The renin–angiotensin–aldosterone system (RAAS) plays a central role in blood pressure regulation and sodium balance, and its overactivity contributes to conditions like hypertension and heart failure. Inhibition of the RAAS with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) lowers blood pressure and reduces cardiovascular risk. Studies have shown that ACE inhibitors and ARBs can slow the progression of renal disease in patients with diabetes, although their impact on long-term cardiovascular outcomes requires further investigation. The ONTARGET trial found that the ARB telmisartan had comparable reno- and cardioprotective effects as the ACE inhibitor
Proteinuria is it a risk marker or a therapeutic target for cardiovascular di...JAFAR ALSAID
1. Multiple studies have found a correlation between proteinuria and increased risk of cardiovascular disease, but recent randomized controlled trials targeting reductions in proteinuria have not found improvements in major cardiovascular outcomes like mortality.
2. The review examines recent evidence from trials on whether proteinuria should be targeted therapeutically or viewed only as a risk marker. Trials found reductions in proteinuria through drugs like ACE inhibitors and ARBs but no benefits for endpoints like heart failure, myocardial infarction, or death.
3. Some combination therapy trials were stopped early due to safety issues from side effects like hypotension and hyperkalemia without benefits for renal or cardiovascular outcomes. Overall, the evidence suggests proteinuria may indicate risk but is not a
Reversing cardiac remodeling with HFtreatmentPraveen Nagula
1. This document summarizes research on reversing cardiac remodeling through heart failure treatment. It discusses what remodeling is, the history of the term in medical literature, and types of remodeling (pathological vs physiological).
2. Studies show treatments that lead to "reverse remodeling" like sacubitril/valsartan improve outcomes for heart failure patients. Trials like PARADIGM-HF and PROVE-HF found sacubitril/valsartan reduced biomarkers and improved ejection fraction, indicating reverse remodeling.
3. Subgroup analyses in PROVE-HF found consistent reverse remodeling effects in newly diagnosed and ACE-ARB naive patients as well as those not reaching target sacubitril/vals
Iron deficiency in Heart Failure - Trial evidencePraveen Nagula
1) Iron deficiency is a common but often unrecognized and undertreated comorbidity in patients with heart failure.
2) Iron deficiency is prevalent in around 76% of Indian patients with heart failure and is associated with increased morbidity and mortality as well as worse patient outcomes and quality of life.
3) Intravenous ferric carboxymaltose is recommended for treating iron deficiency in heart failure patients, as it is more effective than oral iron supplements which are poorly absorbed and do not adequately address the underlying causes of restricted iron availability.
HDL-cholesterol concentrations are inversely associated with CVD.When we consider cardiovascular mortality in women in terms of HDL.Causes of low HDL cholesterol.Lipoprotein subfractions suffer a shift after menopause towards a more atherogenic lipid profile.associations of HDL-C and HDL-P with cIMT and CHD.MESA (Multi-Ethnic Study of therosclerosis. Functional Versus Dysfunctional HDL. High concentrations of HDL - cholesterol are associated with high all-cause mortality in men and women.Improvement of HDL function without necessarily raising HDL-C
Ueda 2016 diabetes mellitus and heart failure - yahia kishkueda2015
Diabetes and heart failure have a bidirectional relationship where each condition can lead to or worsen the other. Over 60% of asymptomatic type 2 diabetes patients have left ventricular diastolic dysfunction. The prevalence of heart failure is higher in diabetics and increases with age. Diabetes increases the risk of heart failure through hypertension, coronary artery disease, diabetic nephropathy and cardiomyopathy. Intensive glucose control can help prevent microvascular complications but does not significantly reduce cardiovascular events. Several diabetes medications need to be used cautiously in heart failure patients. Both conditions are serious with high mortality rates so treatment must target overall improvement.
Chronic heart disease and Anaemia. Heart failure is a very common disease, with severe morbidity and mortality, and is a frequent reason of hospitalization.
Anemia and a concurrent renal impairment are two major risk factors contributing to the severity of the outcome.
Heme iron is absorbed through a separate pathway and does not have to be discontinued when intravenous treatment is started. This can allow for longer intervals between resource-heavy, inconvenient and painful injections. Oxidative stress is also avoided.
Heme iron does not need to be discontinued during injection or EPO therapy like non-heme oral iron.
diabetes is most prevalent disease in asia, incidence of heart failure is also increasing in diabetic population, understanding the pathophysiology is very important to deal with these cases.
This document discusses antiplatelet agents and their use in treating arterial thrombosis, with a focus on the elderly population. It provides details on:
- The increased risk of arterial thrombotic events in the elderly due to associated diseases like diabetes and hypertension.
- The underuse of antithrombotic therapy in geriatric patients, despite increased cardiovascular risk.
