Showing papers by "Marc A. Pfeffer published in 2019"
Harvard University1, University of Glasgow2, University of Minnesota3, Fudan University4, National University of Cordoba5, Baylor University Medical Center6, University Medical Center Groningen7, Université de Montréal8, Medical University of South Carolina9, University of Lorraine10, University of Barcelona11, Northwestern University12, Charité13, University of Groningen14, Cardiovascular Institute of the South15, University of São Paulo16, Semmelweis University17, Novartis18
TL;DR: Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failureand an ejection fraction of 45% or higher, and among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit in patients with lower ejection fractions and in women.
Abstract: Background The angiotensin receptor–neprilysin inhibitor sacubitril–valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients ...
1,306 citations
TL;DR: A meta-analysis of data from all large statin trials to compare the effects of statin therapy at different ages observed a significant reduction in major vascular events in all age groups.
454 citations
TL;DR: The historic development of this component of the heart failure syndrome is addressed, including the epidemiology, pathophysiology, and existing and planned therapeutic studies, including more specific phenotyping and even genotyping of subpopulations.
Abstract: Approximately half of the patients with signs and symptoms of heart failure have a left ventricular ejection fraction that is not markedly abnormal. Despite the historically initial surprise, heightened risks for heart failure specific major adverse events occur across the broad range of ejection fraction, including normal. The recognition of the magnitude of the problem of heart failure with preserved ejection fraction in the past 20 years has spurred an explosion of clinical investigation and growing intensity of informative outcome trials. This article addresses the historic development of this component of the heart failure syndrome, including the epidemiology, pathophysiology, and existing and planned therapeutic studies. Looking forward, more specific phenotyping and even genotyping of subpopulations should lead to improvements in outcomes from future trials.
433 citations
National University of Singapore1, Boston Children's Hospital2, University of Glasgow3, University of Minnesota4, Veterans Health Administration5, Brigham and Women's Hospital6, Duke University7, University of Western Ontario8, National Institutes of Health9, Medical University of South Carolina10, University of Michigan11
TL;DR: Compared with the elderly, younger patients withHFpEF were less likely to be white, were more frequently obese men, and died more often of cardiovascular causes, particularly sudden death, in contrast, elderly patients with HFpEF had more comorbidities and die more often from noncardiovascular causes.
82 citations
New York University1, Brigham and Women's Hospital2, Northwestern University3, Mario Negri Institute for Pharmacological Research4, Monash University5, Washington University in St. Louis6, Copenhagen University Hospital7, St. John's University8, University of São Paulo9, Tufts Medical Center10, Charité11, University of Glasgow12
TL;DR: A large number of patients with diabetes and chronic kidney disease are taking metformin, which has benefits on cardiovascular disease and kidney disease progression but is often withheld from individuals with diabetes because of a concern that it may increase the risk of lactic acidosis.
Abstract: Aims:
Metformin could have benefits on cardiovascular disease and kidney disease progression but is often withheld from individuals with diabetes and chronic kidney disease (CKD) because of a concern that it may increase the risk of lactic acidosis.
Materials and methods:
All‐cause mortality, cardiovascular death, cardiovascular events (death, hospitalization for heart failure, myocardial infarction, stroke or myocardial ischemia), end stage renal disease (ESRD) and the kidney disease composite (ESRD or death) were compared in metformin users and non‐users with diabetes and CKD enrolled in the Trial to Reduce Cardiovascular Events with Aranesp (darbepoeitin‐alfa) Therapy (TREAT) (NCT00093015). Outcomes were compared after propensity matching of users and non‐users and in multivariable proportional hazards models.
Results:
There were 591 individuals who used metformin at baseline and 3447 non‐users. Among propensity‐matched users, the crude incidence rate for mortality, cardiovascular mortality, cardiovascular events and the combined endpoint was lower in metformin users than in non‐users, but ESRD was marginally higher (4.0% vs 3.6%). Metformin use was independently associated with a reduced risk of all‐cause mortality (HR, 0.49; 95% CI, 0.36‐0.69), cardiovascular death (HR, 0.49; 95% CI, 0.32‐0.74), the cardiovascular composite (HR, 0.67, 95% CI, 0.51‐0.88) and the kidney disease composite (HR, 0.77; 95% CI, 0.61‐0.98). Associations with ESRD (HR, 1.01; 95% CI, 0.65‐1.55) were not significant. Results were qualitatively similar in adjusted analyses of the full population. Two cases of lactic acidosis were observed.
