Showing papers by "Marc A. Pfeffer published in 2008"
TL;DR: A graded independent relation between higher levels of RDW and the risk of death and cardiovascular events in people with prior myocardial infarction but no symptomatic heart failure at baseline is found.
Abstract: Background— Higher levels of red blood cell distribution width (RDW) may be associated with adverse outcomes in patients with heart failure. We examined the association between RDW and the risk of all-cause mortality and adverse cardiovascular outcomes in a population of people with coronary disease who were free of heart failure at baseline. Methods and Results— We performed a post hoc analysis of data from the Cholesterol and Recurrent Events study. Baseline RDW was measured in 4111 participants who were randomized to receive pravastatin 40 mg daily or placebo and followed for a median of 59.7 months. We used Cox proportional hazards models to examine the association between RDW and adverse clinical outcomes. During nearly 60 months of follow-up, 376 participants died. A significant association was noted between baseline RDW level and the adjusted risk of all-cause mortality (hazard ratio per percent increase in RDW, 1.14; 95% confidence interval, 1.05 to 1.24). After categorization based on quartile of...
689 citations
TL;DR: Diabetes was an independent predictor of CV morbidity and mortality in patients with HF, regardless of EF, and the relative risk of CV death or HF hospitalization conferred by diabetes was significantly greater in Patients with preserved when compared with those with low EF HF.
Abstract: Aims To determine whether the risk of adverse cardiovascular (CV) outcomes associated with diabetes differs in patients with low and preserved ejection fraction (EF) heart failure (HF).
Methods and results We analysed outcomes in the Candesartan in Heart failure—Assessment of Reduction in Mortality and morbidity (CHARM) programme which randomized 7599 patients with symptomatic HF and a broad range of EF. The prevalence of diabetes was 28.3% in patients with preserved EF (>40%) and 28.5% in those with low EF (≤40%). Diabetes was associated with a greater relative risk of CV death or HF hospitalization in patients with preserved EF [hazard ratio (HR) 2.0 (1.70–2.36)] than in patients with low EF [HR 1.60 (1.44–1.77); interaction test P = 0.0009]. For all-cause mortality, the risk conferred by diabetes was similar in both low and preserved EF groups. The effect of candesartan in reducing CV morbidity and mortality outcomes was not modified by having diabetes at baseline ( P = 0.09 test for interaction).
Conclusion Diabetes was an independent predictor of CV morbidity and mortality in patients with HF, regardless of EF. The relative risk of CV death or HF hospitalization conferred by diabetes was significantly greater in patients with preserved when compared with those with low EF HF.
529 citations
TL;DR: Increased baseline LV mass and abnormal LV geometry portend an increased risk for morbidity and mortality following high-risk myocardial infarction.
Abstract: Objectives This study sought to understand prognostic implications of increased baseline left ventricular (LV) mass and geometric patterns in a high risk acute myocardial infarction. Background The LV hypertrophy and alterations in LV geometry are associated with an increased risk of adverse cardiovascular events. Methods Quantitative echocardiographic analyses were performed at baseline in 603 patients from the VALIANT (VALsartan In Acute myocardial iNfarcTion) echocardiographic study. The left ventricular mass index (LVMi) and relative wall thickness (RWT) were calculated. Patients were classified into 4 mutually exclusive groups based on RWT and LVMi as follows: normal geometry (normal LVMi and normal RWT), concentric remodeling (normal LVMi and increased RWT), eccentric hypertrophy (increased LVMi and normal RWT), and concentric hypertrophy (increased LVMi and increased RWT). Cox proportional hazards models were used to evaluate the relationships among LVMi, RWT, LV geometry, and clinical outcomes. Results Mean LVMi and RWT were 98.8 ± 28.4 g/m 2 and 0.38 ± 0.08. The risk of death or the composite end point of death from cardiovascular causes, reinfarction, heart failure, stroke, or resuscitation after cardiac arrest was lowest for patients with normal geometry, and increased with concentric remodeling (hazard ratio [HR]: 3.0; 95% confidence interval [CI]: 1.9 to 4.9), eccentric hypertrophy (HR: 3.1; 95% CI: 1.9 to 4.8), and concentric hypertrophy (HR: 5.4; 95% CI: 3.4 to 8.5), after adjusting for baseline covariates. Also, baseline LVMi and RWT were associated with increased mortality and nonfatal cardiovascular outcomes (HR: 1.22 per 10 g/m 2 increase in LVMi; 95% CI: 1.20 to 1.30; p Conclusions Increased baseline LV mass and abnormal LV geometry portend an increased risk for morbidity and mortality following high-risk myocardial infarction. Concentric LV hypertrophy carries the greatest risk of adverse cardiovascular events including death. Higher RWT was associated with an increased risk of cardiovascular complications after high-risk myocardial infarction.
