1) The study aims to determine if the urate-lowering agent febuxostat can improve clinical outcomes in chronic heart failure patients with hyperuricemia compared to conventional treatment.
2) It is a randomized, open-label trial that will enroll 200 Japanese chronic heart failure patients with hyperuricemia and assign them to either febuxostat treatment or conventional treatment.
3) The primary outcome is the difference in plasma BNP levels between baseline and 24 weeks of treatment, as measured in a blinded manner. This will investigate the efficacy and safety of febuxostat.
1) Resistant hypertension is defined as blood pressure remaining above goal despite use of 3 antihypertensive agents including a diuretic. 2) Maximizing diuretic therapy is a primary treatment recommendation, through drugs like chlorthalidone and loop diuretics. 3) Adding an aldosterone antagonist like spironolactone is also effective, though it requires monitoring of potassium levels.
This document provides an overview of 8 modules for a sales training on resistant hypertension. Module 1 discusses definitions and prevalence of resistant hypertension. Module 2 covers renal sympathetic activity in metabolic diseases. Module 3 is about differential diagnosis of resistant hypertension. Subsequent modules discuss conventional management, rationale for renal denervation, the renal denervation procedure, clinical trial data, and patient selection.
Acute Heart Failure: Current Standards and Evolution of Care.2015hivlifeinfo
This document provides an overview of the current standards and evolution of care for acute heart failure (AHF). It summarizes the use of biomarkers like natriuretic peptides and troponins in the diagnosis and risk stratification of AHF. It discusses the clinical considerations in stratifying AHF patients, including systolic blood pressure, worsening renal function, and the distribution of left ventricular ejection fraction. The document reviews current treatment options for AHF such as diuretics, vasodilators like nitroglycerin, and nesiritide based on clinical trials and guidelines.
This study evaluated the effects of spironolactone therapy in 175 patients diagnosed with true resistant hypertension based on ambulatory blood pressure monitoring. Patients received doses of 25-100 mg/day of spironolactone and had follow up monitoring after 7 months on average. The results showed mean reductions of 16 mmHg and 9 mmHg in 24-hour systolic and diastolic blood pressures respectively. Controlled ambulatory blood pressure was reached in 48% of patients. Factors associated with better response included higher waist circumference, lower arterial stiffness, and lower serum potassium. The study concluded that spironolactone is a safe and effective addition for lowering blood pressure in resistant hypertension, especially in those with abdominal obesity and
Resistant hypertension is defined as uncontrolled blood pressure despite treatment with three or more antihypertensive medications, including a diuretic. Pseudo-resistant hypertension accounts for around 50% of cases due to issues like inaccurate measurements, poor medication adherence, and inadequate treatment regimens. Ambulatory blood pressure monitoring is important for accurately diagnosing and managing resistant hypertension. Treatment involves optimizing medication regimens with medications like chlorthalidone, spiranolactone, and amiloride-hydrochlorothiazide combinations, and considering interventions for refractory cases involving more than five medications.
The document discusses a clinical trial that evaluated the use of nesiritide in patients with acute decompensated heart failure. The trial found that nesiritide reduced pulmonary capillary wedge pressure and improved dyspnea within 3 hours compared to placebo. However, later studies raised concerns about nesiritide potentially worsening renal function and increasing mortality. While initially approved by the FDA in 2001 based on its vasodilatory effects shown in trials, the risks of nesiritide remain controversial.
Resistant hypertension is defined as uncontrolled hypertension despite treatment with at least 3 antihypertensive drugs. It is increasingly common in clinical practice. The document outlines its definition, epidemiology, pathogenesis, diagnosis, and management approaches including lifestyle modifications, identifying and treating secondary causes, additional drug therapies, and device-based interventions.
Diagnosis & Management of Resistant HypertensionDr.Vinod Sharma
This document discusses diagnosis and management of resistant hypertension. It defines resistant hypertension as blood pressure remaining above goal despite concurrent use of 3 antihypertensive agents of different classes, with one being a diuretic. It estimates the prevalence of resistant hypertension to be approximately 15-20% of hypertensive patients. The document outlines steps to evaluate patients for pseudoresistance versus true resistant hypertension, including confirming nonadherence and ruling out secondary causes through screening tests. It discusses common secondary causes like obstructive sleep apnea, primary aldosteronism, and renal artery stenosis that may underlie resistant hypertension.
1) Resistant hypertension is defined as blood pressure remaining above goal despite use of 3 antihypertensive agents including a diuretic. 2) Maximizing diuretic therapy is a primary treatment recommendation, through drugs like chlorthalidone and loop diuretics. 3) Adding an aldosterone antagonist like spironolactone is also effective, though it requires monitoring of potassium levels.
This document provides an overview of 8 modules for a sales training on resistant hypertension. Module 1 discusses definitions and prevalence of resistant hypertension. Module 2 covers renal sympathetic activity in metabolic diseases. Module 3 is about differential diagnosis of resistant hypertension. Subsequent modules discuss conventional management, rationale for renal denervation, the renal denervation procedure, clinical trial data, and patient selection.
Acute Heart Failure: Current Standards and Evolution of Care.2015hivlifeinfo
This document provides an overview of the current standards and evolution of care for acute heart failure (AHF). It summarizes the use of biomarkers like natriuretic peptides and troponins in the diagnosis and risk stratification of AHF. It discusses the clinical considerations in stratifying AHF patients, including systolic blood pressure, worsening renal function, and the distribution of left ventricular ejection fraction. The document reviews current treatment options for AHF such as diuretics, vasodilators like nitroglycerin, and nesiritide based on clinical trials and guidelines.
This study evaluated the effects of spironolactone therapy in 175 patients diagnosed with true resistant hypertension based on ambulatory blood pressure monitoring. Patients received doses of 25-100 mg/day of spironolactone and had follow up monitoring after 7 months on average. The results showed mean reductions of 16 mmHg and 9 mmHg in 24-hour systolic and diastolic blood pressures respectively. Controlled ambulatory blood pressure was reached in 48% of patients. Factors associated with better response included higher waist circumference, lower arterial stiffness, and lower serum potassium. The study concluded that spironolactone is a safe and effective addition for lowering blood pressure in resistant hypertension, especially in those with abdominal obesity and
Resistant hypertension is defined as uncontrolled blood pressure despite treatment with three or more antihypertensive medications, including a diuretic. Pseudo-resistant hypertension accounts for around 50% of cases due to issues like inaccurate measurements, poor medication adherence, and inadequate treatment regimens. Ambulatory blood pressure monitoring is important for accurately diagnosing and managing resistant hypertension. Treatment involves optimizing medication regimens with medications like chlorthalidone, spiranolactone, and amiloride-hydrochlorothiazide combinations, and considering interventions for refractory cases involving more than five medications.
The document discusses a clinical trial that evaluated the use of nesiritide in patients with acute decompensated heart failure. The trial found that nesiritide reduced pulmonary capillary wedge pressure and improved dyspnea within 3 hours compared to placebo. However, later studies raised concerns about nesiritide potentially worsening renal function and increasing mortality. While initially approved by the FDA in 2001 based on its vasodilatory effects shown in trials, the risks of nesiritide remain controversial.
Resistant hypertension is defined as uncontrolled hypertension despite treatment with at least 3 antihypertensive drugs. It is increasingly common in clinical practice. The document outlines its definition, epidemiology, pathogenesis, diagnosis, and management approaches including lifestyle modifications, identifying and treating secondary causes, additional drug therapies, and device-based interventions.
Diagnosis & Management of Resistant HypertensionDr.Vinod Sharma
This document discusses diagnosis and management of resistant hypertension. It defines resistant hypertension as blood pressure remaining above goal despite concurrent use of 3 antihypertensive agents of different classes, with one being a diuretic. It estimates the prevalence of resistant hypertension to be approximately 15-20% of hypertensive patients. The document outlines steps to evaluate patients for pseudoresistance versus true resistant hypertension, including confirming nonadherence and ruling out secondary causes through screening tests. It discusses common secondary causes like obstructive sleep apnea, primary aldosteronism, and renal artery stenosis that may underlie resistant hypertension.
recent advance in pharmacotherapy of Heart failure priyanka527
This document summarizes recent advances in the management of heart failure. It discusses the pathophysiology, classification, risk factors, diagnosis, and management of heart failure including pharmacological and non-pharmacological treatments. It also discusses several novel agents currently being researched for heart failure treatment, including cardiac myosin activators, vasodilators, SERCA2a activators, ryanodine receptor stabilizers, neuregulins, and novel renin-angiotensin system blockers. Many of these novel agents are undergoing phase 2 or 3 clinical trials and aim to more effectively treat the symptoms and underlying causes of heart failure.
ACEI/ARB are effective medications for treating heart failure (HF) and reducing morbidity and mortality after acute coronary syndrome (ACS). For HF, ACE inhibitors (ACEI) or angiotensin receptor blockers (ARB) are recommended to reduce HF hospitalizations and death by inhibiting the renin-angiotensin-aldosterone system. In ACS patients, ACEI reduce death from cardiovascular causes after myocardial infarction based on evidence from large randomized controlled trials. The combination of an ARB with neprilysin inhibition provides additional benefits for symptomatic HF patients beyond ACEI or ARB alone.
The actual prevalence of RH may be lower than what is
perceived in the literature when triple-A (accuracy of BP
measurement, adherence of medications, and adequacy
of anti-HTN medications) are ensured. It is important to
emphasize that the sea of RH starts when the shore of secondary
HTN is over and the island of RfH is still uncharted. RfH is
emerging as a novel phenotype, and growing evidence suggest
that these patients have sympathetic hyperactivity. However,
the role of beta-blockers and interventions such as RDN and
baroreceptor activation techniques is yet to be studied.
The success of neurohormonal blockade: looking back – looking forward: Beta-b...drucsamal
- The document summarizes the history of beta-blocker treatment for heart failure, from early studies in the 1970s showing potential benefits to large randomized controlled trials in the 1990s and 2000s firmly establishing mortality reduction.
- Key trials included MDC (1993) showing reduced mortality and heart transplantation, CIBIS-II (1999) showing reduced mortality with bisoprolol, MERIT-HF (1999) showing reduced mortality with metoprolol CR/XL, and COPERNICUS (2001) showing reduced mortality, hospitalizations, and worsening heart failure with carvedilol.