Conclusions:
Metformin may be safer for use in CKD than previously considered and may lower the risk of death and cardiovascular events in individuals with stage 3 CKD.
76 citations
Brigham and Women's Hospital1, Novartis2, University of Minnesota3, Fudan University4, The George Institute for Global Health5, Baylor University Medical Center6, Charité7, Mayo Clinic8, Montreal Heart Institute9, University Medical Center Groningen10, University of Lorraine11, Medical University of South Carolina12, British Heart Foundation13, Harvard University14
TL;DR: The PARAGON-HF trial as discussed by the authors reported comprehensive baseline health-related quality of life (HRQL) using Kansas City Cardiomyopathy Questionnaire (KCCQ) administered at randomization after active run-in period.
Abstract: Objectives This study sought to describe baseline health-related quality of life (HRQL) in the PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) trial, the largest heart failure with preserved ejection fraction (HFpEF) trial to date. Background There are limited data characterizing HRQL in patients with HFpEF using validated metrics. Methods The PARAGON-HF trial randomized symptomatic patients with HFpEF (≥45%) ≥50 years of age to either sacubitril/valsartan or valsartan. The study reports comprehensive baseline HRQL using Kansas City Cardiomyopathy Questionnaire (KCCQ) administered at randomization after active run-in period. The study then compares baseline HRQL with patients with heart failure with reduced ejection fraction (HFrEF) (≤40%) enrolled in the PARADIGM-HF (Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Forward multivariable stepwise regression modeling was performed separately in both trials to identify independent clinical correlates of KCCQ-Overall Summary (KCCQ-OS) score. PARADIGM-HF trial patients Results In the PARAGON-HF trial, 4,735 of 4,822 patients (mean age 73 ± 8 years; 48% men) completed baseline KCCQ at randomization. Mean KCCQ-OS score was 71. Women had worse mean KCCQ-OS score than men did. Patients in the PARAGON-HF trial reported lower KCCQ scores in nearly all domains when compared with the PARADIGM-HF trial (KCCQ-OS score 71 ± 19 vs. 73 ± 19; p Conclusions HRQL was largely worse in women and was similar in HFpEF and HFrEF after accounting for variation in demographics, functional status, and symptom burden. Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF [PARAGON-HF] NCT01920711; Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255)
76 citations
University of Glasgow1, Copenhagen University Hospital2, Sapienza University of Rome3, McGill University Health Centre4, University of Minnesota5, Georgetown University6, Brigham and Women's Hospital7, Duke University8, Exempla Saint Joseph Hospital9, University of Western Ontario10, Montreal Heart Institute11, University of Michigan12, University of Gothenburg13, National Institutes of Health14, Medical University of South Carolina15
TL;DR: Despite worse symptoms, more congestion, and lower quality of life, women had similar rates of hospitalization and better survival than men, and the risk of sudden death was half that of men.
Abstract: Background: To describe characteristics and outcomes in women and men with heart failure with preserved ejection fraction. Methods: Baseline characteristics (including biomarkers and quality of lif...
66 citations
TL;DR: Use of spironolactone is supported to treat HFpEF patients with advanced chronic kidney disease only when close laboratory surveillance is possible, and the risk of AEs was amplified in the lower eGFR categories.