- The mechanisms of action of commonly used antiplatelet drugs like aspirin, clopidogrel, and GP IIb/IIIa receptor antagonists, and their effects in different disease states and the geriatric population based on available data.
- Aspirin's mechanism of inhibiting platelet COX-1 activity to interfere with throm
Proteinuria is it a risk marker or a therapeutic target for cardiovascular di...JAFAR ALSAID
1. Multiple studies have found a correlation between proteinuria and increased risk of cardiovascular disease, but recent randomized controlled trials targeting reductions in proteinuria have not found improvements in major cardiovascular outcomes like mortality.
2. The review examines recent evidence from trials on whether proteinuria should be targeted therapeutically or viewed only as a risk marker. Trials found reductions in proteinuria through drugs like ACE inhibitors and ARBs but no benefits for endpoints like heart failure, myocardial infarction, or death.
3. Some combination therapy trials were stopped early due to safety issues from side effects like hypotension and hyperkalemia without benefits for renal or cardiovascular outcomes. Overall, the evidence suggests proteinuria may indicate risk but is not a
Reversing cardiac remodeling with HFtreatmentPraveen Nagula
1. This document summarizes research on reversing cardiac remodeling through heart failure treatment. It discusses what remodeling is, the history of the term in medical literature, and types of remodeling (pathological vs physiological).
2. Studies show treatments that lead to "reverse remodeling" like sacubitril/valsartan improve outcomes for heart failure patients. Trials like PARADIGM-HF and PROVE-HF found sacubitril/valsartan reduced biomarkers and improved ejection fraction, indicating reverse remodeling.
3. Subgroup analyses in PROVE-HF found consistent reverse remodeling effects in newly diagnosed and ACE-ARB naive patients as well as those not reaching target sacubitril/vals
Iron deficiency in Heart Failure - Trial evidencePraveen Nagula
1) Iron deficiency is a common but often unrecognized and undertreated comorbidity in patients with heart failure.
2) Iron deficiency is prevalent in around 76% of Indian patients with heart failure and is associated with increased morbidity and mortality as well as worse patient outcomes and quality of life.
3) Intravenous ferric carboxymaltose is recommended for treating iron deficiency in heart failure patients, as it is more effective than oral iron supplements which are poorly absorbed and do not adequately address the underlying causes of restricted iron availability.
HDL-cholesterol concentrations are inversely associated with CVD.When we consider cardiovascular mortality in women in terms of HDL.Causes of low HDL cholesterol.Lipoprotein subfractions suffer a shift after menopause towards a more atherogenic lipid profile.associations of HDL-C and HDL-P with cIMT and CHD.MESA (Multi-Ethnic Study of therosclerosis. Functional Versus Dysfunctional HDL. High concentrations of HDL - cholesterol are associated with high all-cause mortality in men and women.Improvement of HDL function without necessarily raising HDL-C
Ueda 2016 diabetes mellitus and heart failure - yahia kishkueda2015
Diabetes and heart failure have a bidirectional relationship where each condition can lead to or worsen the other. Over 60% of asymptomatic type 2 diabetes patients have left ventricular diastolic dysfunction. The prevalence of heart failure is higher in diabetics and increases with age. Diabetes increases the risk of heart failure through hypertension, coronary artery disease, diabetic nephropathy and cardiomyopathy. Intensive glucose control can help prevent microvascular complications but does not significantly reduce cardiovascular events. Several diabetes medications need to be used cautiously in heart failure patients. Both conditions are serious with high mortality rates so treatment must target overall improvement.
Chronic heart disease and Anaemia. Heart failure is a very common disease, with severe morbidity and mortality, and is a frequent reason of hospitalization.
Anemia and a concurrent renal impairment are two major risk factors contributing to the severity of the outcome.
Heme iron is absorbed through a separate pathway and does not have to be discontinued when intravenous treatment is started. This can allow for longer intervals between resource-heavy, inconvenient and painful injections. Oxidative stress is also avoided.
Heme iron does not need to be discontinued during injection or EPO therapy like non-heme oral iron.
diabetes is most prevalent disease in asia, incidence of heart failure is also increasing in diabetic population, understanding the pathophysiology is very important to deal with these cases.
This document discusses antiplatelet agents and their use in treating arterial thrombosis, with a focus on the elderly population. It provides details on:
- The increased risk of arterial thrombotic events in the elderly due to associated diseases like diabetes and hypertension.
- The underuse of antithrombotic therapy in geriatric patients, despite increased cardiovascular risk.
- The mechanisms of action of commonly used antiplatelet drugs like aspirin, clopidogrel, and GP IIb/IIIa receptor antagonists, and their effects in different disease states and the geriatric population based on available data.