245 citations
TL;DR: Patients with a CHADS2=1 had a low risk of stroke, yet still derived a modest but statistically significant absolute reduction in stroke with OAC and had low rates of major hemorrhage on OAC.
Abstract: Background and Purpose— In ACTIVE-W, oral anticoagulation (OAC) was more efficacious than combined clopidogrel plus aspirin (C+A) in preventing vascular events in patients with atrial fibrillation. However, because OAC carries important bleeding complications, risk stratification schemes have been devised to identify patients for whom the absolute benefits of OAC exceed its risks. Methods— Participants were risk-stratified with the widely-used CHADS2 scheme. Treatment-specific rates of stroke and major bleeding were calculated for patients with a CHADS2=1 and compared to those with a CHADS2>1. Results— Observed stroke rates for those with a CHADS2=1 were 1.25% per year on C+A and 0.43% per year on OAC (RR=2.96, 95% CI: 1.26 to 6.98, P=0.01). Among patients with a CHADS2>1, the stroke rates were 3.15% per year on C+A and 2.01% per year on OAC (RR=1.58, 95% CI: 1.11 to 2.24, P=0.01) (P for interaction between stroke risk category and efficacy of OAC=0.19). The risk of major bleeding during OAC was significa...
229 citations
TL;DR: In this article, the authors found that decreased right ventricular systolic function is a major risk factor for death, sudden death, heart failure, and stroke after myocardial infarction.
Abstract: Severe right ventricular dysfunction independent of left ventricular ejection fraction increased the risk of heart failure (HF) and death after myocardial infarction (MI). The association between right ventricular function and other clinical outcomes after MI was less clear. Two-dimensional echocardiograms were obtained in 605 patients with left ventricular dysfunction and/or clinical/radiologic evidence of HF from the VALIANT echocardiographic substudy (mean 5.0 ± 2.5 days after MI). Clinical outcomes included all-cause mortality, cardiovascular (CV) death, sudden death, HF, and stroke. Baseline right ventricular function was measured in 522 patients using right ventricular fractional area change (RVFAC) and was related to clinical outcomes. Mean RVFAC was 41.9 ± 4.3% (range 19.2% to 53.1%). The incidence of clinical events increased with decreasing RVFAC. After adjusting for 11 covariates, including age, ejection fraction, and Killip's classification, decreased RVFAC was independently associated with increased risk of all-cause mortality (hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.31 to 1.98), CV death (HR 1.62, 95% CI 1.30 to 2.01), sudden death (HR 1.79, 95% CI 1.26 to 2.54), HF (HR 1.48, 95% CI 1.17 to 1.86), and stroke (HR 2.95, 95% CI 1.76 to 4.95), but not recurrent MI. Each 5% decrease in baseline RVFAC was associated with a 1.53 (95% CI 1.24 to 1.88) increased risk of fatal and nonfatal CV outcomes. In conclusion, decreased right ventricular systolic function is a major risk factor for death, sudden death, HF, and stroke after MI.
190 citations
TL;DR: In this paper, a progressive relationship between hemoglobin A 1c (HbA 1c ) levels and cardiovascular events has been observed in persons with and without diabetes in patients with symptomatic chronic heart failure.