- Meta-analyses demonstrated a consistent mortality reduction of approximately 35% associated with beta-blocker use in
Resistant hypertension is defined as blood pressure that remains above goal despite treatment with three antihypertensive agents from different classes, with one being a diuretic. Approximately 10% of hypertensive patients have resistant hypertension. Pseudoresistance can occur due to factors like poor medication adherence or white coat effect. Evaluation of resistant hypertension involves assessing for secondary causes, target organ damage, and ensuring true treatment resistance by addressing pseudoresistance factors. Treatment focuses on lifestyle modifications, optimizing medication adherence, addressing secondary causes, and adding additional antihypertensive agents such as mineralocorticoid receptor antagonists.
This document discusses beta blockers and focuses on bisoprolol. It summarizes that:
1) Beta blockers are a class of drugs used to treat heart conditions like heart failure and hypertension, but they have diverse properties. Bisoprolol is a selective beta-1 blocker.
2) Studies show bisoprolol provides similar or better blood pressure control compared to other beta blockers like atenolol and metoprolol. It also provides superior heart rate reduction.
3) The CIBIS II trial found bisoprolol reduced all-cause mortality by 34% in heart failure patients when added to standard therapy of diuretics and ACE inhibitors.
This document provides guidance on guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF). It discusses initiation and titration of therapies including angiotensin receptor-neprilysin inhibitors, beta-blockers, sacubitril-valsartan, ivabradine, SGLT2 inhibitors, ACE inhibitors, ARBs, loop diuretics, and aldosterone antagonists. Key points include initiating therapies individually based on patient status, up-titrating doses every 2 weeks to maximize benefits, assessing for response using echocardiograms and biomarkers, and continuing GDMT even if ejection fraction improves to prevent heart failure events. Transcat
This document summarizes guidelines from the 2017 ACC/AHA/HFSA Focused Update for the management of heart failure. It discusses the initial evaluation of heart failure patients including the use of biomarkers for prevention, diagnosis and prognosis. It also reviews pharmacological treatments for stage C heart failure with reduced or preserved ejection fraction. Additionally, it examines important comorbidities seen in heart failure patients such as anemia, hypertension, and sleep disordered breathing.
ACCF / AHA Guideline for the Management of Heart Failuredrucsamal
Risk factor modification is recommended for individuals at risk for heart failure (HF) with no structural heart disease or symptoms (Stage A). Lifestyle modifications and control of hypertension, diabetes, and other vascular risk factors can help prevent or delay the development of structural heart changes and symptoms of HF.
The document summarizes key information about acute heart failure, including epidemiology, pathophysiology, treatment approaches, and trial data. It describes the ASCEND-HF trial which investigated the effects of nesiritide vs placebo on outcomes in over 7,000 patients hospitalized for acute decompensated heart failure. The trial found no significant differences between nesiritide and placebo for its co-primary endpoints of 30-day mortality or heart failure rehospitalization and dyspnea relief at 6 and 24 hours.
This document discusses heart failure with preserved ejection fraction (HFpEF). It begins by defining HFpEF and noting that approximately half of heart failure patients have normal or near-normal ejection fractions. The document then reviews various classification systems for HF, diagnostic criteria, echocardiographic assessment of HFpEF, risk factors, and challenges in diagnosing and treating HFpEF. It concludes by discussing current and potential future treatment approaches for HFpEF, including drugs targeting comorbid conditions that are common in HFpEF patients.
Medical Management of Heart Failure in the ClinicHenry Tran
This document provides guidance on the medical management of heart failure. It reviews definitions of heart failure with reduced ejection fraction (HFrEF) versus heart failure with preserved ejection fraction (HFpEF). It outlines the latest guidelines for initiating and titrating evidence-based medications like beta blockers, ACE inhibitors, ARBs, aldosterone antagonists, and loop diuretics. Newer therapies like sacubitril/valsartan and ivabradine are also discussed. The document addresses how to apply these guidelines to clinical cases and answers questions on the appropriate use and goals of standard heart failure medications.
Acute Heart Failure Management- Old and New WaysDuke Heart
1. The document discusses new and old ways of managing acute heart failure, focusing on decongestion.
2. It reviews trials of diuretics and vasodilators, and explores strategies like targeting different fluid compartments and restricting cardiac preload.
3. Innovative approaches discussed include modulating the splanchnic nerves, optimizing diuresis, directly draining fluid from the kidneys, and mechanically unloading the heart to aid decongestion.
Beta blockers are the most effective therapy for heart failure according to clinical trials. Long term use of beta blockers such as bisoprolol, carvedilol, and sustained release metoprolol succinate can reduce mortality, heart failure hospitalizations, and improve ejection fraction and symptoms of heart failure. While initiation requires slow uptitration, discontinuation of beta blockers during heart failure hospitalization is generally not necessary and may worsen outcomes.
Urocortin-2 Infusion in Acute Decompensated Heart Failure
The study investigated the effects of urocortin-2 infusion compared to placebo in patients with acute decompensated heart failure. Fifty-three patients were randomly assigned to receive either 5 ng/kg/min of urocortin-2 or placebo infusion for 4 hours in addition to standard therapy. Urocortin-2 produced greater increases in cardiac output and decreases in blood pressure and total peripheral resistance compared to placebo. Renal indices fell transiently during urocortin-2 infusion but returned to above baseline levels after infusion. Further studies are needed to understand the full potential of urocortin-2 for treating acute
Pharmacotherapy in Chronical Systolic Heart Failuredrucsamal
This document discusses pharmacological treatment for chronic systolic heart failure. It outlines the goals of treatment as relieving symptoms and preventing hospitalization and death. It provides recommendations from guidelines for evidence-based medications including ACE inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and others. It notes demonstration of benefits from randomized clinical trials including relative risk reductions in mortality from different drug classes.
This document summarizes guidelines for managing resistant hypertension in primary care. It defines resistant hypertension as blood pressure that remains above 140/90 mmHg despite treatment with three antihypertensive medications from different classes, including a diuretic. It estimates that about 10% of hypertensive patients have resistant hypertension. The causes are often multifactorial and secondary causes must be ruled out. Initial treatment involves lifestyle changes and a combination of medications targeting different mechanisms, such as an ACE inhibitor, calcium channel blocker, and thiazide diuretic. Chlorthalidone is recommended over hydrochlorothiazide as the diuretic due to its greater potency, especially for resistant hypertension.
The document discusses catheter-based renal sympathetic denervation as a treatment for resistant hypertension. It summarizes findings from the SYMPLICITY HTN-2 trial, which found that renal denervation significantly reduced blood pressure in patients with resistant hypertension compared to a control group. The European Society of Cardiology has issued guidelines stating renal denervation can be considered for patients with drug-resistant hypertension who cannot lower their blood pressure through lifestyle and pharmacological means. The document also reviews the mechanism of action of renal denervation and safety findings.
This document provides guidelines for the management of heart failure. It defines heart failure and classifies it based on ejection fraction into heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). It recommends treatments for each stage of heart failure, including using ACE inhibitors, ARBs, beta blockers, aldosterone antagonists, and diuretics to treat HFrEF based on the patient's symptoms and ejection fraction. The guidelines provide dosing and efficacy evidence for each drug therapy. It recommends controlling risk factors and comorbidities for early stages of heart failure and using biomarkers and imaging to assist in diagnosis and management.
Guidelines and beyond new drug therapy for heart failure with reduced ejectio...ahvc0858
This document provides information on new guidelines and therapies for heart failure patients. It begins by outlining the challenges of managing heart failure patients and their high mortality rates. It then discusses the history of heart failure treatments from ACE inhibitors in the 1990s to newer drugs like ARNi's. The document defines the different types of heart failure - HFrEF, HFmrEF, and HFpEF - and their diagnostic criteria. It explains how neprilysin inhibition enhances natriuretic peptides while simultaneously suppressing the RAAS. Finally, it summarizes that the new drug LCZ696 combines neprilysin inhibition with an ARB to reduce mortality and hospitalization in heart failure patients beyond existing neurohormonal therapies
Guideline directed medical therapy for “Chronic Heart Failure“Arindam Pande
Medica Lab is NABL accredited for guideline directed medical therapy for chronic heart failure. Dr. Arindam Pande discusses recent guidelines for the treatment of chronic heart failure, including recommendations for pharmacological therapies such as ACE inhibitors, beta-blockers, MRAs, and the new drug sacubitril-valsartan. Clinical trials are underway to evaluate the SGLT2 inhibitor empagliflozin for reducing heart failure hospitalizations and cardiovascular death.
recent advance in pharmacotherapy of Heart failure priyanka527
This document summarizes recent advances in the management of heart failure. It discusses the pathophysiology, classification, risk factors, diagnosis, and management of heart failure including pharmacological and non-pharmacological treatments. It also discusses several novel agents currently being researched for heart failure treatment, including cardiac myosin activators, vasodilators, SERCA2a activators, ryanodine receptor stabilizers, neuregulins, and novel renin-angiotensin system blockers. Many of these novel agents are undergoing phase 2 or 3 clinical trials and aim to more effectively treat the symptoms and underlying causes of heart failure.
ACEI/ARB are effective medications for treating heart failure (HF) and reducing morbidity and mortality after acute coronary syndrome (ACS). For HF, ACE inhibitors (ACEI) or angiotensin receptor blockers (ARB) are recommended to reduce HF hospitalizations and death by inhibiting the renin-angiotensin-aldosterone system. In ACS patients, ACEI reduce death from cardiovascular causes after myocardial infarction based on evidence from large randomized controlled trials. The combination of an ARB with neprilysin inhibition provides additional benefits for symptomatic HF patients beyond ACEI or ARB alone.
The actual prevalence of RH may be lower than what is
perceived in the literature when triple-A (accuracy of BP
measurement, adherence of medications, and adequacy
of anti-HTN medications) are ensured. It is important to
emphasize that the sea of RH starts when the shore of secondary
HTN is over and the island of RfH is still uncharted. RfH is
emerging as a novel phenotype, and growing evidence suggest
that these patients have sympathetic hyperactivity. However,
the role of beta-blockers and interventions such as RDN and
baroreceptor activation techniques is yet to be studied.
The success of neurohormonal blockade: looking back – looking forward: Beta-b...drucsamal
- The document summarizes the history of beta-blocker treatment for heart failure, from early studies in the 1970s showing potential benefits to large randomized controlled trials in the 1990s and 2000s firmly establishing mortality reduction.