- Aspirin's mechanism of inhibiting platelet COX-1 activity to interfere with throm
Diabetic cardiomyopathy refers to myocardial disease in diabetic subjects that cannot be ascribed to hypertension, coronary artery disease (CAD), or any other known cardiac disease. Key aspects discussed include the high prevalence of heart failure in diabetic patients, pathophysiological changes such as hypertrophy and fibrosis, and risk factors like hyperglycemia and hypertension. Management involves tight control of blood pressure and blood glucose, as well as medications like angiotensin-converting enzyme inhibitors, beta blockers, and aldosterone receptor antagonists which have been shown to improve outcomes. Aggressive modification of cardiovascular risk factors is important in the management of diabetic cardiomyopathy.
ONTARGET trial - Summary & Results with Ramipril Global Endpointtheheart.org
The ONTARGET trial compared the angiotensin receptor blocker (ARB) telmisartan to the angiotensin converting enzyme (ACE) inhibitor ramipril and their combination in 25,620 patients with cardiovascular disease or diabetes. The trial found that telmisartan was noninferior to ramipril for the primary outcome of cardiovascular death, heart attack, stroke or hospitalization for heart failure. The combination of telmisartan and ramipril showed no additional benefit compared to ramipril alone and was associated with more side effects such as renal impairment.
The document summarizes the Japan EPA Lipid Intervention Study (JELIS), a large clinical trial examining whether EPA (eicosapentaenoic acid) can improve cardiovascular outcomes when added to HMG-CoA reductase inhibitor treatment in patients with hypercholesterolemia. JELIS involves over 18,000 Japanese participants randomized to receive EPA plus statin or statin alone. The primary endpoint is major coronary events over 5 years. Baseline characteristics showed patients had moderately elevated cholesterol. Results are expected in 2005 to determine if EPA provides additional cardiovascular benefit beyond statin therapy alone.
This study analyzed bleeding complications in 150 patients with acute coronary syndrome (ACS) who received antiplatelet and anticoagulant therapy, comparing outcomes in diabetic and non-diabetic patients. There was no statistically significant difference in major bleeding as defined by TIMI criteria between diabetic and non-diabetic patients or between those who received heparin alone versus heparin plus tirofiban. The most common site of bleeding was the cardiac catheterization access site. While GRACE and CRUSADE risk scores were higher in diabetics, indicating greater disease severity, rates of all TIMI bleeding and blood transfusions were similar between diabetic and non-diabetic patients.
Although many are still concerned with an ARB–MI paradox, our study of close to 60 000 patients with MI should serve as reassurance that ARBs are not associated with adverse outcomes compared with ACEIs. Potential benefits of ARBs as compared with ACEIs in older women with MI should be further evaluated.
This study aims to compare plasma erythropoietin (EPO) and vascular endothelial growth factor (VEGF) levels between patients with chronic kidney disease (CKD) and cardio-renal syndrome (CRS) using enzyme-linked immunosorbent assay (ELISA). The study hypothesizes that hypoxic signaling via hypoxia-inducible factor-1 alpha (HIF-1α) is altered in CRS compared to CKD alone, affecting EPO and VEGF protein levels. Blood samples from 100 CKD patients and 100 CRS patients will be collected and analyzed to quantify and compare EPO and VEGF levels between the two groups. Correlations between the protein levels, kidney function, heart function, and
Role of raas inhibition in management of hypertensionKyaw Win
1) RAAS inhibition plays a central role in the pathogenesis of cardiovascular disease by modulating processes like vasoconstriction, inflammation, endothelial dysfunction, and atherosclerosis.
2) Both ACE inhibitors and ARBs have been shown to reduce target organ damage and improve endothelial function through various mechanisms such as increasing NO and reducing oxidative stress and inflammation.
3) Clinical trials provide evidence that RAAS inhibition can reduce atherosclerosis progression, cardiac hypertrophy, and events in conditions like coronary artery disease and heart failure.
1. The document discusses the relationship between migraine and thrombofilia, specifically looking at the MTHFR C677T polymorphism which is associated with higher homocysteine levels and cardiovascular disease risk.
2. One study found the TT genotype was less common in migraine patients but conferred higher risk of ischemic stroke in those with migraine with aura.
3. A meta-analysis found conflicting data on the association between migraine and the C677T polymorphism with high heterogeneity between studies related to ethnicity.
Eplerenone, a selective aldosterone blocker, inSalman Ahmed
This document summarizes a clinical trial that evaluated the effect of the selective aldosterone blocker eplerenone in patients with left ventricular dysfunction after myocardial infarction. The trial involved over 6,600 patients who received either eplerenone or a placebo in addition to optimal medical therapy. The results showed that eplerenone reduced all-cause mortality by 14.4% compared to 16.7% for placebo and reduced cardiovascular mortality and hospitalization. However, there was an increased risk of serious hyperkalemia with eplerenone. The study concluded that eplerenone improves outcomes for patients with left ventricular dysfunction after a myocardial infarction when added to maximal medical therapy.