Abstract: Background A progressive relationship between hemoglobin A 1c (HbA 1c ) levels and cardiovascular (CV) events has been observed in persons with and without diabetes. To our knowledge, the nature of such a relationship in patients with symptomatic chronic heart failure (HF) has not been studied. Methods A total of 2412 participants (907 with prior diabetes) in the Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program with at least 1 HbA 1c level were followed up for a median of 34 months. The incidence of the primary outcome (CV death or HF hospitalization), CV death, and total mortality was calculated according to eighths of the usual HbA 1c level ranging from 5.8% or less to greater than 8.6%. Adjusted and unadjusted hazard ratios per 1% rise in HbA 1c levels were also calculated. Results A total of 99.6% of eligible participants were followed up until they developed an outcome or the study finished. The risk of the primary composite outcome, CV death, hospitalization for worsening HF, and total mortality rose progressively with higher levels of usual HbA 1c ( P for trend 1c level were 1.25 (95% confidence interval [CI],1.20-1.31), 1.24 (95% CI, 1.17-1.31), 1.25 (95% CI, 1.19-1.31), and 1.22 (95% CI, 1.16-1.29), respectively. This relationship was evident in patients with and without diabetes and with reduced or preserved ejection fraction and persisted after adjustment for diabetes, other risk factors, and allocation to candesartan. Conclusion In diabetic and nondiabetic patients with symptomatic chronic HF, the HbA 1c level is an independent progressive risk factor for CV death, hospitalization for HF, and total mortality.
188 citations
TL;DR: Although succinobucol had no effect on the primary endpoint, changes in the rates of other clinical outcomes-both beneficial and harmful-will need to be further assessed before succinOBucol is used in patients with atherosclerosis or as an antidiabetic agent.
180 citations
TL;DR: In both the CARE and the WOSCOPS trials, carriers of the KIF6 719Arg allele had an increased risk of coronary events, and pravastatin treatment substantially reduced that risk.
168 citations
TL;DR: Among individuals with systolic hypertension, increased PP is primarily attributable to increased wall stiffness and reduced aortic diameter rather than premature wave reflection, and an inverse relation between PP and aorti diameter remained significant.
Abstract: Systolic hypertension is associated with increased pulse pressure (PP) and increased risk for adverse cardiovascular outcomes. However the pathogenesis of increased PP remains controversial. One hypothesis suggests that aortic dilatation, wall stiffening and increased pulse wave velocity result from elastin fragmentation, leading to a premature reflected pressure wave that contributes to elevated PP. An alternative hypothesis suggests that increased proximal aortic stiffness and reduced aortic diameter leads to mismatch between pressure and flow, giving rise to an increased forward pressure wave and increased PP. To evaluate these two hypotheses, we measured pulsatile hemodynamics and proximal aortic diameter directly using tonometry, ultrasound imaging, and Doppler in 167 individuals with systolic hypertension. Antihypertensive medications were withdrawn for at least 1 week before study. Patients with PP above the median (75 mm Hg) had lower aortic diameter (2.94+/-0.36 versus 3.13+/-0.28 cm, P<0.001) and higher aortic wall stiffness (elastance-wall stiffness product: 16.1+/-0.7 versus 15.7+/-0.7 ln[dyne/cm], P<0.001) with no difference in augmentation index (19.9+/-10.4 versus 17.5+/-10.0%, P=0.12). Aortic diameter and wall stiffness both increased with advancing age (P<0.001). However, an inverse relation between PP and aortic diameter remained significant (P<0.001) in models that adjusted for age, sex, height, and weight and then further adjusted for aortic wall stiffness, augmentation index, and mean arterial pressure. Among individuals with systolic hypertension, increased PP is primarily attributable to increased wall stiffness and reduced aortic diameter rather than premature wave reflection.
167 citations
TL;DR: Weight loss and leanness are important predictors of poor prognosis in CHF and the detection of weight change, and particularly weight loss, should be considered as an adverse sign prompting further evaluation.
Abstract: Aims The curiosity that leanness is associated with poor survival in patients with chronic heart failure (CHF) needs further insight by investigating the impact of weight loss on prognosis in a large sample of patients across a broad spectrum of both reduced and preserved left ventricular (LV) systolic function.