- Key trials included MDC (1993) showing reduced mortality and heart transplantation, CIBIS-II (1999) showing reduced mortality with bisoprolol, MERIT-HF (1999) showing reduced mortality with metoprolol CR/XL, and COPERNICUS (2001) showing reduced mortality, hospitalizations, and worsening heart failure with carvedilol.
- Meta-analyses demonstrated a consistent mortality reduction of approximately 35% associated with beta-blocker use in
Resistant hypertension is defined as blood pressure that remains above goal despite treatment with three antihypertensive agents from different classes, with one being a diuretic. Approximately 10% of hypertensive patients have resistant hypertension. Pseudoresistance can occur due to factors like poor medication adherence or white coat effect. Evaluation of resistant hypertension involves assessing for secondary causes, target organ damage, and ensuring true treatment resistance by addressing pseudoresistance factors. Treatment focuses on lifestyle modifications, optimizing medication adherence, addressing secondary causes, and adding additional antihypertensive agents such as mineralocorticoid receptor antagonists.
This document discusses beta blockers and focuses on bisoprolol. It summarizes that:
1) Beta blockers are a class of drugs used to treat heart conditions like heart failure and hypertension, but they have diverse properties. Bisoprolol is a selective beta-1 blocker.
2) Studies show bisoprolol provides similar or better blood pressure control compared to other beta blockers like atenolol and metoprolol. It also provides superior heart rate reduction.
3) The CIBIS II trial found bisoprolol reduced all-cause mortality by 34% in heart failure patients when added to standard therapy of diuretics and ACE inhibitors.
This document provides guidance on guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF). It discusses initiation and titration of therapies including angiotensin receptor-neprilysin inhibitors, beta-blockers, sacubitril-valsartan, ivabradine, SGLT2 inhibitors, ACE inhibitors, ARBs, loop diuretics, and aldosterone antagonists. Key points include initiating therapies individually based on patient status, up-titrating doses every 2 weeks to maximize benefits, assessing for response using echocardiograms and biomarkers, and continuing GDMT even if ejection fraction improves to prevent heart failure events. Transcat
This document summarizes guidelines from the 2017 ACC/AHA/HFSA Focused Update for the management of heart failure. It discusses the initial evaluation of heart failure patients including the use of biomarkers for prevention, diagnosis and prognosis. It also reviews pharmacological treatments for stage C heart failure with reduced or preserved ejection fraction. Additionally, it examines important comorbidities seen in heart failure patients such as anemia, hypertension, and sleep disordered breathing.
ACCF / AHA Guideline for the Management of Heart Failuredrucsamal
Risk factor modification is recommended for individuals at risk for heart failure (HF) with no structural heart disease or symptoms (Stage A). Lifestyle modifications and control of hypertension, diabetes, and other vascular risk factors can help prevent or delay the development of structural heart changes and symptoms of HF.
The document summarizes key information about acute heart failure, including epidemiology, pathophysiology, treatment approaches, and trial data. It describes the ASCEND-HF trial which investigated the effects of nesiritide vs placebo on outcomes in over 7,000 patients hospitalized for acute decompensated heart failure. The trial found no significant differences between nesiritide and placebo for its co-primary endpoints of 30-day mortality or heart failure rehospitalization and dyspnea relief at 6 and 24 hours.
This document discusses heart failure with preserved ejection fraction (HFpEF). It begins by defining HFpEF and noting that approximately half of heart failure patients have normal or near-normal ejection fractions. The document then reviews various classification systems for HF, diagnostic criteria, echocardiographic assessment of HFpEF, risk factors, and challenges in diagnosing and treating HFpEF. It concludes by discussing current and potential future treatment approaches for HFpEF, including drugs targeting comorbid conditions that are common in HFpEF patients.
Medical Management of Heart Failure in the ClinicHenry Tran
This document provides guidance on the medical management of heart failure. It reviews definitions of heart failure with reduced ejection fraction (HFrEF) versus heart failure with preserved ejection fraction (HFpEF). It outlines the latest guidelines for initiating and titrating evidence-based medications like beta blockers, ACE inhibitors, ARBs, aldosterone antagonists, and loop diuretics. Newer therapies like sacubitril/valsartan and ivabradine are also discussed. The document addresses how to apply these guidelines to clinical cases and answers questions on the appropriate use and goals of standard heart failure medications.
Acute Heart Failure Management- Old and New WaysDuke Heart
1. The document discusses new and old ways of managing acute heart failure, focusing on decongestion.
2. It reviews trials of diuretics and vasodilators, and explores strategies like targeting different fluid compartments and restricting cardiac preload.
3. Innovative approaches discussed include modulating the splanchnic nerves, optimizing diuresis, directly draining fluid from the kidneys, and mechanically unloading the heart to aid decongestion.
Beta blockers are the most effective therapy for heart failure according to clinical trials. Long term use of beta blockers such as bisoprolol, carvedilol, and sustained release metoprolol succinate can reduce mortality, heart failure hospitalizations, and improve ejection fraction and symptoms of heart failure. While initiation requires slow uptitration, discontinuation of beta blockers during heart failure hospitalization is generally not necessary and may worsen outcomes.
Urocortin-2 Infusion in Acute Decompensated Heart Failure
The study investigated the effects of urocortin-2 infusion compared to placebo in patients with acute decompensated heart failure. Fifty-three patients were randomly assigned to receive either 5 ng/kg/min of urocortin-2 or placebo infusion for 4 hours in addition to standard therapy. Urocortin-2 produced greater increases in cardiac output and decreases in blood pressure and total peripheral resistance compared to placebo. Renal indices fell transiently during urocortin-2 infusion but returned to above baseline levels after infusion. Further studies are needed to understand the full potential of urocortin-2 for treating acute
Pharmacotherapy in Chronical Systolic Heart Failuredrucsamal
This document discusses pharmacological treatment for chronic systolic heart failure. It outlines the goals of treatment as relieving symptoms and preventing hospitalization and death. It provides recommendations from guidelines for evidence-based medications including ACE inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and others. It notes demonstration of benefits from randomized clinical trials including relative risk reductions in mortality from different drug classes.
This document summarizes guidelines for managing resistant hypertension in primary care. It defines resistant hypertension as blood pressure that remains above 140/90 mmHg despite treatment with three antihypertensive medications from different classes, including a diuretic. It estimates that about 10% of hypertensive patients have resistant hypertension. The causes are often multifactorial and secondary causes must be ruled out. Initial treatment involves lifestyle changes and a combination of medications targeting different mechanisms, such as an ACE inhibitor, calcium channel blocker, and thiazide diuretic. Chlorthalidone is recommended over hydrochlorothiazide as the diuretic due to its greater potency, especially for resistant hypertension.
The document discusses catheter-based renal sympathetic denervation as a treatment for resistant hypertension. It summarizes findings from the SYMPLICITY HTN-2 trial, which found that renal denervation significantly reduced blood pressure in patients with resistant hypertension compared to a control group. The European Society of Cardiology has issued guidelines stating renal denervation can be considered for patients with drug-resistant hypertension who cannot lower their blood pressure through lifestyle and pharmacological means. The document also reviews the mechanism of action of renal denervation and safety findings.
This document provides guidelines for the management of heart failure. It defines heart failure and classifies it based on ejection fraction into heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). It recommends treatments for each stage of heart failure, including using ACE inhibitors, ARBs, beta blockers, aldosterone antagonists, and diuretics to treat HFrEF based on the patient's symptoms and ejection fraction. The guidelines provide dosing and efficacy evidence for each drug therapy. It recommends controlling risk factors and comorbidities for early stages of heart failure and using biomarkers and imaging to assist in diagnosis and management.
Guidelines and beyond new drug therapy for heart failure with reduced ejectio...ahvc0858
This document provides information on new guidelines and therapies for heart failure patients. It begins by outlining the challenges of managing heart failure patients and their high mortality rates. It then discusses the history of heart failure treatments from ACE inhibitors in the 1990s to newer drugs like ARNi's. The document defines the different types of heart failure - HFrEF, HFmrEF, and HFpEF - and their diagnostic criteria. It explains how neprilysin inhibition enhances natriuretic peptides while simultaneously suppressing the RAAS. Finally, it summarizes that the new drug LCZ696 combines neprilysin inhibition with an ARB to reduce mortality and hospitalization in heart failure patients beyond existing neurohormonal therapies
Guideline directed medical therapy for “Chronic Heart Failure“Arindam Pande
Medica Lab is NABL accredited for guideline directed medical therapy for chronic heart failure. Dr. Arindam Pande discusses recent guidelines for the treatment of chronic heart failure, including recommendations for pharmacological therapies such as ACE inhibitors, beta-blockers, MRAs, and the new drug sacubitril-valsartan. Clinical trials are underway to evaluate the SGLT2 inhibitor empagliflozin for reducing heart failure hospitalizations and cardiovascular death.
"Heart failure is a typical clinical accompanied by symptoms syndrome (e.g. shortness of breath, ankle swelling and fatigue) that lead to structural or functional abnormalities of the heart (e.g. high venous pressure, pulmonary edema and peripheral edema).
In recent years, the significant role of B-type natriuretic peptide has been revealed in the pathogenesis of heart disease and the use of the drug sacubitril/valsartan has started. It has a positive effect on the regulation of the level of B-type natriuretic peptide in the body. It is obviously seen from the the world literature that natriuretic peptides play an important role in the pathophysiology of heart failure. For this reason, many studies suggest that the importance of natriuretic peptides in the diagnosis and treatment of heart failure is recommended.
Due to this, we tried to investigate the effects of a comprehensive medication therapy with a combination of sacubitril/valsartan in the patients with chronic heart failure."
This document summarizes two cases presented at a cardiology grand rounds meeting. Case 1 involves a 55-year-old male with ischemic dilated cardiomyopathy, heart failure with reduced ejection fraction, and coronary artery disease. Case 2 involves a 36-year-old male with non-ischemic dilated cardiomyopathy and heart failure with reduced ejection fraction. The document then reviews heart failure epidemiology, etiology, evaluation, classification, management, complications, and prognosis.
Nuove Prospective nel trattamento dello scompenso acutodrucsamal
This document summarizes recent perspectives on the treatment of acute heart failure syndrome. It discusses various therapeutic targets including fluids, renal function, contractility, diastole, vasomotion. It reviews drugs that can help achieve these targets, such as loop diuretics, inotropes, vasodilators, novel agents like istaroxime, urocortins, nesiritide, and chimeric natriuretic peptides. Large trials on rolofylline and nesiritide are also summarized that investigated effects on renal function and other outcomes in acute heart failure patients.