This document discusses various types of cardiomyopathy including hypertrophic cardiomyopathy, dilated cardiomyopathy, and restrictive cardiomyopathy. It describes the genetic causes and mutations involved in each type. For many cardiomyopathies, genetic testing can help with clinical management, guide family screening, and identify individuals who may develop disease later in life. The document also discusses genetic causes of congenital heart disease, channelopathies, and the role of pharmacogenomics in personalized treatment of cardiac conditions.
Relative risk of cardiovascular morbidity is increased in Chronic Kidney Disease (CKD). According to current KDIGO guideline
cardiovascular risk can be estimated from Glomerular Filtration Rate (GFR) and proteinuria.
This document discusses guidelines for lowering LDL cholesterol levels to reduce cardiovascular risk. It notes that while normal LDL levels are considered low risk, even normal levels still carry some risk. Current guidelines recommend lowering LDL as much as possible, by at least 50%, with a target under 70 mg/dL or lower for high-risk patients. Clinical trials have shown lower LDL levels are associated with greater risk reduction, down to levels under 40 mg/dL, though very low levels below 25 mg/dL require more evidence. Potential safety risks of extremely low levels are also examined. The conclusion emphasizes the importance of early detection and management of dyslipidemia to prevent cardiovascular disease.
SGLT2 inhibitors in Heart failure: A prized addition to HF treatment optionsahvc0858
Early Diabetes and Dyslipidaemia Treatment Optimisation.
Presentation by Dr Chan Wan Xian
Cardiologist, Echocardiologist
Heart Failure Intensivist
Asian Heart & Vascular Centre
www.ahvc.com.sg
Diabetic cardiomyopathy is characterized by abnormal myocardial structure and function in patients with diabetes but without other known causes of heart disease. It is caused by prolonged hyperglycemia and metabolic alterations that result in changes like fibrosis and impaired relaxation and filling of the heart. Diagnosis involves echocardiography and tissue Doppler imaging to detect early diastolic dysfunction. Treatment focuses on strict glycemic control as well as medications like ACE inhibitors, ARBs, beta-blockers, and statins to counter the effects of diabetes on the heart.
In cardiology practice, we often come across patients presenting with anginal pain who undergo coronary angiogram which reveals either normal or non-obstructive epicardial coronaries. Importance is given to epicardial coronaries and the coronary microvasculature which could be the cause of angina is often overlooked. These patients are then labeled to have non-cardiac chest pain and musculoskeletal or psychogenic etiology is suggested. However, with growing interest in coronary microvasculature which are the tiny blood vessels at the tissue level in myocardium, diagnostic modalities and treatment options for coronary microvascular disease are being explored.
1) The study aimed to determine if incomplete inhibition of platelet thromboxane production by aspirin (ASA), as measured by urinary 11-dehydro thromboxane B2 levels, was associated with increased cardiovascular risk in patients in the CHARISMA trial.
2) Urinary 11-dehydro thromboxane B2 levels were measured in 3261 patients to identify determinants of thromboxane production and whether clopidogrel added to ASA could reduce thromboxane biosynthesis.
3) Baseline characteristics and outcomes were compared between patients who did and did not experience a primary endpoint of stroke, MI or cardiovascular death during follow-up. Determinants of urinary 11-dehydro throm
Management of CAD in Diabetes the cardiovascular equivalent is challenging.The slides take you from the epidemiology,ADD,and CV benefit and how to manage CAD
This review article discusses microvascular and macrovascular disease in systemic hypertension. It summarizes that:
1) Cardiac imaging plays a crucial role in risk stratifying hypertensive patients and identifying management strategies by properly diagnosing microvascular and coronary artery disease.
2) The nitric oxide synthase (eNOS) G298 gene allele may be a marker for microvascular angina in hypertensive patients, as studies have found it to be more prevalent in hypertensive patients with chest pain and reversible myocardial defects but normal coronary arteries.
3) Both structural changes like capillary rarefaction and functional changes like endothelial dysfunction can cause microvascular dysfunction and angina in hypertensive individuals in the absence of
The document provides a summary of the history of diabetes treatment. It describes how treatment typically begins with lifestyle changes like diet and exercise. If those don't control blood sugar levels, oral medications like metformin and sulfonylureas may be prescribed. Over time, additional drugs from different classes like glitazones, sitagliptin, meglitinides, and alpha-glucosidase inhibitors are often added to better control blood sugar. Eventually, many patients transition to taking insulin to manage their diabetes.
The history of diabetes dates back to ancient Egyptians in approximately 1550 BC when an Egyptian papyrus first described symptoms of rapid weight loss and frequent urination. In the 1st century CE, the Greek physician Aretaeus named the condition "diabetes" and described its characteristic symptoms. It was not until the 1920s that scientists like Moses Barron and Frederick Banting linked diabetes to the pancreas and discovered the hormone insulin, revolutionizing treatment. Today, while prevention and management remain challenging, life for diabetics continues to improve.
