Publications by authors named "Milton Packer"
Several trials have evaluated diuretic-based strategies to improve symptoms and outcomes in patients with acute heart failure (AHF). The authors sought to summarize the effect of different combination strategies on symptoms, physical signs, physiological variables, and outcomes in patients with AHF. Twelve trials were identified that assessed the addition of thiazide diuretics, sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor antagonists, vasopressin receptor antagonists, carbonic anhydrase inhibitors, or loop diuretic intensification to conventional therapy for AHF.
View Article and Find Full Text PDFBackground: The importance of nutritional status is underappreciated in patients with heart failure (HF). This study aimed to describe the range of the prognostic nutrition index (PNI), and the clinical characteristics and outcomes according to PNI, in patients with HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). The primary outcome was the composite of HF hospitalization or cardiovascular death.
View Article and Find Full Text PDFAims: To evaluate clinical outcomes, echocardiographic features, and the efficacy and safety of sacubitril/valsartan compared to valsartan across age groups in the PARAGON-HF trial.
Methods And Results: A total of 4796 participants ≥50 years of age with chronic heart failure (HF) and left ventricular ejection fraction (LVEF) ≥45% were divided into three age groups: <65 years (n = 825), 65-74 years (n = 1772), and ≥75 years (n = 2199). Echocardiograms of 1097 patients were analysed in a standardized fashion at a core imaging laboratory.
Background: Lower estimated glomerular filtration rate (eGFR) may be one of the major reasons for hesitation or failure to initiate potentially beneficial therapies in patients with heart failure (HF).
Objectives: This study sought to assess if the effects of sacubitril/valsartan (vs valsartan) on cardiovascular outcomes differ according to baseline kidney function in patients with HF with preserved ejection fraction.
Methods: The PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) trial was global clinical trial of 4,796 patients with chronic HF and left ventricular ejection fraction (LVEF) ≥45% randomly assigned to sacubitril/valsartan or valsartan.
Article Synopsis
- Obesity is linked to heart failure with preserved ejection fraction (HFpEF), characterized by changes in heart structure and increased epicardial adipose tissue (EAT), which can lead to negative health outcomes.
- The SUMMIT trial's CMR substudy aimed to assess how tirzepatide influenced cardiac structure and function in patients with obesity-related HFpEF, focusing on its potential to lower left ventricular (LV) mass and EAT.
- Results showed that tirzepatide treatment significantly reduced LV mass by 11 g and paracardiac adipose tissue by 45 ml compared to placebo, with changes in LV mass correlated to body weight and other cardiac measures.
Aims: Beta-blockers may inhibit neprilysin activity and conversely, neprilysin inhibition may have a sympatho-inhibitory action. Consequently, sacubitril/valsartan may have a greater effect in patients not receiving a beta-blocker compared to those treated with a beta-blocker.
Methods And Results: We examined the effect of sacubitril/valsartan compared to enalapril on outcomes according to background beta-blocker treatment in the 8399 patients with heart failure with reduced ejection fraction enrolled in PARADIGM-HF.
Background: Patients with heart failure, a preserved ejection fraction (HFpEF), and obesity have significant disability and suffer frequent exacerbations of heart failure. We hypothesized that tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, would improve a comprehensive suite of clinical endpoints, including measures of health status, functional capacity, quality of life, exercise tolerance, patient well-being, and medication burden in these patients.
Methods: 731 patients in class II-IV heart failure, ejection fraction ≥50%, and body mass index ≥30 kg/m were randomized(double-blind) to tirzepatide(titrated up to 15mg subcutaneously weekly)(n=364) or placebo(n=367), added to background therapy for a median of 104 weeks (Q1=66, Q3=126 weeks).
Background: Obesity increases the risk of heart failure with preserved ejection fraction. Tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, causes considerable weight loss, but data are lacking with respect to its effects on cardiovascular outcomes.
Methods: In this international, double-blind, randomized, placebo-controlled trial, we randomly assigned, in a 1:1 ratio, 731 patients with heart failure, an ejection fraction of at least 50%, and a body-mass index (the weight in kilograms divided by the square of the height in meters) of at least 30 to receive tirzepatide (up to 15 mg subcutaneously once per week) or placebo for at least 52 weeks.
Patients with obesity-related heart failure with preserved ejection fraction (HFpEF) display circulatory volume expansion and pressure overload contributing to cardiovascular-kidney end-organ damage. In the SUMMIT trial, patients with HFpEF and obesity were randomized to the long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist tirzepatide (n = 364, 200 women) or placebo (n = 367, 193 women). As reported separately, tirzepatide decreased cardiovascular death or worsening heart failure.
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- Heart failure events in cardiovascular trials are often evaluated through centralized review, but its impact on treatment effect accuracy (in terms of hazard ratios) is uncertain.