Samir Morcos Rafla is an emeritus professor of cardiology at Alexandria University who has published guidelines on acute heart failure. Heart failure can be chronic or acute, with acute heart failure defined as a rapid onset of symptoms requiring urgent therapy. It is classified based on systolic blood pressure into normotensive, hypertensive, non-hypertensive, and hypotensive subtypes. Acute heart failure is a global public health problem associated with high rates of hospitalization and mortality.
This document summarizes a clinical review on the current and future management of acute heart failure syndromes. It discusses how over 1/3 of heart failure patients will be rehospitalized or die within 90 days of discharge, despite use of evidence-based chronic heart failure therapies in the hospital. Traditional therapies for acute heart failure like diuretics and nitrates remain the standard of care. The review introduces the concept of "cardiac reconstruction" to potentially improve outcomes by preserving or improving myocardial function. It also discusses classifying acute heart failure patients based on their clinical presentation and cardiac structure/function to help guide therapeutic goals and options.
This study examined the incidence and predictors of acute renal failure (ARF) in congestive heart failure (CHF) patients treated with angiotensin-converting enzyme inhibitors (ACEIs). The researchers followed 114 CHF patients treated with ACEIs over 30 days. They found that 25% developed ARF, 15% developed hyperkalemia, and 3% developed severe hyperkalemia. Predictors of ARF included a decrease in average blood pressure of 25 mm Hg or more after starting ACEI treatment, class IV CHF, diabetes, and hypertension. A decrease in blood pressure of 25 mm Hg or more and class IV CHF were independent predictors of ARF based on multivariate analysis.
Tentiran GP Provita Acute Heart Failure (2).pptxWayan Gunawan
Acute heart failure requires urgent evaluation and management according to three steps:
1. Initial management focuses on treating life-threatening conditions like acute coronary syndrome, arrhythmias, or pulmonary embolism.
2. Diagnosis involves ruling in or ruling out acute heart failure based on symptoms of congestion and hypoperfusion.
3. Management is then based on symptoms, providing diuretics and vasodilators for congestion or inotropes for hypoperfusion, with a goal of achieving a "warm dry" state for discharge. Early initiation of evidence-based oral therapies and close follow-up after discharge are also emphasized.
Iron deficiency is an extremely common comorbidity in patients with heart failure, affecting up to 50% of all ambulatory patients. It is associated with reduced exercise capacity and physical well-being and reduced quality of life. Cutoff values have been identified for diagnosing iron deficiency in heart failure with reduced ejection fraction as serum ferritin, <100 μg/l, or ferritin, 100 to 300 μg/l, with transferrin saturation of <20%. Oral iron products have been shown to have little efficacy in heart failure, where the preference is intravenous iron products. Most clinical studies have been performed using ferric carboxymaltose with good efficacy in terms of improvements in 6-min walk test distance, peak oxygen consumption, quality of life, and improvements in New York Heart Association functional class. Data from meta-analyses also suggest beneficial effects for hospitalization rates for heart failure and reduction in cardiovascular mortality rates. A prospective trial to investigate effects on morbidity and mortality is currently ongoing. This paper highlights current knowledge of the pathophysiology of iron deficiency in heart failure, its prevalence and clinical impact, and its possible treatment options
The PARADIGM-HF trial compared the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan to the ACE inhibitor enalapril in patients with heart failure with reduced ejection fraction. It found that sacubitril/valsartan reduced cardiovascular mortality and heart failure hospitalizations compared to enalapril, as well as reducing overall mortality. The trial established sacubitril/valsartan as a new standard of care for treating HFrEF.
This document contains summaries of several studies presented at the ACC24 conference around cardiovascular diseases like hypertension, angina, CAD, MI, AF, and HF. One study found that CSL112 infusions did not significantly reduce cardiovascular outcomes in AMI patients over 90 days compared to placebo. Another study found that a transcatheter inter-atrial shunt did not improve symptoms or prognosis in HF patients after 2 years regardless of LVEF. A third study found that Empagliflozin reduced HF hospitalization risk by 23-33% in post-MI patients but did not reduce all-cause mortality.
Mixed results for heart failure therapies, journel clubDr Virbhan Balai
1. A study compared the angiotensin receptor–neprilysin inhibitor LCZ696 to enalapril in patients with heart failure and reduced ejection fraction. LCZ696 was superior to enalapril in reducing risks of death and hospitalization for heart failure.
2. A trial investigated spironolactone in patients with heart failure and preserved ejection fraction. Spironolactone did not significantly reduce the primary outcome but did lower the risk of hospitalization for heart failure. It increased hyperkalemia but with monitoring, serious adverse events were similar to placebo.
3. A study examined intravenous ferric carboxymaltose in patients with heart failure, reduced
Early initiation of ARNI in ADHF - final.pptxAmeetRathod3
- ARNI (angiotensin receptor-neprilysin inhibitor) drugs like sacubitril/valsartan work by inhibiting neprilysin, which breaks down natriuretic peptides, leading to increased levels of natriuretic peptides that can reduce blood pressure and cardiac remodeling.
- Evidence shows ARNI drugs are effective in reducing hospitalizations and mortality in chronic heart failure patients with reduced ejection fraction. However, their role in acute decompensated heart failure is still being investigated.
- Ongoing studies are exploring if early initiation of ARNI after admission for acute decompensated heart failure can help prevent cardiac remodeling and readmissions compared to initiating ARNI only after stabilization.
- The purpose of this focused update is to revise sections of the 2013 ACCF/AHA Guideline for the Management of Heart Failure based on new evidence, including biomarkers, new therapies for HFrEF, updates on HFpEF, comorbidities, and prevention.
- Biomarkers such as BNP and NT-proBNP are useful for diagnosing and establishing prognosis in HF. New data suggest biomarker screening and early intervention may prevent HF development.
- For HFrEF Stage C/D, ARNI is now recommended to replace ACE-I or ARB to further reduce morbidity/mortality based on new trials. Concomitant use of ACE-I and ARNI may be harmful
1) The document discusses treatment of heart failure with aldosterone antagonists like spironolactone and the risk of hyperkalemia. It notes that while the RALES study showed low risk, other studies found higher rates.
2) It recommends identifying risk factors for hyperkalemia in heart failure patients on these drugs. Close monitoring of potassium and renal function before and after starting or increasing the drugs is strongly advised.
3) Drugs should be started at low doses and dose increases only made after considering safety, to help prevent hyperkalemia in patients treated with renin-angiotensin-aldosterone system blockers alone or combined.
This document discusses cardiac dysfunction in patients with cirrhosis of the liver. It aims to study cardiac dysfunction in these patients and correlate it with the severity of cirrhosis. It also aims to study the course of cardiac dysfunction during treatment. The document provides background on cirrhotic cardiomyopathy and discusses characteristic features like attenuated response to stress and structural/histological changes. It outlines the study design, materials and methods, including inclusion/exclusion criteria and tests to be performed. Abnormal cardiovascular responses to stressors and drugs in cirrhotic patients are summarized. Prolonged QT interval on ECG and elevated cardiac markers are discussed as features of cardiac dysfunction in cirrhosis.
Cor pulmonale, also known as pulmonary heart disease, is a type of heart disease where the right side of the heart enlarges and fails over time due to high blood pressure in the lungs or pulmonary hypertension. It is usually caused by lung diseases like chronic obstructive pulmonary disease (COPD) that result in low oxygen levels and resistance within the pulmonary arteries of the lungs. The enlarged right ventricle must work harder to pump blood into the lungs, causing it to thicken and eventually fail if left untreated.
Peptic ulcers develop in the lining of the stomach or small intestine. Common causes are infection by H. pylori bacteria and use of pain medications like ibuprofen. Symptoms include stomach pain that is worse when the stomach is empty. Diagnosis involves tests to detect H. pylori infection and endoscopy to view the digestive tract. Treatment eliminates the bacteria with antibiotics if present, reduces acid production, and promotes healing with proton pump inhibitors or acid blockers. Preventive measures include careful use of pain medications and protecting against infections.
Pancreatitis is inflammation of the pancreas that can be acute or chronic. It occurs when digestive enzymes in the pancreas are activated and damage pancreatic cells. Common causes include alcoholism, gallstones, certain medications, abdominal injuries, and genetic factors. Symptoms vary but often include abdominal pain that worsens with eating as well as nausea and vomiting. Diagnosis involves blood tests, imaging scans, and endoscopy. Treatment focuses on relieving symptoms, treating underlying causes, and managing complications. To prevent pancreatitis, avoiding excessive alcohol consumption and following a low-fat diet can help reduce risk.
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder defined by abdominal pain and changes in bowel habits. The causes are unclear but may involve stress, infection, or brain-gut interactions. Symptoms include abdominal pain, gas, bloating, and diarrhea or constipation. Diagnosis is based on symptoms, and tests rule out other conditions. Treatment focuses on lifestyle changes like diet, exercise, and stress relief. Medications may help control symptoms but no single treatment works for everyone with this common disorder.
Inflammatory bowel disease (IBD) describes disorders that involve chronic inflammation of the digestive tract, including ulcerative colitis and Crohn's disease. The exact cause is unknown but is likely related to malfunctions of the immune system. Symptoms vary in severity from mild to severe and include diarrhea, abdominal pain, bleeding, and weight loss. Diagnosis involves blood tests, endoscopy, imaging, and ruling out other potential causes. Treatment aims to reduce inflammation and includes anti-inflammatory drugs, immunosuppressants, antibiotics, and surgery in some cases.
Helicobacter pylori is a type of bacteria that infects the stomach and is the most common cause of gastritis and peptic ulcers worldwide. Infection is very common and increases with age. H. pylori bacteria can be transmitted through direct contact with infected feces or vomit, or through contaminated food or water. While most infected people never show symptoms, potential symptoms include abdominal pain, nausea, loss of appetite, and weight loss. Diagnosis involves tests of the blood, breath, or stool to detect H. pylori. Treatment consists of antibiotics along with medication to reduce stomach acid in order to kill the bacteria and allow the stomach lining to heal.
Gastroesophageal reflux disease (GERD) occurs when stomach acid returns up into the esophagus and causes irritation. It is common for people to experience acid reflux occasionally, but GERD is when it occurs at least twice a week or more severely once a week. Risk factors include obesity, pregnancy, smoking, and certain medications. Symptoms include heartburn, nausea, coughing, and sore throat. Diagnosis is usually based on symptoms, but tests like endoscopy or pH monitoring can be done. Treatment involves lifestyle changes like losing weight, avoiding foods and drinks that trigger symptoms, and medications to reduce acid production. Surgery may be an option for severe cases that do not improve with other treatments.