Diabetic cardiomyopathy refers to myocardial disease in diabetic subjects that cannot be ascribed to hypertension, coronary artery disease (CAD), or any other known cardiac disease. Key aspects discussed include the high prevalence of heart failure in diabetic patients, pathophysiological changes such as hypertrophy and fibrosis, and risk factors like hyperglycemia and hypertension. Management involves tight control of blood pressure and blood glucose, as well as medications like angiotensin-converting enzyme inhibitors, beta blockers, and aldosterone receptor antagonists which have been shown to improve outcomes. Aggressive modification of cardiovascular risk factors is important in the management of diabetic cardiomyopathy.
ONTARGET trial - Summary & Results with Ramipril Global Endpointtheheart.org
The ONTARGET trial compared the angiotensin receptor blocker (ARB) telmisartan to the angiotensin converting enzyme (ACE) inhibitor ramipril and their combination in 25,620 patients with cardiovascular disease or diabetes. The trial found that telmisartan was noninferior to ramipril for the primary outcome of cardiovascular death, heart attack, stroke or hospitalization for heart failure. The combination of telmisartan and ramipril showed no additional benefit compared to ramipril alone and was associated with more side effects such as renal impairment.
The document summarizes the Japan EPA Lipid Intervention Study (JELIS), a large clinical trial examining whether EPA (eicosapentaenoic acid) can improve cardiovascular outcomes when added to HMG-CoA reductase inhibitor treatment in patients with hypercholesterolemia. JELIS involves over 18,000 Japanese participants randomized to receive EPA plus statin or statin alone. The primary endpoint is major coronary events over 5 years. Baseline characteristics showed patients had moderately elevated cholesterol. Results are expected in 2005 to determine if EPA provides additional cardiovascular benefit beyond statin therapy alone.
This study analyzed bleeding complications in 150 patients with acute coronary syndrome (ACS) who received antiplatelet and anticoagulant therapy, comparing outcomes in diabetic and non-diabetic patients. There was no statistically significant difference in major bleeding as defined by TIMI criteria between diabetic and non-diabetic patients or between those who received heparin alone versus heparin plus tirofiban. The most common site of bleeding was the cardiac catheterization access site. While GRACE and CRUSADE risk scores were higher in diabetics, indicating greater disease severity, rates of all TIMI bleeding and blood transfusions were similar between diabetic and non-diabetic patients.
Although many are still concerned with an ARB–MI paradox, our study of close to 60 000 patients with MI should serve as reassurance that ARBs are not associated with adverse outcomes compared with ACEIs. Potential benefits of ARBs as compared with ACEIs in older women with MI should be further evaluated.
This study aims to compare plasma erythropoietin (EPO) and vascular endothelial growth factor (VEGF) levels between patients with chronic kidney disease (CKD) and cardio-renal syndrome (CRS) using enzyme-linked immunosorbent assay (ELISA). The study hypothesizes that hypoxic signaling via hypoxia-inducible factor-1 alpha (HIF-1α) is altered in CRS compared to CKD alone, affecting EPO and VEGF protein levels. Blood samples from 100 CKD patients and 100 CRS patients will be collected and analyzed to quantify and compare EPO and VEGF levels between the two groups. Correlations between the protein levels, kidney function, heart function, and
Role of raas inhibition in management of hypertensionKyaw Win
1) RAAS inhibition plays a central role in the pathogenesis of cardiovascular disease by modulating processes like vasoconstriction, inflammation, endothelial dysfunction, and atherosclerosis.
2) Both ACE inhibitors and ARBs have been shown to reduce target organ damage and improve endothelial function through various mechanisms such as increasing NO and reducing oxidative stress and inflammation.
3) Clinical trials provide evidence that RAAS inhibition can reduce atherosclerosis progression, cardiac hypertrophy, and events in conditions like coronary artery disease and heart failure.
1. The document discusses the relationship between migraine and thrombofilia, specifically looking at the MTHFR C677T polymorphism which is associated with higher homocysteine levels and cardiovascular disease risk.
2. One study found the TT genotype was less common in migraine patients but conferred higher risk of ischemic stroke in those with migraine with aura.
3. A meta-analysis found conflicting data on the association between migraine and the C677T polymorphism with high heterogeneity between studies related to ethnicity.
Eplerenone, a selective aldosterone blocker, inSalman Ahmed
This document summarizes a clinical trial that evaluated the effect of the selective aldosterone blocker eplerenone in patients with left ventricular dysfunction after myocardial infarction. The trial involved over 6,600 patients who received either eplerenone or a placebo in addition to optimal medical therapy. The results showed that eplerenone reduced all-cause mortality by 14.4% compared to 16.7% for placebo and reduced cardiovascular mortality and hospitalization. However, there was an increased risk of serious hyperkalemia with eplerenone. The study concluded that eplerenone improves outcomes for patients with left ventricular dysfunction after a myocardial infarction when added to maximal medical therapy.