Methods and results We investigated the change in weight over 6 months in 6933 patients in the Candesartan in Heart failure: Reduction in Mortality and morbidity (CHARM) programme, and its association with subsequent mortality (1435 deaths) over a median 32.9 months follow-up using Cox proportional hazard models to account for the impact of body mass index and other risk predictors. We then used time-updated Cox models to relate each patient’s ongoing data on annual weight change to their mortality hazard. The percentage weight loss over 6 months had a highly significant monotonically increasing association with excess mortality, both for cardiovascular and for other causes of death. Patients with 5% or greater weight loss in 6 months had over a 50% increase in hazard compared with those with stable weight. Weight loss carried a particularly high risk in patients who were already lean at study entry. Findings were similar in the presence of dependent oedema, preserved or reduced LV ejection fraction, and treatment with candesartan, although weight loss was significantly less common on candesartan. The time-updated analyses revealed an even stronger link between weight loss and short-term risk of dying, i.e. risk increased more than four-fold for patients whose last recorded annual weight loss exceeded 10%. Weight gain had a more modestly increased short-term mortality risk. Weight loss accelerates in the year prior to death.
Conclusions Weight loss and leanness are important predictors of poor prognosis in CHF. Being lean and losing weight is particularly bad. The detection of weight change, and particularly weight loss, should be considered as an adverse sign prompting further evaluation.
167 citations
TL;DR: Baseline LA size is an independent predictor of death or HF hospitalization following high-risk MI, and LA remodelling during the first month after infarction is associated with adverse outcome.
Abstract: Aims To assess the relationship between left atrial (LA) size and outcome after high-risk myocardial infarction (MI) and to study dynamic changes in LA size during long-term follow-up.
Methods and results The VALIANT Echocardiography study prospectively enrolled 610 patients with left ventricular (LV) dysfunction, heart failure (HF), or both following MI. We assessed LA volume indexed to body surface area (LAVi) at baseline, 1 month, and 20 months after MI. Baseline LAVi was an independent predictor of all-cause death or HF hospitalization ( P = 0.004). In patients who survived to 20 months, LAVi increased a mean of 3.00 ± 7.08 mL/m2 from baseline. Hypertension, lower estimated glomerular filtration rate, and LV mass were the only baseline independent predictors of LA remodelling. Changes in LA size were related to worsening in MR and increasing in LV volumes. LA enlargement during the first month was significantly greater in patients who subsequently died or were hospitalized for HF than in patients without events.
Conclusion Baseline LA size is an independent predictor of death or HF hospitalization following high-risk MI. Moreover, LA remodelling during the first month after infarction is associated with adverse outcome.
TL;DR: HF post high risk-MI occurs in a time-dependent fashion and is usually not directly related to re-infarction, but patients who experience HF beyond the acute phase have increased mortality.
Abstract: Aims We sought to assess the incidence of and prognostic factors for heart failure (HF) hospitalization among survivors of high-risk acute myocardial infarction (MI).
Methods and results We assessed the risk of an initial hospitalization for HF in 11 040 stable MI patients (no major non-fatal cardiovascular events or deaths within 45 days of randomization) without a prior history of HF enrolled in the VALIANT trial. Multivariable models were developed to identify independent predictors of HF and HF or cardiovascular death. Of 11 040 stable post-MI patients, 1139 (10.3%) developed HF during the median 25-month follow-up at a rate of ∼3.4% per year. Most patients, 824 (72.3%), did not have a symptomatic recurrent MI between randomization and the onset of HF. The most important predictors of HF were older age, antecedent diabetes, prior MI before index MI, and reduced renal function. HF markedly increased the risk of death [HR(hazard ratio) 8.22; 95% CI(confidence interval), 7.49–9.01].
Conclusion HF post high risk-MI occurs in a time-dependent fashion and is usually not directly related to re-infarction. Patients who experience HF beyond the acute phase have increased mortality. Long-term survivors of high-risk MI should be followed closely and treated aggressively beyond the acute MI period.