Gastroenteritis is inflammation of the stomach and intestines that is usually caused by viruses, bacteria, or parasites. Common symptoms include diarrhea, nausea, vomiting, and abdominal pain. While generally self-limiting, gastroenteritis can cause dehydration, which is more common and dangerous in infants and young children. Oral rehydration solutions are the recommended treatment for mild to moderate dehydration. Prevention involves proper food handling and drinking clean water, especially when traveling.
1. Gastrointestinal stromal tumors (GIST) are rare tumors that can develop in the wall of the gastrointestinal tract and can be cancerous (malignant) or non-cancerous (benign). Risk factors include inherited genetic mutations and rare genetic syndromes.
2. Symptoms of GIST tumors include blood in stool or vomit, abdominal pain, fatigue, difficulty swallowing, and feeling full after eating small amounts of food. Diagnosis involves physical exams, CT scans, MRI scans, endoscopic ultrasounds, and biopsies of suspicious tissue.
3. Treatment depends on the stage and location of the tumor and may involve surgical resection as the only potentially curative treatment
1. Gastritis is inflammation of the lining of the stomach that is usually caused by Helicobacter pylori infection or excessive alcohol or drug use. It can be acute or chronic.
2. Common causes include H. pylori infection, NSAIDs, alcohol, bile reflux, autoimmune disorders, and stress. Symptoms may include abdominal pain, nausea, vomiting, and black stools from bleeding.
3. Diagnosis involves blood tests, endoscopy, and stool tests. Treatment focuses on eliminating the cause, using antacids or other drugs to reduce stomach acid, and antibiotics to treat H. pylori infection. Preventing overuse of NSAIDs and limiting alcohol and sp
1. Esophageal motor disorders are alterations in the peristaltic activity of the esophageal body and/or functioning of the sphincters. There are primary motor disorders that affect the esophageal body and lower esophageal sphincter including achalasia, diffuse esophageal spasm, and hypercontractile disorders.
2. The etiology of spastic motor disorders is divided into primary and secondary causes. The primary causes include diffuse esophageal spasm, nutcracker esophagus, and hypertensive lower esophageal sphincter. The pathophysiology involves alterations in nitric oxide synthesis and degradation affecting normal peristalsis.
3. Symptoms include chest pain, dysphagia
Dyspepsia, also known as indigestion, refers to discomfort or pain in the upper abdomen that is often caused by eating. Common symptoms include pain, swelling, heartburn, and nausea. While the specific cause is unknown in most cases, potential causes include stress, medications like aspirin, Helicobacter pylori bacteria, smoking, alcohol, spicy or greasy foods, and large meal sizes. Diagnosis involves tests like abdominal ultrasounds and endoscopies of the esophagus, stomach, and duodenum. Treatment focuses on diet changes, antibiotics to eliminate H. pylori if present, and medications to reduce acid like omeprazole. Prevention includes relaxing after
This document discusses diseases of the rectum and anus. It begins with definitions and explains that these diseases are commonly seen in primary care. It describes some of the main diseases including their causes, symptoms, and risk factors. Some of the diseases covered include hemorrhoids, anal fissures, abscesses, and anal cancer. The document discusses how these diseases are diagnosed, often through examination with an anoscope or sigmoidoscope. It also outlines treatments for some conditions like surgery, radiation therapy, and chemotherapy for anal cancer. Lastly, it discusses some ways to prevent diseases like avoiding risk factors, screening high risk patients, and vaccinations to prevent HPV infections.
The document discusses diseases of the mouth cavity. It defines the mouth and its functions, and describes common mouth problems like cold sores, canker sores, and infections. Diagnosis involves examination by a dentist, and treatment depends on the specific problem but may include cleaning, surgery, or maintenance visits. Prevention strategies include avoiding tobacco and excessive alcohol, eating fruits and vegetables, protecting lips from sun, and regular dental exams.
The document discusses digestive hemorrhage, also known as gastrointestinal bleeding. It defines high and low hemorrhages based on their origin in the digestive tract. Some common causes of digestive hemorrhage include anal fissures, hemorrhoids, ulcers, and cancers of the digestive system. Symptoms include vomiting blood or black tarry stools. Diagnosis involves endoscopy, imaging tests, or surgery depending on the location of bleeding. Treatment focuses on stabilization, determining the cause through endoscopy, and addressing the specific condition causing the hemorrhage. Prevention strategies target those with risk factors like ulcers, cirrhosis, or who take anti-inflammatory drugs.
1. Diarrhea is defined as more frequent bowel movements with soft and liquid stools. It is usually caused by viruses, bacteria, parasites, certain foods, medications, and other digestive disorders.
2. Symptoms of diarrhea include soft, watery stools, abdominal cramps, pain, fever, blood in stool, swelling, and urgency. It can cause dehydration, especially in children.
3. Doctors may perform blood tests, stool analysis, and imaging tests to diagnose the cause. Treatment depends on the cause but often involves replacing fluids and electrolytes, antibiotics if bacteria is involved, and managing any underlying conditions.
Constipation is defined as having less than three bowel movements per week or hard stools that are difficult to pass. Common causes include low-fiber diets, lack of physical activity, certain medications, and ignoring the urge to have a bowel movement. Diagnosis involves physical exams, blood tests, and imaging tests of the colon and rectum. Treatment begins with lifestyle changes like increasing fiber intake and exercise. If those don't help, doctors may prescribe laxatives, stool softeners, or suppositories to relieve constipation symptoms.
Sleep apnea is a potentially serious sleep disorder where breathing stops and starts repeatedly during sleep. There are three main types - obstructive, central, and complex. Risk factors include being overweight, having a narrow throat, and certain facial structures. Symptoms include loud snoring, waking with shortness of breath, and daytime sleepiness. Diagnosis involves a physical exam and polysomnogram sleep test. Treatment options include lifestyle changes, CPAP devices, dental devices, and sometimes surgery. Losing weight and avoiding alcohol can help prevent sleep apnea.
1. Pulmonary tuberculosis is a chronic infectious disease caused by the bacterium Mycobacterium tuberculosis, which usually affects the lungs. It spreads through the air when people who are sick with TB cough, sneeze or speak.
2. Symptoms include a persistent cough lasting more than two weeks, coughing up blood, weight loss, fever, night sweats and fatigue. Diagnosis involves physical exams, chest x-rays, sputum tests and tuberculosis skin tests.
3. Treatment involves a multi-drug regimen administered by a tuberculosis specialist to prevent drug resistance. Patients are advised to rest at home and cover their mouth when coughing to prevent spreading the disease until treatment has reduced their contagious
1. Pulmonary embolism is caused by a blood clot in the lung, usually formed in the deep veins of the lower limbs. It is a leading cause of preventable death in hospitalized patients.
2. Symptoms include shortness of breath, chest pain, increased heart rate, coughing up blood, and fainting. Diagnosis involves assessing risk factors and test like D-dimer and CT scan.
3. Treatment involves anticoagulant drugs to dissolve clots initially by injection and then orally for 3-6 months. Prevention focuses on continuing anticoagulants, lifestyle changes like exercise and diet, wearing compression stockings, and early movement after surgery.
Climate Change All over the World .pptxsairaanwer024
Climate change refers to significant and lasting changes in the average weather patterns over periods ranging from decades to millions of years. It encompasses both global warming driven by human emissions of greenhouse gases and the resulting large-scale shifts in weather patterns. While climate change is a natural phenomenon, human activities, particularly since the Industrial Revolution, have accelerated its pace and intensity
Microbial characterisation and identification, and potability of River Kuywa ...Open Access Research Paper
Water contamination is one of the major causes of water borne diseases worldwide. In Kenya, approximately 43% of people lack access to potable water due to human contamination. River Kuywa water is currently experiencing contamination due to human activities. Its water is widely used for domestic, agricultural, industrial and recreational purposes. This study aimed at characterizing bacteria and fungi in river Kuywa water. Water samples were randomly collected from four sites of the river: site A (Matisi), site B (Ngwelo), site C (Nzoia water pump) and site D (Chalicha), during the dry season (January-March 2018) and wet season (April-July 2018) and were transported to Maseno University Microbiology and plant pathology laboratory for analysis. The characterization and identification of bacteria and fungi were carried out using standard microbiological techniques. Nine bacterial genera and three fungi were identified from Kuywa river water. Clostridium spp., Staphylococcus spp., Enterobacter spp., Streptococcus spp., E. coli, Klebsiella spp., Shigella spp., Proteus spp. and Salmonella spp. Fungi were Fusarium oxysporum, Aspergillus flavus complex and Penicillium species. Wet season recorded highest bacterial and fungal counts (6.61-7.66 and 3.83-6.75cfu/ml) respectively. The results indicated that the river Kuywa water is polluted and therefore unsafe for human consumption before treatment. It is therefore recommended that the communities to ensure that they boil water especially for drinking.
Evolving Lifecycles with High Resolution Site Characterization (HRSC) and 3-D...Joshua Orris
The incorporation of a 3DCSM and completion of HRSC provided a tool for enhanced, data-driven, decisions to support a change in remediation closure strategies. Currently, an approved pilot study has been obtained to shut-down the remediation systems (ISCO, P&T) and conduct a hydraulic study under non-pumping conditions. A separate micro-biological bench scale treatability study was competed that yielded positive results for an emerging innovative technology. As a result, a field pilot study has commenced with results expected in nine-twelve months. With the results of the hydraulic study, field pilot studies and an updated risk assessment leading site monitoring optimization cost lifecycle savings upwards of $15MM towards an alternatively evolved best available technology remediation closure strategy.