This document discusses various types of cardiomyopathy including hypertrophic cardiomyopathy, dilated cardiomyopathy, and restrictive cardiomyopathy. It describes the genetic causes and mutations involved in each type. For many cardiomyopathies, genetic testing can help with clinical management, guide family screening, and identify individuals who may develop disease later in life. The document also discusses genetic causes of congenital heart disease, channelopathies, and the role of pharmacogenomics in personalized treatment of cardiac conditions.
Relative risk of cardiovascular morbidity is increased in Chronic Kidney Disease (CKD). According to current KDIGO guideline
cardiovascular risk can be estimated from Glomerular Filtration Rate (GFR) and proteinuria.
This document discusses guidelines for lowering LDL cholesterol levels to reduce cardiovascular risk. It notes that while normal LDL levels are considered low risk, even normal levels still carry some risk. Current guidelines recommend lowering LDL as much as possible, by at least 50%, with a target under 70 mg/dL or lower for high-risk patients. Clinical trials have shown lower LDL levels are associated with greater risk reduction, down to levels under 40 mg/dL, though very low levels below 25 mg/dL require more evidence. Potential safety risks of extremely low levels are also examined. The conclusion emphasizes the importance of early detection and management of dyslipidemia to prevent cardiovascular disease.
SGLT2 inhibitors in Heart failure: A prized addition to HF treatment optionsahvc0858
Early Diabetes and Dyslipidaemia Treatment Optimisation.
Presentation by Dr Chan Wan Xian
Cardiologist, Echocardiologist
Heart Failure Intensivist
Asian Heart & Vascular Centre
www.ahvc.com.sg
Diabetic cardiomyopathy is characterized by abnormal myocardial structure and function in patients with diabetes but without other known causes of heart disease. It is caused by prolonged hyperglycemia and metabolic alterations that result in changes like fibrosis and impaired relaxation and filling of the heart. Diagnosis involves echocardiography and tissue Doppler imaging to detect early diastolic dysfunction. Treatment focuses on strict glycemic control as well as medications like ACE inhibitors, ARBs, beta-blockers, and statins to counter the effects of diabetes on the heart.
In cardiology practice, we often come across patients presenting with anginal pain who undergo coronary angiogram which reveals either normal or non-obstructive epicardial coronaries. Importance is given to epicardial coronaries and the coronary microvasculature which could be the cause of angina is often overlooked. These patients are then labeled to have non-cardiac chest pain and musculoskeletal or psychogenic etiology is suggested. However, with growing interest in coronary microvasculature which are the tiny blood vessels at the tissue level in myocardium, diagnostic modalities and treatment options for coronary microvascular disease are being explored.
1) The study aimed to determine if incomplete inhibition of platelet thromboxane production by aspirin (ASA), as measured by urinary 11-dehydro thromboxane B2 levels, was associated with increased cardiovascular risk in patients in the CHARISMA trial.
2) Urinary 11-dehydro thromboxane B2 levels were measured in 3261 patients to identify determinants of thromboxane production and whether clopidogrel added to ASA could reduce thromboxane biosynthesis.
3) Baseline characteristics and outcomes were compared between patients who did and did not experience a primary endpoint of stroke, MI or cardiovascular death during follow-up. Determinants of urinary 11-dehydro throm
Management of CAD in Diabetes the cardiovascular equivalent is challenging.The slides take you from the epidemiology,ADD,and CV benefit and how to manage CAD
This review article discusses microvascular and macrovascular disease in systemic hypertension. It summarizes that:
1) Cardiac imaging plays a crucial role in risk stratifying hypertensive patients and identifying management strategies by properly diagnosing microvascular and coronary artery disease.
2) The nitric oxide synthase (eNOS) G298 gene allele may be a marker for microvascular angina in hypertensive patients, as studies have found it to be more prevalent in hypertensive patients with chest pain and reversible myocardial defects but normal coronary arteries.
3) Both structural changes like capillary rarefaction and functional changes like endothelial dysfunction can cause microvascular dysfunction and angina in hypertensive individuals in the absence of
The document provides a summary of the history of diabetes treatment. It describes how treatment typically begins with lifestyle changes like diet and exercise. If those don't control blood sugar levels, oral medications like metformin and sulfonylureas may be prescribed. Over time, additional drugs from different classes like glitazones, sitagliptin, meglitinides, and alpha-glucosidase inhibitors are often added to better control blood sugar. Eventually, many patients transition to taking insulin to manage their diabetes.