TL;DR: Six months after a high-risk myocardial infarction, elevated systolic blood pressure, a potentially modifiable risk factor, is associated with an increased risk of subsequent stroke and cardiovascular events.
Abstract: The influence of blood pressure on outcomes after high-risk myocardial infarction is not well characterized. We studied the relationship between blood pressure and the risk of cardiovascular events in 14 703 patients with heart failure, left ventricular systolic dysfunction, or both after acute myocardial infarction in the Valsartan in Myocardial Infarction Trial. We assessed the relationship between antecedent hypertension and outcomes and the association between elevated (systolic: >140 mm Hg) or low blood pressure (systolic: <100 mm Hg) in 2 of 3 follow-up visits during the first 6 months and subsequent cardiovascular events over a median 24.7 months of follow-up. Antecedent hypertension independently increased the risk of heart failure (hazard ratio [HR]: 1.19; 95% CI: 1.08 to 1.32), stroke (HR: 1.27; 95% CI: 1.02 to 1.58), cardiovascular death (HR: 1.11; 95% CI: 1.01 to 1.22), and the composite of death, myocardial infarction, heart failure, stroke, or cardiac arrest (HR: 1.13; 95% CI: 1.06 to 1.21). While low blood pressure in the postmyocardial infarction period was associated with increased risk of adverse events, patients with elevated blood pressure (n=1226) were at significantly higher risk of stroke (adjusted HR: 1.64; 95% CI: 1.17 to 2.29) and combined cardiovascular events (adjusted HR: 1.14; 95% CI: 1.00 to 1.31). Six months after a high-risk myocardial infarction, elevated systolic blood pressure, a potentially modifiable risk factor, is associated with an increased risk of subsequent stroke and cardiovascular events. Whether aggressive antihypertensive treatment can reduce this risk remains unknown.
TL;DR: In a population of patients without overt renal disease, moderate reductions in estimated GFR remain an important prognostic marker and increased CV hazard associated with an estimated G FR <60 mL/min is independent and additive to markers of inflammation.
TL;DR: In men not on pravastatin, those homozygous for the 227Pro allele of ADAMTS1 have a nearly 2-fold increased risk of coronary heart disease events compared with noncarriers.
Abstract: Objective— The purpose of this study was to investigate the association between the Ala227Pro polymorphism in the ADAMTS1 metalloproteinase gene and coronary heart disease and benefit from statin t...
TL;DR: In patients with low EF heart failure, the relative risks and benefits of candesartan treatment were similar in patients with a low BP compared to those with a higher BP, and low SBP and DBP were associated with worse clinical outcomes.
TL;DR: Older patients were at a greaterabsolute risk of adverse CV mortality and morbidity outcomes but derived a similar relative risk reduction and, therefore, a greater absolute benefit from treatment with candesartan, despite receiving a somewhat lower mean daily dose.
Abstract: Aims Ageing may affect drug efficacy and safety in patients with heart failure (HF). The Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) programme offered an opportunity to study the relationship between increasing age and the efficacy and safety of treatment in an uniquely broad spectrum of patients with symptomatic HF and either reduced or preserved left ventricular ejection fraction.
Methods and results A total of 7599 patients in NYHA Class II–IV HF were randomized to candesartan (target dose 32 mg once daily, mean dose 24 mg) or placebo, including 3169 patients age >70 years. Mean follow-up was 37.7 months. The proportional hazards model was used to estimate the treatment effect on efficacy and safety within five age groups: <50 years ( n = 605) (8% of all study patients), 50–59 years ( n = 1474) (19%), 60–69 years ( n = 2351) (31%), 70–79 years ( n = 2474) (33%), and ≥80 years ( n = 695) (9%). The risk of cardiovascular (CV) death or HF hospitalization (primary outcome) increased from 24% in the lowest age group to 46% in the highest age group (and mortality from 13 to 42%). The relative reduction in risk of the primary outcome with candesartan (15% in the overall study population) was similar irrespective of age. Consequently, the absolute benefit was greater with advancing age (3.8 patients avoided a primary outcome per 100 patients treated in the lowest age group compared with 6.8 in the highest). Adverse events leading to drug discontinuation were more frequent in the candesartan group: placebo/candesartan risk (%), lowest compared with highest age category: hyperkalemia (0.0/1.6 vs. 0.6/2.7), increased serum creatinine (1.0/3.9 vs. 6.1/5.4) and hypotension (1.7/2.0 vs. 2.8/5.7).