Kinetic studies on malachite green dye adsorption from aqueous solutions by A...Open Access Research Paper
Water polluted by dyestuffs compounds is a global threat to health and the environment; accordingly, we prepared a green novel sorbent chemical and Physical system from an algae, chitosan and chitosan nanoparticle and impregnated with algae with chitosan nanocomposite for the sorption of Malachite green dye from water. The algae with chitosan nanocomposite by a simple method and used as a recyclable and effective adsorbent for the removal of malachite green dye from aqueous solutions. Algae, chitosan, chitosan nanoparticle and algae with chitosan nanocomposite were characterized using different physicochemical methods. The functional groups and chemical compounds found in algae, chitosan, chitosan algae, chitosan nanoparticle, and chitosan nanoparticle with algae were identified using FTIR, SEM, and TGADTA/DTG techniques. The optimal adsorption conditions, different dosages, pH and Temperature the amount of algae with chitosan nanocomposite were determined. At optimized conditions and the batch equilibrium studies more than 99% of the dye was removed. The adsorption process data matched well kinetics showed that the reaction order for dye varied with pseudo-first order and pseudo-second order. Furthermore, the maximum adsorption capacity of the algae with chitosan nanocomposite toward malachite green dye reached as high as 15.5mg/g, respectively. Finally, multiple times reusing of algae with chitosan nanocomposite and removing dye from a real wastewater has made it a promising and attractive option for further practical applications.
Optimizing Post Remediation Groundwater Performance with Enhanced Microbiolog...Joshua Orris
Results of geophysics and pneumatic injection pilot tests during 2003 – 2007 yielded significant positive results for injection delivery design and contaminant mass treatment, resulting in permanent shut-down of an existing groundwater Pump & Treat system.
Accessible source areas were subsequently removed (2011) by soil excavation and treated with the placement of Emulsified Vegetable Oil EVO and zero-valent iron ZVI to accelerate treatment of impacted groundwater in overburden and weathered fractured bedrock. Post pilot test and post remediation groundwater monitoring has included analyses of CVOCs, organic fatty acids, dissolved gases and QuantArray® -Chlor to quantify key microorganisms (e.g., Dehalococcoides, Dehalobacter, etc.) and functional genes (e.g., vinyl chloride reductase, methane monooxygenase, etc.) to assess potential for reductive dechlorination and aerobic cometabolism of CVOCs.
In 2022, the first commercial application of MetaArray™ was performed at the site. MetaArray™ utilizes statistical analysis, such as principal component analysis and multivariate analysis to provide evidence that reductive dechlorination is active or even that it is slowing. This creates actionable data allowing users to save money by making important site management decisions earlier.
The results of the MetaArray™ analysis’ support vector machine (SVM) identified groundwater monitoring wells with a 80% confidence that were characterized as either Limited for Reductive Decholorination or had a High Reductive Reduction Dechlorination potential. The results of MetaArray™ will be used to further optimize the site’s post remediation monitoring program for monitored natural attenuation.
Improving the viability of probiotics by encapsulation methods for developmen...Open Access Research Paper
The popularity of functional foods among scientists and common people has been increasing day by day. Awareness and modernization make the consumer think better regarding food and nutrition. Now a day’s individual knows very well about the relation between food consumption and disease prevalence. Humans have a diversity of microbes in the gut that together form the gut microflora. Probiotics are the health-promoting live microbial cells improve host health through gut and brain connection and fighting against harmful bacteria. Bifidobacterium and Lactobacillus are the two bacterial genera which are considered to be probiotic. These good bacteria are facing challenges of viability. There are so many factors such as sensitivity to heat, pH, acidity, osmotic effect, mechanical shear, chemical components, freezing and storage time as well which affects the viability of probiotics in the dairy food matrix as well as in the gut. Multiple efforts have been done in the past and ongoing in present for these beneficial microbial population stability until their destination in the gut. One of a useful technique known as microencapsulation makes the probiotic effective in the diversified conditions and maintain these microbe’s community to the optimum level for achieving targeted benefits. Dairy products are found to be an ideal vehicle for probiotic incorporation. It has been seen that the encapsulated microbial cells show higher viability than the free cells in different processing and storage conditions as well as against bile salts in the gut. They make the food functional when incorporated, without affecting the product sensory characteristics.
Presented by The Global Peatlands Assessment: Mapping, Policy, and Action at GLF Peatlands 2024 - The Global Peatlands Assessment: Mapping, Policy, and Action
Enhanced action and stakeholder engagement for sustainable peatland management
Heart failure
1. CLINICAL STUDY
Randomized Trial of Effect of Urate-Lowering Agent Febuxostat in
Chronic Heart Failure Patients with Hyperuricemia (LEAF-CHF)
Study Design
Takashi Yokota,1
MD, Arata Fukushima,1
MD, Shintaro Kinugawa,1
MD, Takahiro Okumura,2
MD,
Toyoaki Murohara,2
MD and Hiroyuki Tsutsui,3
MD
Summary
Hyperuricemia is an independent predictor of mortality in patients with chronic heart failure. The aim of
the study is to determine whether a urate-lowering agent febuxostat, an inhibitor of xanthine oxidase, may im-
prove the clinical outcomes in chronic heart failure patients with hyperuricemia when compared to conventional
treatment. This multicenter, prospective, randomized, open-label, blinded endpoint study with a follow-up period
of 24 weeks will enroll 200 Japanese chronic heart failure patients with hyperuricemia. The eligibility criteria
include a diagnosis of chronic heart failure (New York Heart Association functional class II-III with a history of
hospitalization due to worsening of heart failure within the last 2 years), reduced left ventricular systolic func-
tion (left ventricular ejection fraction < 40%) and increased plasma natriuretic peptide [plasma B-type natriu-
retic peptide (BNP) "100 pg/mL or N-terminal pro BNP (NT-proBNP) "400 pg/mL], and hyperuricemia (se-
rum uric acid >7.0 mg/dL and !10 mg/dL) at the screening visit. The primary outcome is the difference in the
plasma BNP levels between the baseline and 24 weeks of treatment. The plasma BNP levels are measured in
the central laboratory in a blinded manner. This study investigates the efficacy and safety of febuxostat in
chronic heart failure patients with hyperuricemia.
(Int Heart J 2018; 59: 976-982)
Key words: BNP, Oxidative stress, Xanthine oxidase inhibitor
H
yperuricemia is a common finding in patients
with chronic heart failure (CHF) and is a known
independent predictor of mortality and rehospi-
talization due to worsening heart failure (HF).1-4)
The Japa-
nese Cardiac Registry of Heart Failure in Cardiology
(JCARE-CARD) reported that 56% of CHF patients had
hyperuricemia with a higher incidence of all-cause and
cardiac death, and rehospitalization due to worsening HF.3)
In addition, hyperuricemia is closely linked to the occur-
rence of atrial fibrillation, which can be a trigger of wors-
ening HF.5)
The mechanism by which hyperuricemia is as-
sociated with worse clinical outcomes in CHF patients
may be explained by the detrimental effects of uric acid
(UA) on the vascular endothelium through the activation
of inflammatory cytokines.6)
In patients with CHF, xan-
thine oxidase (XO) is highly activated, and increased reac-
tive oxygen species (ROS) emission from XO in the vas-
cular endothelium can cause endothelial dysfunction in the
peripheral vessels, leading to increased cardiac afterload.7)
UA is produced via XO and, thus, it can be a useful
marker for systemic oxidative stress in patients with CHF.
Emerging evidence has drawn more attention to the ef-
fects of XO inhibitors on clinical outcomes.
Previous studies have shown that allopurinol, a
widely used XO inhibitor for patients with hyperuricemia,
may be effective in the treatment of cardiovascular dis-
ease.8)
High-dose allopurinol has been reported to reduce
HF-related death in CHF patients.9,10)
In addition, previous
studies have shown that in patients with CHF, allopurinol
decreases B-type natriuretic peptide (BNP) levels,11)
which
is known as a strong predictive biomarker of HF-related
death.12)
However, a randomized trial to investigate the ef-
fect of oxypurinol, a metabolite of allopurinol, in patients
with CHF did not improve clinical outcomes,13)
and a re-
cent clinical trial using allopurinol also failed to improve
clinical status, exercise capacity, quality of life, or cardiac
function in hyperuricemic HF patients.14)
Febuxostat, a novel urate-lowering agent for treat-
ment against gout and hyperuricemia, inhibits XO via a
different pathway from allopurinol. Febuxostat has dem-
onstrated superiority to allopurinol in XO inhibition in vi-
tro studies15,16)
and lowering serum UA in clinical stud-
ies.17)
Since febuxostat is finally eliminated via not only
renal but also via hepatic pathways, it can be safely and
From the 1
Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan,
2
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan and 3
Department Cardiovascular Medicine, Faculty of Medical
Sciences, Kyusyu University, Fukuoka, Japan.
Address for correspondence: Shintaro Kinugawa, MD, Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine,
Hokkaido University, Kita-15 Nishi-7, Kita-Ku, Sapporo 060-8638. E-mail: tuckahoe@med.hokudai.ac.jp
Received for publication September 30, 2017. Revised and accepted December 15, 2017.
Released in advance online on J-STAGE August 11, 2018.
doi: 10.1536/ihj.17-560
All rights reserved by the International Heart Journal Association.
976
2. Int Heart J
September 2018 977EFFECT OF FEBUXOSTAT IN CHRONIC HEART FAILURE
Table. Inclusion and Exclusion Criteria in the LEAF-CHF Study
Criteria
Inclusion criteria 1 Male and female ambulatory patients aged ≥20 years at the time of enrollment with heart failure, or inpatients with sta-
ble heart failure when informed consent is obtained.
2 Patients with hyperuricemia, as indicated by a serum uric acid level between > 7.0 mg/dL and ≤ 10.0 mg/dL at the time
of enrollment.
3 Chronic heart failure patients with stable NYHA functional class II to III with no change in the dose of the baseline
therapies, including ACE-Is, ARBs, and β-blockers, within 4 weeks prior to enrollment.
4 Patients with plasma BNP concentration ≥ 100 pg/mL or NT-proBNP concentration ≥ 400 pg/mL at the time of enroll-
ment.
5 LVEF < 40%, as measured by echocardiography within 8 weeks before enrollment.
6 Eligible patients with a history of admission due to worsening heart failure before enrollment.
7 Patients who provide written informed consent prior to participation.
Exclusion criteria 1 Patients who receive treatment with anti-hyperuricemic agents, including allopurinol, benzbromarone, probenecid, bu-
colome, topiroxostat, and febuxostat within 2 weeks prior to enrollment.
2 Patients receiving mercaptopurine hydrate, azathioprine, vidarabine, and didanosine at the time of enrollment.
3 Patients with a history of acute coronary syndrome or coronary revascularization within the last 3 months.
4 Patients with valvular disease or congenital heart disease as the cause of heart failure.
5 Patients with active gouty tophus or those who have symptoms of acute gouty arthritis within 1 year prior to enroll-
ment.