The history of diabetes dates back to ancient Egyptians in approximately 1550 BC when an Egyptian papyrus first described symptoms of rapid weight loss and frequent urination. In the 1st century CE, the Greek physician Aretaeus named the condition "diabetes" and described its characteristic symptoms. It was not until the 1920s that scientists like Moses Barron and Frederick Banting linked diabetes to the pancreas and discovered the hormone insulin, revolutionizing treatment. Today, while prevention and management remain challenging, life for diabetics continues to improve.
The document summarizes proteinuria tests as useful clinical tools. It discusses how urine tests can examine kidney function by checking for protein in the urine. The easiest test is a urine dipstick that detects albumin above 150 mg/L, indicating macroalbuminuria. Microalbuminuria between 20-150 mg/L is an early sign of diabetic nephropathy. Newer tests can detect microalbuminuria through the urine albumin-creatinine ratio. Therapies like ACE inhibitors and ARBs can reduce proteinuria and slow kidney disease progression. Urine protein monitoring provides important information for managing and prognosticating kidney disease.
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
All manuscripts are subject to rapid peer review. Those of high quality (not previously published and not under consideration for publication in another journal) will be published without delay
Diabetes is a chronic disease that requires lifelong treatment and monitoring by a physician. There are several potential complications of diabetes including heart disease, kidney disease, eye complications, nerve damage, and foot complications. Left unmanaged, diabetes can lead to serious health issues such as heart attack, stroke, kidney failure, blindness, and lower limb amputations. It is important for those with diabetes to work closely with their healthcare team to manage blood sugar, blood pressure, cholesterol levels and prevent or treat any complications through medication, lifestyle changes, and regular screening exams.
The history of diabetes dates back to 1500 BC, with the earliest descriptions found in ancient Egyptian and Hindu manuscripts. The Greeks coined the term "diabetes" in the 2nd century BC to mean "to pass through" referring to the excessive urination. In the 4th-5th century AD, Indian physicians were the first to distinguish between type 1 and type 2 diabetes. The role of the pancreas in diabetes was discovered in 1889, leading to the discovery of insulin in the 1920s and its use as a treatment. Major advances in the 20th century included distinguishing type 1 and type 2 diabetes, determining insulin's amino acid sequence, and developing new insulin therapies and delivery methods.
1. A study found that early treatment of a first episode of acute pericarditis with colchicine in addition to standard anti-inflammatory therapy reduced the risk of recurrence compared to anti-inflammatory therapy alone.
2. The STOP-HF trial found that screening high-risk patients for heart failure with BNP and providing further assessment and care for those with elevated BNP resulted in less left ventricular dysfunction, heart failure, and emergency hospitalizations compared to usual care.
3. The EchoCRT trial of CRT in patients with narrow QRS found no benefit of CRT and more deaths with CRT, suggesting CRT is not recommended for patients with narrow QRS.
Serum uric acid as a marker of left ventricular failure in acute myocardial i...iosrjce
IOSR Journal of Dental and Medical Sciences is one of the speciality Journal in Dental Science and Medical Science published by International Organization of Scientific Research (IOSR). The Journal publishes papers of the highest scientific merit and widest possible scope work in all areas related to medical and dental science. The Journal welcome review articles, leading medical and clinical research articles, technical notes, case reports and others.
This document summarizes recent studies on stroke prevention strategies and risk factors. It discusses advances in neurorehabilitation, drug development, and other therapies. It then reviews major risk factors for stroke like hypertension, dyslipidemia, diabetes, smoking, obesity, lack of physical activity, and prior stroke or TIA. Several studies are highlighted that show treating modifiable risk factors can reduce stroke risk by 82-90%. The document also reviews guidelines for treating hypertension and targets for LDL cholesterol in secondary stroke prevention. It discusses trials comparing antiplatelet therapies like clopidogrel plus aspirin versus aspirin alone for reducing recurrent stroke risk.
- The document discusses recent advances in stroke management including neurorehabilitation, drug development, robotics, cortical stimulation, and stem cell therapies.
- It then discusses various risk factors for ischemic and hemorrhagic stroke, noting that hypertension, diet, physical inactivity, smoking, and abdominal obesity account for the majority of population-attributable risk.
- Specific guidelines and studies are discussed regarding management of hypertension, dyslipidemia, anti-platelet therapy including clopidogrel and aspirin, and LDL cholesterol targets after ischemic stroke to reduce risk of recurrent events.
1) Telmisartan is advantageous over ACE inhibitors for patients with cardiovascular risk as it provides renin-angiotensin system blockade with fewer side effects and better treatment adherence, leading to reduced cardiovascular risk.
2) Telmisartan more effectively controls blood pressure throughout the 24-hour dosing period compared to ramipril, including better control of the early morning blood pressure surge which is important for reducing cardiovascular risk.
3) High adherence to antihypertensive treatment is associated with a 10% reduced risk of coronary artery disease, so assessing and supporting adherence is important for primary prevention of CAD in hypertensive patients.