Abstract: Objectives This study investigated the association between baseline renal function and the net benefit of spironolactone in patients with heart failure (HF) with a preserved ejection fraction (HFpEF). Background Guidelines recommend consideration of spironolactone to reduce HF hospitalization in HFpEF. However, spironolactone may increase risk for hyperkalemia and worsening renal function, particularly in patients with chronic kidney disease. Methods This investigation analyzed data from patients enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) Americas study (N = 1,767) to examine the association between the baseline estimated glomerular filtration rate (eGFR) and the primary composite outcome of cardiovascular death, HF hospitalization, or aborted cardiac arrest, as well as safety outcomes, including hyperkalemia, worsening renal function, and permanent drug discontinuation for adverse events (AEs). Variations in the efficacy and safety of spironolactone according to eGFR were examined in Cox models using interaction terms. Results The incidence of both the primary outcome and drug-related AEs increased with declining eGFR. Compared with placebo, across all eGFR categories, spironolactone was associated with lower relative risk for the primary efficacy outcome and for hypokalemia, but higher relative risk for hyperkalemia, worsening renal function, and drug discontinuation. During 4-year follow-up, the absolute risk for AEs that prompted drug discontinuation was amplified in the lower eGFR categories, which suggested heightened risk for drug intolerance with declining renal function. Conclusions Although consistent efficacy of spironolactone was observed across the range of eGFR, the risk of AEs was amplified in the lower eGFR categories. These data supported use of spironolactone to treat HFpEF patients with advanced chronic kidney disease only when close laboratory surveillance is possible.
54 citations
University of Lorraine1, Indiana University2, United States Department of Veterans Affairs3, University of Montpellier4, Novartis5, French Institute of Health and Medical Research6, Children's Hospital at Westmead7, University of Sydney8, Veterans Health Administration9, University Medical Center Groningen10, Université Paris-Saclay11, AstraZeneca12, Brigham and Women's Hospital13, National Institutes of Health14, European University of Madrid15, Center for Drug Evaluation and Research16, Campbell University17, Aarhus University Hospital18, Population Health Research Institute19, University of Alabama at Birmingham20, Georgetown University21, University of Michigan22
TL;DR: Cardiovascular and renal clinical trialists must partner to address the uncertainties in the field through collaborative research and design clinical trials that reflect the specific needs of the chronic and end-stage kidney disease populations, with the shared goal of generating robust evidence to guide the management of cardiovascular disease in patients with kidney disease.
Abstract: Although cardiovascular disease is a major health burden for patients with chronic kidney disease, most cardiovascular outcome trials have excluded patients with advanced chronic kidney disease. Moreover, the major cardiovascular outcome trials that have been conducted in patients with end-stage renal disease have not demonstrated a treatment benefit. Thus, clinicians have limited evidence to guide the management of cardiovascular disease in patients with chronic kidney disease, particularly those on dialysis. Several factors contribute to both the paucity of trials and the apparent lack of observed treatment effect in completed studies. Challenges associated with conducting trials in this population include patient heterogeneity, complexity of renal pathophysiology and its interaction with cardiovascular disease, and competing risks for death. The Investigator Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT), an international organization of academic cardiovascular and renal clinical trialists, held a meeting of regulators and experts in nephrology, cardiology, and clinical trial methodology. The group identified several research priorities, summarized in this paper, that should be pursued to advance the field towards achieving improved cardiovascular outcomes for these patients. Cardiovascular and renal clinical trialists must partner to address the uncertainties in the field through collaborative research and design clinical trials that reflect the specific needs of the chronic and end-stage kidney disease populations, with the shared goal of generating robust evidence to guide the management of cardiovascular disease in patients with kidney disease.
38 citations
TL;DR: Limited data exist on the prognostic value of Klotho and FGF‐23 levels in combination or their ability to predict benefit from angiotensin‐converting enzyme (ACE) inhibition.
Abstract: AIMS Klotho, an essential co-receptor for fibroblast growth factor (FGF)-23, has potentially beneficial inhibitory effects on the renin-angiotensin system. Limited data exist on the prognostic value of Klotho and FGF-23 levels in combination or their ability to predict benefit from angiotensin-converting enzyme (ACE) inhibition. METHODS AND RESULTS A total of 3555 patients with stable ischaemic heart disease and left ventricular ejection fraction > 40% enrolled in the PEACE trial of trandolapril vs. placebo had Klotho levels drawn at randomization. Patients were characterized by quartiles of Klotho and FGF-23 concentrations. Six-year Kaplan-Meier rates and adjusted risk were calculated in the placebo arm for the composite of cardiovascular (CV) death or hospitalization for heart failure and its components. Low [quartile (Q) 1-3] Klotho concentration was associated with an increased rate of CV death or hospitalization for heart failure as compared with Q4 (8.2% vs. 4.2%; P = 0.03). After multivariable adjustment for clinical variables and renal and CV biomarkers (estimated glomerular filtration rate, cystatin-C, urine albumin-to-creatinine ratio, FGF-23, high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein), low Klotho concentration remained strongly associated with increased risk of CV death or hospitalization for heart failure [adjusted hazard ratio (HR) 2.62; 95% confidence interval (CI) 1.35-5.08; P < 0.01]. The combination of low Klotho and high (Q4) FGF-23 concentration identified patients at particularly elevated risk (adjusted HR 3.99; 95% CI 1.67-9.56; P < 0.01). This high-risk combination additionally predicted benefit from trandolapril (HR 0.39; 95% CI 0.23-0.68; Pinteraction < 0.01). CONCLUSIONS Low Klotho concentration is associated with an increased risk of CV death or heart failure hospitalization in patients with stable ischaemic heart disease. The combination of low Klotho and high FGF-23 further identifies patients at distinctly elevated risk who derive clinical benefit from the ACE-inhibitor trandolapril.