6 Patients who have serious liver disease, renal impairment (eGFR < 30 mL/minute or on dialysis), or malignancy.
7 Patients with a history of hypersensitivity to febuxostat.
8 Patients who are not appropriate for participation in this study as determined by the investigators.
ACE-I indicates angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BNP, B-type natriuretic peptide; eGFR, estimated
glomerular filtration rate; LVEF, left ventricular ejection fraction; and NYHA, New York Heart Association.
efficiently used even in patients with mild to moderate re-
nal dysfunction. A randomized trial reported that fe-
buxostat demonstrated superiority to allopurinol in reduc-
ing oxidative stress and in improving cardiac and renal
function in patients with hyperuricemia who underwent
cardiac surgery.18)
Accordingly, febuxostat is expected to
have a stronger inhibitory effect than allopurinol on XO.
The aim of the randomized LEAF-CHF (Effect of
urate-LowEring Agent Febuxostat in Chronic Heart Fail-
ure patients with hyperuricemia) study is to determine
whether febuxostat may improve morbidity and mortality
in patients with HF with reduced ejection fraction
(HFrEF) and hyperuricemia. BNP levels are evaluated as a
primary endpoint of this study, with a follow-up period of
24 weeks to assess the efficacy of febuxostat in CHF pa-
tients. All the subjects receive the general lifestyle guid-
ance for hyperuricemia recommended by the Japanese So-
ciety of Gout and Nucleic Acid Metabolism19)
throughout
the study period.
Methods
Study design: LEAF-CHF is a multicenter, prospective,
randomized, open-label, blinded endpoint (PROBE) study
that investigates whether the urate-lowering agent, fe-
buxostat, reduces plasma BNP levels in CHF patients with
hyperuricemia. This study is approved by the institutional
ethics committee at each participating site and is con-
ducted in accordance with the ethical principles described
in the Declaration of Helsinki (2013 revised version).
Written informed consent is provided by all the enrolled
patients prior to any study-related procedures. The study
has been registered at the University Hospital Medical In-
formation Network (UMIN ID: 000013330).
Patient population: The inclusion and exclusion criteria
are listed in the Table. We enroll a total of 200 ambula-
tory or admitted HF patients with hyperuricemia, who do
not meet any exclusion criteria. Briefly, eligible patients
have New York Heart Association (NYHA) functional
class II or III and left ventricular ejection fraction (LVEF)
< 40% with elevated plasma BNP and hyperuricemia (se-
rum UA levels > 7.0 mg/dL and !10.0 mg/dL). The
LVEF is calculated from the apical four- and two-chamber
views based on the modified Simpson’s method by echo-
cardiography.
Randomization: After providing written informed con-
sent, eligible patients are randomly assigned to the fe-
buxostat group or the control group in a 1:1 ratio through
a Web-based randomization system. Patient allocation is
performed by the minimization method according to the
following baseline variables: age, serum UA, plasma BNP
or NT-proBNP, and LVEF. Since eligible participants have
asymptomatic hyperuricemia as shown by the serum UA
levels > 7.0 mg/dL and !10.0 mg/dL, all the subjects are
provided lifestyle guidance aimed at decreasing the UA
levels.
In the febuxostat group, the investigators prescribe
the febuxostat preparation (FeburicⓇ
Tablets, Teijin
Pharma, Tokyo, Japan) per the dosage schedule listed in
the protocol (Figure 1), and the control group is also fol-
lowed. The data on the dosing condition in the febuxostat
group and concomitant therapies in both groups are fol-
lowed from the time of enrollment until the completion of
the study or withdrawal from the study.
Study protocol: Figure 1 and Figure 2 summarize the
study schema and the visit schedule. The duration of the
study is 24 weeks, which includes a 12-week titration
phase of stepwise dose increases and a 12-week dose-
maintenance phase, defined by the previous finding of the
BNP-lowering effect of allopurinol at 12 weeks.11)
Prelimi-
3. Int Heart J
September 2018978 Yokota, ET AL
Figure 1. Intervention schedule. After randomization to the febuxostat or the control group, patients are followed up for 24 weeks. In the fe-
buxostat group, patients receive 10 mg/day febuxostat at the baseline (Day 0), and the dose is increased every 4 weeks until it reaches the target
dose (60 mg/day), unless serum uric acid is < 2.0 mg/dL. The target dose of febuxostat is typically administered for 12 weeks during the last
study period. In both the febuxostat and control groups, the patient receives lifestyle modification to decrease serum UA throughout the study
period.
nary screening for trial eligibility is based on clinical in-
formation from a review of medical records by investiga-
tors at or before the baseline visit. The initial dose of fe-
buxostat is 10 mg/day.
The dose is up-titrated to 20 mg/day at the 4-week
visit, then, increased to 40 mg/day at the 8-week visit to
reach the target dose of 60 mg/day at 12 weeks, unless
the serum UA< 2.0 mg/dL. The target dose of 60 mg/day
is maintained until the end of the study (24 weeks) after
randomization. If the serum UA is < 2.0 mg/dL, the dos-
age is reduced by 20 mg from the previous dose. The tar-
get dose of 60 mg was determined to exert the maximum
inhibitory effect of febuxostat on UA levels and ROS
emission via the potent suppression of XO.
Patient demographic data such as age, gender, height
and body weight, etiology of HF, and medical history are
recorded at the baseline in all the patients. Signs and
symptoms of HF, NYHA functional class, systolic and
diastolic blood pressure, and heart rate are monitored at
the baseline and every 4 weeks. Chest X-ray and echocar-
diography are performed at the baseline and at 24 weeks.
To ensure objectivity, the plasma BNP levels are measured
at a central laboratory under blind conditions at the base-
line and every 4 weeks thereafter. Plasma oxidized low-
density lipoprotein cholesterol (ox-LDL), serum high-
sensitivity C-reactive protein (hs-CRP), and urinary 8-
isoprostanes and 8-hydroxydeoxyguanosine (8-OHdG) are
all measured in a central laboratory at the baseline and at
24 weeks. In addition, the following blood examinations
are measured at the baseline and every 4 weeks: hemoglo-
bin (Hb), serum UA, and serum creatinine. The estimated
glomerular filtration rate (eGFR) is calculated from serum
creatinine value and age using the Japanese equation20)
as
follows: eGFR=194 × (serum creatinine in mg/dL) - 1.094
× (age in years) - 0.287 × (0.739 if female).
Study endpoints: The primary endpoint is the change in
plasma BNP concentration from the baseline to 24 weeks.
Plasma BNP is an established surrogate marker that
strongly predicts death and cardiovascular events in HF
patients,21)
and previous studies have shown the reducing
effect of allopurinol on plasma BNP concentration.11,22)
For
between-group comparison of the change in log-
transformed BNP levels, the analysis of covariance will be
performed using the baseline BNP levels as the covariate.
The secondary endpoints include: (1) LVEF and E/e’, the
ratio of peak early transmitral ventricular filling velocity
to early diastolic tissue Doppler velocity, measured at the
baseline and at 24 weeks; (2) NYHA functional class,
eGFR, serum UA, Hb, and the plasma BNP concentration
during the study period; and (3) all-cause mortality or ma-
jor cardiovascular events.
The independent Endpoint Evaluation Committee will
centrally review the events reported by the investigators
per the event adjudication criteria in a blinded manner.
The exploratory endpoint is to determine the effect of fe-
buxostat on the following: (1) markers of inflammatory
activation (hs-CRP), (2) oxidative stress (ox-LDL, 8 iso-
prostanes, and 8-OHdG), and (3) renal function (ratio of
urine albumin and creatinine).
Sample size calculation: The sample size of the present
study is assumed on the basis of a previous study by Ga-
vin, et al.11)
In that randomized, double-blinded, placebo-
controlled trial, 50 patients with CHF were randomly as-
signed to 3 months of treatment with allopurinol (300 mg/
4. Int Heart J
September 2018 979EFFECT OF FEBUXOSTAT IN CHRONIC HEART FAILURE
Figure 2. Visit schedule for enrollment, assessments, and central measurements. BNP indicates B-type natriuretic peptide; eGFR, estimated
glomerular filtration rate; NYHA, New York Heart Association: and UA, uric acid.
day) or placebo. The BNP levels in the allopurinol group
were 14.5 pmol/L (51 pg/mL) before treatment and 11.9
pmol/L (42 pg/mL) after treatment, whereas those in the
placebo group were unaltered. Based on those results, it is
presumed that the difference in the change in log-
transformed BNP levels is 0.2 and that the standard devia-
tion is twice as large as the change in log-transformed
BNP levels.
To detect the between-group difference by analyzing
covariance under conditions of two-sided α = 0.05, β =
0.9, and allocation ratio = 1.0, the sample sizes of the
needed patient populations were calculated to be 86 for
HF and 86 for controls. Estimating a 15% loss due to
withdrawals and dropouts, we set the target population
size as 100 patients in each group (total 200 patients).
Statistical analysis: Efficacy endpoints will be analyzed
primarily by using the full analysis set (FAS), which in-
cludes all the enrolled and randomized subjects, and
eliminating subjects who do not respond to treatment after
enrollment. The per-protocol set (PPS) of patients meeting
all the inclusion and exclusion criteria will be also ana-
lyzed for reference. Safety endpoints will be evaluated us-
ing the safety analysis population, which comprises all the
enrolled and randomized patients.
As a primary analysis, the summary statistics of the
BNP levels at the baseline and at 24 weeks, as well as the
ratio of the BNP levels at the baseline to the levels at 24
weeks, will be calculated for each treatment group. For
the between-group comparison of the change in the log-
transformed BNP levels from the baseline to 24 weeks,
analysis of covariance will be performed using dummy
variables that represent the treatment groups, as well as
the log-transformed BNP levels at the baseline as the co-
variates. If the study is terminated before 24 weeks, the
BNP levels at the termination of the study will be used
instead of those at 24 weeks in the primary analysis. In
addition, the paired t-test will be conducted to compare
the change in the log-transformed BNP levels from the
baseline to 24 weeks in each treatment group.
As a secondary analysis, the paired t-test will be per-
formed to compare the LVEF, E/E’, serum UA, eGFR, he-
moglobin, and each exploratory endpoint from the base-
line to 24 weeks or study termination. The analysis of co-
variance will be performed for the comparison of the
between-group change in those variables from the baseline
to 24 weeks. The changes of the NYHA class from the
baseline to 24 weeks will be analyzed within groups by
the Wilcoxon signed-rank test and are compared among
groups by the Wilcoxon rank-sum test. Furthermore, the
Kaplan-Meier method will be used to estimate the event
rate throughout 24 weeks for each treatment group, and
the log-rank test will be used to compare those event
rates.