Conclusion Older patients were at a greater absolute risk of adverse CV mortality and morbidity outcomes but derived a similar relative risk reduction and, therefore, a greater absolute benefit from treatment with candesartan, despite receiving a somewhat lower mean daily dose of candesartan. Adverse effects were more common with candesartan than with placebo, although the relative risk of adverse effects was similar across age groups. The benefit to risk ratio for candesartan was thus favourable across all age groups.
TL;DR: After AMI, risk factors and outcomes of the young differ substantively from their older counterparts, underscoring the need for aggressive risk factor modification post-AMI.
TL;DR: The CHARM-Added trial described the largest experience of using multiple inhibitors of the renin-angiotensin-aldosterone system (RAAS) together as discussed by the authors, and showed that ARB may provide added benefit, at acceptable risk, in heart failure patients already taking spironolactone as well as an ACE-I and a beta blocker.
Abstract: Background:
The efficacy and safety of adding an angiotensin receptor blocker (ARB) in heart failure (HF) patients already taking an angiotensin-converting enzyme-inhibitor (ACE-I) plus an aldosterone antagonist is uncertain (especially if taking a beta blocker as well). The CHARM-Added trial describes the largest experience of using multiple inhibitors of the renin–angiotensin–aldosterone system (RAAS) together.
Methods and results:
2548 HF patients, taking an ACE-I (936 no spironolactone/no beta blocker; 1175 no spironolactone/beta blocker; 199 spironolactone/no beta blocker; 238 sprionolactone/beta blocker), were randomized to placebo or candesartan and followed for 41 months (median). The primary outcome was cardiovascular death or HF hospitalization. In patients taking both a beta blocker and spironolactone (in addition to an ACE-I) at baseline, the candesartan:placebo hazard ratio was 0.85(95% CI 0.56, 1.29), compared to 0.85(95% CI 0.75, 0.96) in all randomized patients (interaction p value 0.49).
The relative risk of discontinuation of candesartan (compared to placebo) because of hypotension, increased serum creatinine or hyperkalemia was not increased in patients taking spironolactone at baseline.
Conclusions:
An ARB may provide added benefit, at acceptable risk, in HF patients already taking spironolactone as well as an ACE-I and beta blocker. These findings must be confirmed in a prospective randomized trial before this approach can be recommended, routinely.
TL;DR: Although dm is associated with higher risk of renal dysfunction and adverse cv outcomes, patients without dm had a relation between renal function and cv risk similar to that for patients with dm after high-risk acute myocardial infarction.
Abstract: Renal dysfunction is an independent risk factor for cardiovascular (cv) disease and its associated complications. diabetes mellitus (dm) is a common cause of renal dysfunction. whether the presence or absence of dm modifies the relation between renal dysfunction and cv disease is unclear. the valiant trial identified 14,527 patients with acute myocardial infarction complicated by either clinical or radiologic signs of heart failure and/or left ventricular dysfunction for whom baseline creatinine was measured. patients were randomly assigned to receive captopril, valsartan, or both. glomerular filtration rate (gfr) was estimated using the 4-component modification of diet in renal disease equation. using multivariable cox proportional modeling, the relation of overall mortality and composite cardiovascular events with estimated gfr (egfr) between patients with and without dm was compared. mean egfrs were 66.8 ± 22.0 and 71.2 ± 21.0 ml/min/1.73 m 2 for patients with (n = 3,358) and without dm (n = 11,169), respectively. the likelihood of experiencing death or the composite end point was higher in patients with than without dm for each level of renal function. the augmentation in risk of cv events based on reduced renal function was similar between groups. each decrease in egfr by 10 units was associated with hazards of 1.09 (95% confidence interval 1.06 to 1.12, p
TL;DR: Patients with CHF, who develop an ACS, have markedly increased subsequent mortality, particularly in the early phase after an MI, which is twice that of patients without an ACS.