36 citations
Tufts Medical Center1, University of California, San Francisco2, University of North Carolina at Chapel Hill3, London Health Sciences Centre4, University of California, San Diego5, Tufts University6, University of Alabama at Birmingham7, Toronto General Hospital8, National Institutes of Health9, Ohio State University10, Brigham and Women's Hospital11, Duke University12, University of Maryland, Baltimore13, Rhode Island Hospital14
TL;DR: In a large population of stable kidney transplant recipients, elevated baseline ACR is independently associated with allograft failure, CVD, and death.
TL;DR: In heart failure with preserved ejection fraction, the physical exam provides independent prognostic value for adverse outcomes and is a modifiable risk factor.
Abstract: Background: The prognostic value of physical examination, its relation to quality of life, and influence of therapy in heart failure with preserved ejection fraction is not well known. Methods and ...
TL;DR: In adjusted analyses, higher NT-proBNP levels were less predictive of HF hospitalization than mortality in patients with AF compared with those without, and the relationship between NT- ProBNP and outcomes differs with lower absolute risk in patients who have AFCompared with those who do not have AF.
Abstract: Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) is useful in diagnosis and prognostication in heart failure (HF). We examined the relationship between NT-proBNP and outcomes in patients with HF and preserved ejection fraction, with and without atrial fibrillation (AF). Methods and Results Among 3835 HF with preserved ejection fraction patients enrolled in the I-Preserve (Irbesartan in Heart Failure With Preserved Systolic Function trial) or TOPCAT trial (Treatment of Preserved Cardiac Function in Heart Failure With an Aldosterone Antagonist), 719 (19%) patients had AF on their baseline ECG. Median (Q1-Q3) levels of NT-proBNP were 1286 pg/mL (778-2072) in those with AF and 288 pg/mL (122-704) in those without ( P<0.001). We analyzed patients using 4 NT-proBNP bands: <400, 400 to 999 (reference), 1000 to 1999, and ≥2000 pg/mL. The event rates for the primary composite outcome of cardiovascular death or HF hospitalization were higher in patients with AF versus patients without or those without without AF in the lowest NT-proBNP band (<400 pg/mL; 8.0 versus 3.2 per 100 patient-years), whereas for the higher bands the opposite was true (1000-1999 pg/mL; 11.4 versus 13.2 per 100 patient-years and ≥2000 pg/mL; 17.4 versus 25.6 per 100 patient-years). In adjusted analyses, higher NT-proBNP levels were less predictive of HF hospitalization than mortality in patients with AF compared with those without. Conclusions Event rates in HF with preserved ejection fraction patients without AF and with NT-proBNP <400 pg/mL are low. Among patients with NT-proBNP ≥400 pg/mL, the relationship between NT-proBNP and outcomes differs with lower absolute risk in patients who have AF compared with those who do not have AF. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifiers: NCT00094302 and NCT00095238.
Harvard University1, University of São Paulo2, Stanford University3, Monash University4, University of Erlangen-Nuremberg5, Northwestern University6, Tufts Medical Center7, Washington University in St. Louis8, University of Glasgow9, Memorial University of Newfoundland10, Copenhagen University Hospital11, University of Milan12, Mario Negri Institute for Pharmacological Research13, University of Texas Southwestern Medical Center14
TL;DR: Despite initiating dialysis therapy with a higher hemoglobin level, prior treatment with darbepoetin was not associated with a reduction in mortality, myocardial infarction, or heart failure in the first 180 days, but a higher frequency of stroke was observed.