The differences are considered statistically significant
when P< 0.05. The same analysis will be performed using
PPS to confirm the robustness of the results. An interim
analysis is not scheduled during the study.
Role of the sponsor and the authors: The LEAF-CHF
study is being supported by the sponsor (Teijin Pharma
Ltd., Tokyo, Japan), which will not participate in the data
collection, the event evaluation, and the data analysis. The
study was designed by the authors in collaboration with
the sponsor and the contract research organization (CRO;
Hubitgenomix Co., Tokyo, Japan). The study is conducted
by the LEAF-CHF investigators with the assistance with
the CRO. The first draft of the manuscript was written by
Go Ichien (Hubitgenomix Co.), and was fully reviewed
and revised by all the authors. The authors had final re-
5. Int Heart J
September 2018980 Yokota, ET AL
sponsibility for the decision to submit for publication.
Discussion
The LEAF-CHF study is designed to test the hy-
pothesis that the inhibition of XO by febuxostat, when
added to optimal HF therapy, may be beneficial clinically
in patients with HFrEF. It will not compare the efficacy of
febuxostat with that of allopurinol, although febuxostat is
expected to exert a stronger effect of XO inhibition than
allopurinol, based on the previous studies.15-18)
It compares
the changes in the plasma BNP levels as well as clinical
outcomes between the febuxostat group and the control
group in patients with HFrEF.
The total study period for the LEAF-CHF is 24
weeks; the patients assigned to the active treatment group
will receive febuxostat 60 mg/day as a target dose for 12
weeks after titration, with stepwise dose increases for 12
weeks. A previous study revealed a significant decrease in
the BNP levels after allopurinol treatment for 12 weeks in
patients with CHF.11)
In addition, the administration of 60
mg/day of febuxostat for 6 months, including the dose-
escalation period, has been reported to lower serum UA
significantly more than allopurinol 300 mg/day and to
have a superior inhibitory effect on oxidative stress in pa-
tients with hyperuricemia who underwent cardiac sur-
gery.18)
Taken together, the study period and the target
dose in the present trial appears to be sufficient to evalu-
ate the efficacy of febuxostat in CHF patients.
For this study, the range of serum UA in the inclu-
sion criteria is > 7.0 mg/dL to !10 mg/dL. Although no
universally accepted definition of hyperuricemia exists, we
employed the definition of hyperuricemia as serum UA >
7.0 mg/dL based on the Guideline for the Management of
Hyperuricemia and Gout 2010 of the Japanese Society of
Gout and Nucleic Acid Metabolism.19)
While the guideline
recommends the initiation of pharmacotherapy at a serum
concentration of UA "9.0 mg/dL in patients with asymp-
tomatic hyperuricemia,19)
and in particular, the risk of gout
increases at a serum concentration of UA "10.0 mg/dL.
Thus, patients allocated to the control group will be with-
drawn from the study and subsequently receive appropri-
ate therapy if their serum UA levels increase and exceed
10.0 mg/dL during the study period.
We determined the primary endpoint of this study as
the difference in plasma BNP levels between the baseline
and 24 weeks of treatment, since the absolute value of
plasma BNP is influenced by the left ventricular hypertro-
phy and renal dysfunction. BNP is widely used as a clini-
cally relevant diagnostic and predictive marker for HF and
is a powerful predictor of short- and long-term prognosis
and rehospitalization due to worsening HF in CHF pa-
tients.12,23)
A meta-analysis of studies in patients with CHF
has shown that each 100 pg/mL rise in BNP levels is as-
sociated with a 35% increase in the relative risk of
death.21)
To ensure objectivity, the BNP levels will be
measured in a central laboratory in a blinded manner.
Secondary endpoints include all-cause death, cardio-
vascular events, including cardiovascular death, rehospi-
talization due to worsening HF, NYHA class, LVEF, E/e’,
absolute values of plasma BNP, eGFR, hemoglobin (Hb),
and serum UA. As a parameter of left ventricular (LV)
function, E/e’ will be measured to assess LV diastolic
function and LVEF will be used to assess LV systolic
function. Previous studies have shown that elevated serum
UA inversely correlates with the LV diastolic function.24)
In the LEAF-CHF study, we will evaluate eGFR and Hb
because the JCARE-CARD has reported that chronic kid-
ney disease and anemia are powerful and independent
prognostic factors in CHF patients.25,26)
Plasma ox-LDL, and urinary 8-isoprostanes and 8-
OHdG will be measured at the baseline and at 24 weeks
of treatment to assess the inhibitory effect of febuxostat
on systemic oxidative stress in CHF patients. Growing
evidence suggests that oxidative stress is a key to the
pathogenesis and development of HF.27)
In addition, serum
UA levels are not necessarily associated with the cardiac
function and the severity of HF.28)
Our hypothesis is that
febuxostat treatment may improve clinical outcomes via
reduced ROS emission originating from XO rather than
lowered serum UA. In accordance with this hypothesis,
the dosage of febuxostat is increased stepwise up to 60
mg/day even after serum UA level reaches 7.0 mg/dL or
less (except for < 2.0 mg/dL). In previous studies, fe-
buxostat was administered targeting serum UA !6.0 mg/
dL.17,18)
Until now, there is no report of the harmful effect
of febuxostat in a concentration-dependent manner.
LEAF-CHF Study has already begun enrollment in
August 2014. The enrollment of patients will be com-
pleted in December 2017 and the follow-up of the en-
rolled patients will be finished in June 2018. This study
may provide evidence for a novel therapeutic approach to
CHF patients targeting the reduction of not only the se-
rum UA levels but also XO-induced ROS emission.
Acknowledgments
The authors thank all the enrolled patients, participat-
ing cardiologists and other medical professionals who
contributed substantially to this cooperative study.
Disclosures
Conflicts of interest: T.Y., A.F., and S.K. have no conflict
of interest that should be declared. T.O has received re-
search grants from Ono Pharmaceutical, Bayer Yakuhin,
and Daiichi-Sankyo; scholarship funds from Mitsubishi
Tanabe Pharma. T.M. has received speakers’ bureau/hono-
rarium from Teijin Pharma and Pfizer Japan; scholarship
funds from Teijin Pharma and Pfizer Japan. H.T. has re-
ceived speakers’ bureau/honorarium from Astellas Pharma,
Otsuka Pharmaceutical, Takeda Pharmaceutical, Daiichi-
Sankyo, Mitsubishi Tanabe Pharma, Teijin Pharma, Nip-
pon Boehringer Ingelheim, Novartis Pharma K.K, Bayer
Yakuhin, and Bristol- Myers Squibb; honorarium for writ-
ing promotional material for Medical Review; research
grants from Actelion Pharmaceuticals Japan; scholarship
funds from Astellas Pharma and Daiichi-Sankyo.
6. Int Heart J
September 2018 981EFFECT OF FEBUXOSTAT IN CHRONIC HEART FAILURE
Appendix
Study organization: The study is managed by the princi-
pal investigator (Hiroyuki Tsutsui) and the Steering Com-
mittee as an investigator-initiated clinical study. The Inde-
pendent Data Monitoring Committee and the Event Evalu-
ation Committee are organized independently from the
study group. A study statistician (Koji Oba, Tokyo Univer-
sity) contributes to ensure statistical accuracy.
Steering committee: Hiroyuki Tsutsui (chair, Kyusyu
University), Toyoaki Murohara (vice chair, Nagoya Uni-
versity Graduate School of Medicine), Mitsuaki Isobe
(Sakakibara Heart Institute), Hiroshi Ito (Okayama Uni-
versity), Takayuki Inomata (Kitasato University Kitasato
Institute Hospital), Koichiro Kinugawa (Internal Medicine,
University of Toyama), Issei Komuro (The University of
Tokyo Hospital), Yoshihiko Saito (Nara Medical Univer-
sity), Yasushi Sakata (Osaka University Graduate School
of Medicine), Yasuhiko Sakata (Tohoku University Gradu-
ate School of Medicine), Hiroaki Shimokawa (Tohoku
University Graduate School of Medicine), Ichiro Hisatome
(Graduate School of Medical Science, Tottori University),
Satoru Masuyama (Hyogo College of Medicine), Shinichi
Momomura (Jichi Medical University Saitama Medical
Center), Masafumi Yano (Yamaguchi University Graduate
School of Medicine), Kazuhiro Yamamoto (Tottori Univer-
sity Faculty of Medicine), and Michihiro Yoshimura (The
Jikei University School of Medicine)
Independent data monitoring committee: Hitonobu To-
moike (chair, Sakakibara Heart Institute), Yutaka Kiyohara
(Hisayama LIFE Institute), and Hideki Orikasa (University
of Toyama)
Event evaluation committee: Masafumi Kitakaze (chair,
National Cerebral and Cardiovascular Center), Hisashi Kai
(Kurume University Medical Center), and Naoyuki
Hasebe (Asahikawa Medical University)
Research institute: Kyusyu University Hospital, Hok-
kaido University Hospital, Nagoya University Hospital,
Tokyo Medical and Dental University, Okayama Univer-
sity Hospital, Kitasato University Hospital, The University
of Tokyo Hospital, Nara Medical University Hospital,
Osaka University Hospital, Tohoku University Hospital,
Hyogo College of Medicine, Jichi Medical University Sai-
tama Medical Center, Yamaguchi University Hospital, Tot-
tori University Hospital, The Jikei University School of
Medicine, Sapporo Medical University Hospital, Heart-
sounds Mori Clinic, Tosei General Hospital, Nishio Mu-
nicipal Hospital, Osaka General Medical Center, Sakura-
bashi Watanabe Hospital, National Cerebral and Cardio-
vascular Center, Sakakibara Heart Institute, Toranomon
Hospital, St. Marianna University School of Medicine,
Nagoya City University Hospital, Hiroshima University,
Osaka Medical College Hospital, Medical Corporation JR
Hiroshima Hospital, Masao Fujii Memorial Hospital, Hi-
roshima Prefectural Hospital, Otaru Kyokai Hospital,
Showa University Hospital, Sapporo City General Hospi-
tal, Tokuyama Central Hospital, Graduate School of Medi-
cine and Faculty of Medicine Kyoto University, Saiseikai
Yamaguchi hospital, and Yamaguchi Prefectural Grand
Medical Center.
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