- In a study of seven trials, positive adjudication rates for heart failure events were generally lower than for cardiovascular deaths, affecting subsequent mortality risk.
- Overall, while central adjudication showed some correlation between event types, it didn’t significantly change the results, suggesting that the need for centralized review should be tailored to each trial's objectives.
Background: Bladder dysfunction entails overactive bladder (OAB) defined as symptoms of urinary urgency, frequency, and/or nocturia with or without incontinence if there is no obvious pathology or infection or lower urinary tract symptoms (LUTS) that includes recognized causes of bladder dysfunction.
Methods: Literature search.
Results: Symptoms of OAB are reported in about 15% of the adult US population.
Article Synopsis
- There's uncertainty about the effects of stopping heart failure drugs after long-term use, with four main patterns of withdrawal impact observed.
- Discontinuing some medications can lead to worsening symptoms, while others may show lingering benefits before decline.
- Overall evidence indicates patients often experience significant clinical deterioration shortly after stopping heart failure treatments, highlighting the importance of maintaining consistent drug therapy.
Article Synopsis
- SGLT2 inhibitors, like empagliflozin, are shown to improve outcomes for heart failure patients and reduce uric acid levels, with a focus on those having heart failure with preserved ejection fraction (HFpEF).
- In a study of patients receiving empagliflozin, about 49% had elevated uric acid levels, which were linked to worse heart failure severity and higher risk of severe outcomes like hospitalization.
- Empagliflozin significantly lowered uric acid levels early on and reduced related clinical events by 38%, with its effectiveness in improving heart failure outcomes not impacted by initial uric acid levels.
Aims: Resting heart rate (HR) is a strong risk marker in patients with heart failure (HF), but the clinical implications of visit-to-visit changes in HR (ΔHR) are less well established. We aimed to explore the association between ΔHR and subsequent outcomes in a pooled dataset of two well-characterized cohorts of patients with HF across the full range of left ventricular ejection fraction (LVEF).
Methods And Results: PARADIGM-HF and PARAGON-HF were randomized trials testing sacubitril/valsartan versus enalapril or valsartan, respectively, in patients with HF and LVEF ≤40% (PARADIGM-HF) or LVEF ≥45% (PARAGON-HF).
Background: Cognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood.
Methods: We analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks.
Article Synopsis
- - The study investigated how race influences the effects of the heart failure treatment sacubitril/valsartan, comparing its safety and efficacy among White, Asian, and Black patients based on data from two large clinical trials (PARADIGM-HF and PARAGON-HF).
- - Results showed that Black and Asian patients had a higher risk of heart failure hospitalization or cardiovascular death compared to White patients, even though the treatment was effective for all racial groups, with no significant difference in efficacy observed across races.
- - Severe angioedema (swelling) was more common in Black patients receiving sacubitril/valsartan compared to those on alternative treatments, highlighting potential racial disparities in treatment response and safety.
Aims: Glucagon-like peptide-1 receptor agonists reduce major adverse cardiovascular events (MACE) and cardiovascular mortality in people with type 2 diabetes (T2D). However, previous studies suggest the effects on heart failure outcomes vary according to left ventricular ejection fraction (LVEF). We aimed to evaluate the effects of exenatide on cardiovascular events according to LVEF in people with T2D.
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- The study investigated the impact of hypotension on heart failure outcomes using data from the PARADIGM-HF trial, focusing on the differences between asymptomatic and symptomatic hypotension.
- Out of 8,399 patients, 16% had only asymptomatic hypotension, while 11.1% experienced symptomatic hypotension, with those having symptomatic hypotension being older and having more cardiovascular issues.
- Despite the risks associated with either type of hypotension, the heart failure medication sacubitril/valsartan showed consistent effectiveness and safety compared to enalapril across all patient groups.
Article Synopsis
- In randomized trials, deaths that are unrelated to the primary outcome being studied are classified as competing risks, and traditional analysis methods may inaccurately treat these deaths like censored data.
- The Fine and Gray model, often used for analyzing competing risks, can be misapplied and potentially deliver misleading results.
- The authors suggest a new multiple imputation approach that better accounts for the risk factors associated with both death and the outcomes of interest, and they provide recommendations for future trials based on their findings from three cardiovascular studies.
Aims: Renin-angiotensin system inhibitors (RASi) have been shown to lower haemoglobin levels, potentially related to reductions in erythropoietin levels and haematopoiesis. We examined whether sacubitril/valsartan might attenuate this effect of RASi alone on incident anaemia in patients with heart failure (HF) with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF).
Methods And Results: PARAGON-HF was a global, multicentre randomized clinical trial of sacubitril/valsartan versus the RASi valsartan in patients with HF and left ventricular ejection fraction ≥45%.