TL;DR: In conclusion, the apparent increased risk of adverse outcomes in patients with heart failure and preserved left ventricular ejection fraction and ITDM merits future research to improve the prognosis of these high-risk patients.
Abstract: We aimed to evaluate the impact of diabetes mellitus (DM) and insulin treatment on clinical outcomes in patients with heart failure and preserved left ventricular ejection fraction enrolled in the TOPCAT study. We investigated the influence of DM status (insulin-treated [ITDM], non-insulin treated [NITDM], and no diabetes [non-DM]) at baseline on time to development of the primary end point, a composite of cardiovascular (CV) mortality, heart failure hospitalization, and aborted cardiac arrest. Secondary end points included the individual components of the primary end point, myocardial infarction, stroke, all-cause mortality, hyperkalemia, and worsened renal function. Due to marked regional differences in characteristics and outcomes of the TOPCAT patients, with much lower events in patients enrolled in Russia/Georgia, we restricted our analyses on findings from patients enrolled from the Americas. Compared to patients without DM, patients with ITDM had approximately 2-fold increased risk for the primary end point, heart failure hospitalization, and myocardial infarction (hazard ratios: 1.80, 1.97, and 2.27, respectively) and approximately 50% increases in all-cause and CV mortality. The risks for these outcomes were also increased in patients with ITDM in comparison to patients with NITDM as well (hazard ratios: 1.63, 1.65, and 2.73, respectively, and approximately 40% increases in all-cause and CV mortality). Patients with NITDM had similar risks for the primary end point and all secondary end points as patients without DM. In conclusion, the apparent increased risk of adverse outcomes in patients with heart failure and preserved left ventricular ejection fraction and ITDM merits future research to improve the prognosis of these high-risk patients.
TL;DR: An implantable cardioverter‐defibrillator is recommended for reducing the risk of sudden cardiac death in myocardial infarction patients with a left ventricular ejection fraction ≤30%, as well as patients with an LVEF and heart failure symptoms.
Abstract: Aims:
An implantable cardioverter‐defibrillator (ICD) is recommended for reducing the risk of sudden cardiac death (SCD) in myocardial infarction (MI) patients with a left ventricular ejection fraction (LVEF) ≤ 30%, as well as patients with a LVEF ≤ 35% and heart failure symptoms. Diabetes and/or impaired kidney function may confer additional SCD risk. We assessed the association between these two risk factors with SCD and non‐SCD among MI survivors taking account of age and LVEF.
Methods and results:
A total of 17 773 patients from the High‐Risk MI Database were evaluated. Overall, diabetes and estimated glomerular filtration rate 35% and with diabetes, impaired kidney function, or both (2.0%, 2.5% and 2.7%, respectively) were comparable to rates observed in patients with LVEF 30–35% but no such risk factors (1.7%). However, these patients had also similarly higher non‐SCD rates, such that the ratio of SCD to non‐SCD was not increased. Importantly, this ratio was mostly dependent on age, with higher overall ratios in youngest subgroups (0.89 in patients < 55 years vs. 0.38 in patients ≥ 75 years), regardless of risk factors.
Conclusion:
Although MI survivors with LVEF > 35% with diabetes, impaired kidney function, or both are at increased risk of SCD, the risk of non‐SCD risk is even higher, suggesting an extension of the current indication for an ICD to them is unlikely to be worthwhile. MI survivors with low LVEF and aged < 55 years are likely to have the greatest potential benefit from ICD implantation.
TL;DR: Insulin-treated diabetes patients had higher event rates than diabetes patients taking oral treatments and patients without diabetes, however, insulin-treated Diabetes patients had more comorbidities and atherosclerotic disease, precluding any causality suggestion between insulin treatment and outcomes.
Abstract: Background:Diabetes is associated with poor cardiovascular outcomes, and insulin-treated patients usually have a worse prognosis than non-insulin-treated subjects. The relationship between insulin ...
TL;DR: Findings raise the possibility that right ventricular pacing-induced left ventricular dyssynchrony may be detrimental in patients with heart failure with preserved ejection fraction (HFpEF).
