and includes decreased production of erythropoietin (EPO), iron deficiency, inflammation, and EPO resistance. To better understand the trajectory of these parameters, we described temporal trends in hemoglobin (Hb), ferritin, transferrin saturation, C-reactive protein (CRP), and darbepoetin dosing in the Trial to Reduce cardiovascular Events with Aranesp Therapy (TREAT). Methods: We performed a post hoc analysis of 4,038 participants in TREAT. Mixed effects linear regression models were used to determine the trajectory of parameters of interest prior to end-stage renal disease (ESRD). Likelihood ratio tests were used to determine the overall differences in biomarker values and differences in trajectories between those who did and did not develop ESRD. Results: Hb declined precipitously in the year prior to the development of ESRD (irrespective of treatment assignment), and was on average 1.15 g/dL (95% CI –1.26 to –1.04) lower in those who developed ESRD versus those who did not, at the time of ESRD/end of follow-up. Simultaneously, the mean darbepoetin dose and CRP concentration increased, while serum ferritin and transferrin saturations were >140 μg/L and 20%, respectively. Conclusions: Our analyses provide descriptive insights regarding the temporal changes of Hb, darbepoetin dose, and related parameters as ESRD approaches in participants of TREAT. Hb declined as much as 1–2 years prior to the development of ESRD, without biochemical evidence of iron deficiency. The most precipitous decline occurred in the months immediately prior to ESRD, despite administration of escalating doses of darbepoetin and in parallel with an increase in CRP.
TL;DR: The principal findings were that compared with their existing programme, the intensive strategy was associated with higher costs, but did not produce improvements in survival, hospital admissions, and most indices of patient-reported quality-of-life.
Abstract: Physicians have the privilege and responsibility to use and incorporate the best available data in their shared decision-making with their patients. Fortunately, in well-studied conditions such as heart failure, multiple therapeutic interventions have been rigorously tested in randomized controlled clinical trials demonstrating meaningful improvements in clinical outcomes. These trials also generate much needed information regarding the safety profile of these therapies. Based largely on the results of these trials, professional societies have developed practice guidelines to provide some weighted consideration for evidence-based therapeutic options. The heavy reliance of treatment guidelines in cardiology on the results of randomized controlled treatment trials has fuelled a somewhat reductionist view of clinical trial evidence in practice. Trials are commonly viewed as ‘positive’, ‘neutral’, or, even worse, ‘negative’, with the implication that neutral results are largely uninformative, while the positive trials may be practice changing. However, this emphasis on the P-value for the primary trial result as the only meaningful sound bite from a large, multicentre randomized trial often fails to do justice to the tremendous effort expended by patients and investigators. There is a wealth of clinical information in even ‘negative’ trials that is belied by this one-word characterization, and clinicians should take note of what can be learned even when the P-value is < 0.05. Moreover, the management of patients with heart failure is not ‘plug and play’ since responses vary and the therapies need to be frequently adjusted by treating physicians and other caregivers. With the accompanying age-related co-morbidities and frailty of many patients with heart failure, the capacity of these efficacious therapies, especially in combinations, to produce untoward effects is particularly problematic. This challenge to assist the individual patient in optimizing their benefits while minimizing the risks, the art of medicine, is a common thread that attracts compassionate physicians to be caregivers for patients with the healthcare burdens associated with heart failure, and is a central focus of chronic heart failure disease management programmes. In this issue of the journal, Schuffman et al. present the principal results of the (Which Heart failure Intervention is most Cost-Effective in reducing Hospital stay) WHICH? II trial. The Stewart team from Australia conducted a rigorous randomized clinical trial comparing two strategies of delivering post-discharge multidisciplinary heart failure care. This experienced group has already set the bar high with their existing, well-established heart failure disease management programme and was testing whether an even more intensive heart failure management strategy incorporating more home-based intervention supplemented with structured telephone support would further reduce total healthcare costs during 12 months of follow-up. The principal findings were that compared with their existing programme, the intensive strategy was associated with higher costs, but did not produce improvements in survival, hospital admissions, and most indices of patient-reported quality-of-life. The extra support provided to the subjects in the intervention arm was substantial, including additional home visits to remote sites, telephone contacts, and laboratory tests over standard management. In this way, the findings confirm those of the COACH study, in which more intensive heart failure management strategies also did not appear to influence the rate of death or hospitalization for heart failure over 18 months. With an adequate number of events and no hint of a difference between groups for all hospital events reported (Schuffman et al. table 2), this should be considered a definitively neutral study, meaning that other attempts to evaluate these two strategies will not be likely to yield a difference. These results challenge the conventional assumption that more
TL;DR: This work utilized TOPCAT data to assess the relationship between EF and cause specific death in HFpEF and found that left ventricular ejection fraction is principal determinant of cardiovascular risk in patients with heart failure.
Journal Article•
TL;DR: In this paper, Klotho, an essential co-receptor for fibroblast growth factor (FGF)-23, has potentially beneficial inhibitory effects on the renin-angiotensin system.
Abstract: Introduction: Klotho, an essential co-receptor for fibroblast growth factor (FGF)-23, has potentially beneficial inhibitory effects on the renin-angiotensin system. Hypotheses: Low Klotho concentra...
TL;DR: From basic investigations, case reports, observational analyses, and randomized controlled trials (RCTs), the pace of generating and publishing medical information continues to accelerate at an overwhelming rate, and the results of RCTs range in quality and reliability.
Abstract: > We are drowning in information while starving for wisdom .
>
> — E.O. Wilson
From basic investigations, case reports, observational analyses, and randomized controlled trials (RCTs), the pace of generating and publishing medical information continues to accelerate at an overwhelming rate.1 Separating the wisdom from the rapidly growing cacophony of less dependable to actually unreliable material represents an increasing challenge. Across the spectrum of medical information, the results of RCTs are considered less susceptible to bias and more reliable. However, RCTs range in quality and reliability.
The preponderance of RCTs are small, early-phase studies, a substantial portion of which do not even result in a publication.2 Those designed to test whether an intervention can alter clinical outcomes are considerably larger and more resource-intense. These major clinical-outcome RCTs are the handful that provides estimates of benefits, and harms of a prospective intervention, as well. The most elite outcome RCTs offer results that inform clinical decisions.
Despite the intensity of the effort and extensive information collected in these relatively uncommon clinical-outcome RCTs, all too frequently, their results are conveyed by a single word, either positive or negative. With a statistically nonsignificant primary objective, the seemingly less harsh neutral designation can be equally dismissive. Admittedly, it is essential for a valid statistical construct to first either reject or accept the null hypothesis for the declared (registered) primary objective using the prespecified analysis plan. However, that critical primary analysis conveys only a fraction of the information generated from such a major effort.
When the primary objective of a RCT is met (positive), further hierarchical statistical testing of secondary analyses provides a legitimate statistical framework to …