Abstract: Aims We explored the impact of having a hospital admission for an acute coronary syndrome (ACS) on the subsequent prognosis among patients with chronic heart failure (CHF).
Methods and results A total of 7599 patients with CHF, New York Heart Association Classes II–IV, were randomly assigned to candesartan or placebo. We assessed the risk of death after a first ACS using time-updated Cox proportional hazard models adjusted for baseline predictors. During a mean follow-up of 3.3 years, 1174 patients experienced at least one ACS. Myocardial infarction (MI) was the first ACS in 442 subjects and unstable angina (UA) in 732. After these events, 219 (49.5%) and 167 (22.8%) patients died during follow-up. The early risk of death was more pronounced after MI: 30.2% died within 30 days compared with 3.6% after UA. After an ACS event, the risk of death declined steadily over time, although 18 months after an MI the risk was still twice that of patients without an ACS.
Conclusion Patients with CHF, who develop an ACS, have markedly increased subsequent mortality, particularly in the early phase after an MI.
TL;DR: African Americans sustaining an acute MI with left ventricular systolic dysfunction and/or HF had similar clinical outcomes compared with white Americans and Valsartan, captopril, or the combination had comparable effects on cardiovascular morbidity and mortality in African Americans and white Americans.
TL;DR: Discussion by Dr Pfeffer on the conduct of these trials to be relevant to trials of other therapies in nephrology, such as those for phosphorus binding agents, for example the DCOR (Dialysis Clinical Outcomes Revisited) study presented elsewhere in this issue of AJKD.
Journal Article•
TL;DR: In this paper, the authors measured pulsatile hemodynamics and proximal aortic diameter directly using tonometry, ultrasound imaging, and Doppler in 167 individuals with systolic hypertension.
Abstract: -Systolic hypertension is associated with increased pulse pressure (PP) and increased risk for adverse cardiovascular outcomes. However the pathogenesis of increased PP remains controversial. One hypothesis suggests that aortic dilatation, wall stiffening and increased pulse wave velocity result from elastin fragmentation, leading to a premature reflected pressure wave that contributes to elevated PP. An alternative hypothesis suggests that increased proximal aortic stiffness and reduced aortic diameter leads to mismatch between pressure and flow, giving rise to an increased forward pressure wave and increased PP. To evaluate these two hypotheses, we measured pulsatile hemodynamics and proximal aortic diameter directly using tonometry, ultrasound imaging, and Doppler in 167 individuals with systolic hypertension. Antihypertensive medications were withdrawn for at least 1 week before study. Patients with PP above the median (75 mm Hg) had lower aortic diameter (2.94±0.36 versus 3.13±0.28 cm, P<0.001) and higher aortic wall stiffness (elastance-wall stiffness product: 16.1±0.7 versus 15.7±0.7 1n[dyne/cm], P<0.001) with no difference in augmentation index (19.9 ±10.4 versus 17.5± 10.0%, P=0.12). Aortic diameter and wall stiffness both increased with advancing age (P<0.001). However, an inverse relation between PP and aortic diameter remained significant (P<0.001) in models that adjusted for age, sex, height, and weight and then further adjusted for aortic wall stiffness, augmentation index, and mean arterial pressure. Among individuals with systolic hypertension, increased PP is primarily attributable to increased wall stiffness and reduced aortic diameter rather than premature wave reflection.
TL;DR: The lessons in humility offered by these neutral or negative outcomes trials underscore the importance of obtaining crucial risk–benefit data before widespread adoption of even an apparently favorable therapy.