Abstract: Objectives: This study examined the relationship between prior pacemaker implantation and clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF).Backgroun...
TL;DR: Genetic profiling using FADS2 genotype can predict the therapeutic benefits of O-3FA treatment against adverse cardiac remodeling during the convalescent phase of AMI.
Abstract: Background The double-blind OMEGA-REMODEL placebo-controlled randomized trial of high-dose omega-3 fatty acids (O-3FA) post-acute myocardial infarction (AMI) reported improved cardiac remodeling and attenuation of non-infarct myocardial fibrosis. Fatty acid desaturase 2 (FADS2) gene cluster encodes key enzymes in the conversion of essential omega-3 and omega-6 fatty acids into active arachidonic (ArA) and eicosapentaenoic acids (EPA), which influence cardiovascular outcomes. Methods and results We tested the hypothesis that the genotypic status of FADS2 (rs1535) modifies therapeutic response of O-3FA in post-AMI cardiac remodeling in 312 patients. Consistent with known genetic polymorphism of FADS2, patients in our cohort with the guanine-guanine (GG) genotype had the lowest FADS2 activity assessed by arachidonic acid/linoleic acid (ArA/LA) ratio, compared with patients with the adenine-adenine (AA) and adenine-guanine (AG) genotypes (GG:1.62±0.35 vs. AA: 2.01±0.36, p<0.0001; vs. AG: 1.76±0.35, p = 0.03). When randomized to 6-months of O-3FA treatment, GG patients demonstrated significant lowering of LV end-systolic volume index (LVESVi), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and galectin-3 levels compared to placebo (-4.4 vs. 1.2 ml/m2, -733 vs. -181 pg/mL, and -2.0 vs. 0.5 ng/mL; p = 0.006, 0.006, and 0.03, respectively). In contrast, patients with either AA or AG genotype did not demonstrate significant lowering of LVESVi, NT-proBNP, or galectin-3 levels from O-3FA treatment, compared to placebo. The odds ratios for improving LVESVi by 10% with O-3FA treatment was 7.2, 1.6, and 1.2 in patients with GG, AG, and AA genotypes, respectively. Conclusion Genetic profiling using FADS2 genotype can predict the therapeutic benefits of O-3FA treatment against adverse cardiac remodeling during the convalescent phase of AMI. Clinical trial registration information clinicaltrials.gov Identifier: NCT00729430.
TL;DR: This paper studies the stochastic properties of the two-sample naive estimator conditional on the ancillary statistics, the observed treatment allocation proportions and/or the stratum sizes, and presents a biased-adjusted estimator, which is asymptotically equivalent to the augmentation estimators proposed under the unconditional setting.
Abstract: For a two-group comparative study, a stratified inference procedure is routinely used to estimate an overall group contrast to increase the precision of the simple two-sample estimator. Unfortunately, most commonly used methods including the Cochran-Mantel-Haenszel statistic for a binary outcome and the stratified Cox procedure for the event time endpoint do not serve this purpose well. In fact, these procedures may be worse than their two-sample counterparts even when the observed treatment allocations are imbalanced across strata. Various procedures beyond the conventional stratified methods have been proposed to increase the precision of estimation when the naive estimator is consistent. In this paper, we are interested in the case when the treatment allocation proportions vary markedly across strata. We study the stochastic properties of the two-sample naive estimator conditional on the ancillary statistics, the observed treatment allocation proportions and/or the stratum sizes, and present a biased-adjusted estimator. This adjusted estimator is asymptotically equivalent to the augmentation estimators proposed under the unconditional setting. Moreover, this consistent estimation procedure is also equivalent to a rather simple procedure, which estimates the mean response of each treatment group first via a stratum-size weighted average and then constructs the group contrast estimate. This simple procedure is flexible and readily applicable to any target patient population by choosing appropriate stratum weights. All the proposals are illustrated with the data from a cardiovascular clinical trial, whose treatment allocations are imbalanced.
TL;DR: The next generation of drugs to treat central nervous system disorders will need to be developed in a manner that reduces the chance of adverse events and increases the likelihood of treatment-side effects.
Abstract: Circulation. 2019;140:2044–2046. DOI: 10.1161/CIRCULATIONAHA.119.041991 2044
TL;DR: There were considerable effects of age on increased rates of adverse safety outcomes and these results should be weighed when considering spironolactone for older heart failure with preserved ejection fraction patients.
Abstract: Objectives The authors examined efficacy and safety of spironolactone by age in the Americas region (N = 1,767) of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. Background Heart failure with preserved ejection fraction disproportionately affects older adults who may exhibit changes in physiology and variable pharmacokinetics. Methods TOPCAT enrolled patients with heart failure and a left ventricular ejection fraction ≥45% who were age 50 or older with an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 and prior heart failure hospitalization or elevated natriuretic peptide levels. Participants were randomized to spironolactone or placebo with a mean follow-up duration of 3.3 years. We assessed treatment effect and safety by protocol-defined age categories ( Results The mean age was 72 ± 10 years (range 50 to 97 years) with 41% over the age of 75 years. Participants ≥75 years were more commonly women and white and had a lower body mass index and estimated glomerular filtration rate compared with the younger age categories. Spironolactone reduced the primary composite outcome compared with placebo across all age categories (p interaction = 0.42). However, spironolactone was associated with an increased risk of the safety endpoint (hazard ratio: 2.54; 95% confidence interval: 1.91 to 3.37; p Conclusions In this post hoc, exploratory analysis of the TOPCAT trial data from the Americas region, although there was no effect of age on efficacy, there were considerable effects of age on increased rates of adverse safety outcomes. These results should be weighed when considering spironolactone for older heart failure with preserved ejection fraction patients. (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist [TOPCAT]; NCT00094302 )
TL;DR: Randomized evidence is reviewed to provide guidance to primary care providers regarding the use of adjunctive drug therapies for the primary prevention of cardiovascular disease and aggressive multifactorial management of diabetes.
Abstract: The increasing burden of cardiovascular disease worldwide, including the United States, underscores the need for the more widespread use of adjunctive drug therapies of proven net benefit in the primary prevention of cardiovascular disease. These include aspirin to reduce mortality from cardiovascular disease, statins to lower LDL-cholesterol levels, appropriate use of multiple antihypertensive drug therapies to lower blood pressure, and aggressive multifactorial management of diabetes. This article reviews randomized evidence to provide guidance to primary care providers regarding the use of adjunctive drug therapies.
TL;DR: This in perspective article is designed to offer a past and present framework of this multifaceted disorder to enhance (expand) the dialogue between caregivers and investigators to better understand this complex heterogeneous disorder.
Abstract: In Response: Our perspective on heart failure with preserved ejection fraction was designed to offer a past and present framework of this multifaceted disorder to enhance (expand) the dialogue between caregivers and investigators.1 Our major focus was on providing a context to better understand the emerging clinical trial and epidemiological data. The pathophysiologic and compensatory mechanisms producing and responding to the elevated ventricular filling pressure, central to the signs and symptoms of heart failure across the spectrum of ejection fractions, were only briefly highlighted. The complimentary comments from Drs. Nikolva, Hong, and Shaw are appreciated as is their calling their recently published innovative study on the potential importance of cardiac bridging integrator 1 as a possible biomarker of heart failure with preserved ejection fraction to our attention.2,3 These types of productive exchanges are needed to continue to improve our understanding of this diverse disorder. Better mechanistic identification and stratification tools will undoubtedly facilitate more precision in future clinical trials. We hope our in perspective article will stimulate other interchanges to expand the discourse to better understand this complex heterogeneous disorder. ARTICLE INFORMATION
TL;DR: In a nationwide study spanning 9 consecutive influenza seasons including more than 600,000 hypertensive patients without significant cardiovascular disease identified through medication use, influenza vaccination was significantly associated with a reduced risk of death from all-causes, cardiovascular causes and AMI/stroke.
Abstract:
Influenza infection is associated with an increased risk of acute myocardial infarction (AMI) and stroke. It is currently unknown whether influenza vaccination may reduce mortality in patients with hypertension.
To determine whether influenza vaccination is associated with lower risks of death in hypertensive patients without significant cardiovascular or other chronic disease.