Abstract: Properly designed and conducted randomized controlled clinical trials (RCTs) are the premier tool for both testing mechanistic hypotheses and critically ascertaining the risks and benefits of a therapy or strategy for clinical care. The sample size of a trial is mainly a function of the rates of its primary objectives and the presumed influence of the intervention. Trials focusing on a primary outcome variable that can be readily quantified in each subject, such as blood pressure or plasma cholesterol levels, require substantially fewer participants and shorter durations to determine whether their predefined measurement is altered compared with a morbidity and mortality trial. Trials designed to determine whether clinical prognosis is altered by an intervention depend on the proportion of patients experiencing the predefined adverse clinical event(s) and often require 100s-fold–greater patient-time exposures to test their primary hypothesis and provide even modest information about safety. These resource-intense morbidity and mortality trials are generally only performed when information from observational studies as well as smaller mechanistic and surrogate- outcomes RCTs are so highly supportive of a favorable outcome that they justify the effort. Despite this understandable stacking of the cards with the best available information, many of the morbidity and mortality trials conducted to test for a potential favorable impact of an intervention conclude by not supporting the prestudy hypothesis-generating data.1 The lessons in humility offered by these neutral or negative outcomes trials underscore the importance of obtaining crucial risk–benefit data before widespread adoption of even an apparently favorable therapy.2
Articles pp 2506 and 2515
For rational therapeutic decision making, we would ideally like to have both a framework of reliable mechanistic information and robust clinical outcomes and safety data. Sometimes major clinical outcomes trials are designed with a complement of embedded ancillary trials to generate a more complete picture …
TL;DR: The importance of having a placebo-controlled trial in this patient population to better assess the risk benefit profile of erythropoietic stimulating agents is outlined.
Abstract: Epidemiologic observations showing associations between higher levels of some biologic markers such as blood pressure and serum cholesterol with heightened risk of death and non-fatal cardiovascular events have provided important data to develop hypotheses regarding pharmacologic therapies to modify these markers to improve prognosis. Randomized controlled trials have shown that strategies to reduce blood pressure with a variety of antihypertensive agents and LDL cholesterol with statins do, indeed, result in important improvements in clinical outcomes. However, there are several instances where a hypothesis based on strong observational data has been rejected based on surprising counterintuitive evidence generated from randomized controlled clinical trials. Use of inotropic therapies for patients with reduced left ventricular ejection fraction heart failure, administration of class I antiarrhythmic agents to suppress ventricular arrhythmias in high-risk patients, and use of hormone replacement therapy for postmenopausal women have each shown that therapies presumed to be of benefit may actually be producing unfavorable clinical results. Use of erythropoietic stimulating agents (ESA) in chronic kidney disease patients with anemia is similarly based on strong observational data indicating that the degree of anemia is independently associated with higher risk for cardiovascular morbidity and mortality. In non-dialysis patients with mild to moderate anemia, current clinical outcome studies have only addressed arbitrary hemoglobin targets for ESA therapy and have shown that targeting the higher hemoglobin levels was not associated with the benefit and may even result in harm. This review will outline the importance of having a placebo-controlled trial in this patient population to better assess the risk benefit profile of this therapy.
Journal Article•
TL;DR: In this article, the authors used landmark analysis and Cox proportional hazards modeling to predict SCD during hospitalization, from discharge to 30 days, 30 days to 6 months, and 6 months to 3 years.
Journal Article•
TL;DR: Perlstein et al. as discussed by the authors proposed Perlstein and Weuve as discussed by the authors, a novel approach to the problem of breast cancer diagnosis and treatment, which is referred to as the Perlstein-Weuve approach.
Abstract: 1253 Todd S Perlstein, Brigham and Women’s Hosp, Boston, MA; Jennifer Weuve, Harvard Sch of Public Health, Boston, MA; Marc A Pfeffer, Joshua A Beckman, Brigham and Women’s Hosp, Boston, M...
TL;DR: The authors appreciate the insights provided by Drs Hoglund and Nilsson regarding their recent publication on the risk associated with heart failure hospitalization and request that models should also adjust for time-updated covariates.
Abstract: We appreciate the insights provided by Drs Hoglund and Nilsson regarding our recent publication on the risk associated with heart failure hospitalization.1 Although in principle their request that models should also adjust for time-updated covariates is of interest, in practice it is liable to be unrealistic in most follow-up studies of this kind. When a clinical event such as a hospitalization for heart failure …