Using nationwide registers, we identified all patients with hypertension in Denmark during 9 consecutive influenza seasons in the period 2007–2016 who were treated with at least 2 different classes of antihypertensive medication (beta-blockers, diuretics, calcium antagonists or renin-angiotensin system inhibitors). Patients who were not 18–100 years old or had ischemic heart disease, heart failure, chronic obstructive lung disease, cancer or cerebrovascular disease were excluded. Prior to each influenza season we assessed the exposure to influenza vaccination. End-points were death from all causes, from AMI or stroke, or cardiovascular death. For each season, patients were followed from December 1 until April 1 the next year, spanning the period of high influenza activity in Denmark.
A total of 608,452 Patients were followed for a median of 5 seasons (interquartile-range: 2–8 seasons), with total follow-up time of 975,902 person-years. The vaccine coverage during study seasons ranged from 26% to 36%. During follow-up, 21,571 patients died of all-causes (3.5%), 12,270 patients died of cardiovascular causes (2.0%) and 3,846 patients died of AMI/stroke (0.6%). Vaccination was associated with older age, Diabetes Mellitus, atrial fibrillation, lower educational level, lower income and higher medication use. In unadjusted analysis considering all seasons, vaccination was significantly associated with increased risk of all-cause death, cardiovascular death and death from AMI/stroke. However, following adjustment for season, age, sex, comorbidities, medications, income, education, and more, vaccination was significantly associated with reduced risks of all-cause death, cardiovascular death and death from AMI/stroke (Figure).
PY, person-years.
In a nationwide study spanning 9 consecutive influenza seasons including more than 600,000 hypertensive patients without significant cardiovascular disease identified through medication use, influenza vaccination was significantly associated with a reduced risk of death from all-causes, cardiovascular causes and AMI/stroke. Influenza vaccination may improve patient outcome in hypertension.
Daniel Modin was supported by the Herlev & Gentofte University Hospital Internal Research Fund and by the Novo Nordisk Foundation.
TL;DR: The findings, that between-patient heterogeneity and treatment discontinuation rates have implications for both the design and analysis of trials, remain valid even in the presence of more complex trial designs.
Abstract: Circulation. 2019;139:422–423. DOI: 10.1161/CIRCULATIONAHA.118.038478 422 Brian Claggett, PhD Stuart Pocock, PhD L. J. Wei, PhD Marc A. Pfeffer, MD, PhD John J.V. McMurray, MD Scott D. Solomon, MD In Response: We agree that any analysis of both safety and efficacy outcomes in a clinical trial can be complicated by nonrandom censoring. Our goal was to clarify how best to analyze efficacy events. Safety issues represent an important, but separate concern beyond the scope of this article. Nevertheless, we wish to clarify that the types of censoring processes implemented1 in both our simulations and analyses of real trial data, with recurrent events, and with time-to-first-event analyses, as well, were based on intention-totreat principles. Ultimately, the interpretation of any clinical trial represents a tradeoff between the completeness and complexity of the information collection and the resulting interpretability of the final metric that is used to compare the 2 randomized treatments.2 Even in traditional time-to-first-event analyses, there are well-known difficulties with the interpretation of the hazard ratio for the composite end point, in particular in scenarios where the treatment effect is not consistent across the various components, as might be expected when combining so-called efficacy and safety end points. Although it might seem that introducing recurrent events might only further complicate the resulting analyses, the conventional composite outcome approach is itself limited by counting only the first (eg, nonfatal) event and ignoring any subsequent (eg, fatal) events. As a general principle, collecting more data allows for a more complete analysis of the patient journey during the course of study follow-up. When occurrences of multiple types of events are of interest, and especially when treatment effects are not necessarily consistent across event types, it may become necessary to prioritize,3 rank,4 or weight5 different types of clinical outcomes to properly interpret the final comparison between treatment arms. The types of recurrent event models analyzed in our article (ie, negative binomial, Lin-Wei-YangYing model) are not designed to make these distinctions but rather to count the number of outcomes that a patient experiences over the course of follow-up. This decision was made to make a more direct comparison between time-to-first and recurrent events without the added complexity of deciding how to value potentially disparate treatment effects on different outcomes. We believe our findings, that between-patient heterogeneity and treatment discontinuation rates have implications for both the design and analysis of trials, remain valid even in the presence of more complex trial designs.