This summary outlines the key findings of the EMPA-KIDNEY trial which evaluated the effect of empagliflozin treatment on kidney disease progression and cardiovascular outcomes in patients with chronic kidney disease (CKD). The randomized, double-blind trial involved over 6,600 patients with CKD across 8 countries. Patients received either empagliflozin 10mg or placebo daily. The primary outcome of kidney disease progression or cardiovascular death occurred in 13.1% of the empagliflozin group versus 16.9% of the placebo group, representing a 28% lower risk with empagliflozin. Secondary outcomes also favored empagliflozin treatment, including lower rates of hospitalization. The benefits were
Cardiorenal syndromes describe disorders where dysfunction in the heart and kidneys negatively impact one another. There are 5 subtypes based on etiology and chronicity. Type 1 involves acute kidney injury secondary to heart failure. Type 2 is chronic cardiac dysfunction causing chronic kidney disease. Type 3 is acute worsening of kidney function inducing heart issues. Type 4 is primary chronic kidney disease contributing to cardiac complications. Type 5 involves systemic conditions affecting both organs. Managing cardiorenal syndromes focuses on decongestion through diuresis while preventing worsening of renal function with neurohormonal blockade.
A Tab from GOD: Aspirins for CVS Dr.AKS.pptxKyawMyoHtet10
The document summarizes key information about aspirin, including its history, mechanisms of action, dosing, and clinical trial evidence regarding its effects on cardiovascular disease outcomes and risks of bleeding. Some key points:
1) Aspirin was first used in the 5th century BC and was isolated in 1897. It works by irreversibly inhibiting platelet aggregation.
2) Clinical trials show aspirin reduces cardiovascular events by around 25% in secondary prevention but the benefits are less clear in primary prevention where average patient risks are lower.
3) The optimal daily aspirin dose is 75-325mg, with 75mg achieving maximal platelet inhibition more quickly. Higher doses increase bleeding risks.
4) Combining
The document discusses the use of aspirin for the primary prevention of cardiovascular disease in patients with diabetes. While aspirin is proven to be effective for secondary prevention, its benefits for primary prevention in patients without a history of vascular disease are unclear based on previous studies which have been underpowered. The document describes two recent clinical trials, POPADAD and JPAD, which also did not provide definitive evidence due to low event rates. It encourages participation in the ongoing ASCEND trial, which aims to recruit 10,000 patients, in order to help resolve the uncertainty around aspirin's role in primary prevention for patients with diabetes.
Emerging MRA-Based Treatments for End-Stage Renal Disease (ESRD) Patients on ...wackysavior4064
- Chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients have high rates of cardiovascular disease mortality due to increased risk factors like hypertension, inflammation, and fibrosis.
- Recent studies have explored using mineralocorticoid receptor antagonists (MRAs) like spironolactone or eplerenone to treat CKD and ESRD patients given their cardiovascular benefits, but concerns about hyperkalemia have limited their use.
- Ongoing and planned clinical trials are investigating the effectiveness and safety of MRAs in reducing cardiovascular events for CKD and ESRD patients, including how new potassium-binding drugs may help address hyperkalemia risks.
Bleeding complications in secondary stroke prevention by antiplatelet therapy...Duwan Arismendy
Abstract
Abstract. Boysen G (University of Copenhagen, Copenhagen, Denmark). Bleeding complications in secondary stroke prevention by antiplatelet therapy: a benefit–risk analysis (Review). J Intern Med 1999; 246: 239–245.
This review analyses the benefit–risk ratio of antiplatelet drugs in secondary stroke prevention and is based on the published data from eight large stroke prevention trials. In patients with prior transient ischaemic attack (TIA) or stroke, aspirin prevented one to two vascular events (stroke, AMI, or vascular death) per 100 treatment-years with an excess risk of fatal and severe bleeds of 0.4–0.6 per 100 treatment-years. The gastrointestinal bleeding risk was significantly lower with ticlopidine and clopidogrel, which were both somewhat more effective than aspirin in the prevention of vascular events. The combination of dipyridamole and aspirin prevented 2.82 strokes at the expense of an excess risk of 0.61 (95% CI = 0.27–0.95) fatal or severe bleeds per 100 treatment-years.
In the acute phase of stroke, the aspirin-associated risk of haemorrhagic complications was much increased compared with that in the stable phase after stroke, with 0.48 (95% CI = 0.13–0.83) fatal or severe bleeds per 100 treated patients for the first 4 weeks after stroke in the Chinese Acute Stroke Trial and 0.41 (95% CI = 0.05–0.77) in the International Stroke Trial. Still, there was a net benefit with the prevention of about one death or non-fatal ischaemic stroke per 100 treated patients.
1. Cardio-renal syndrome (CRS) describes conditions where acute or chronic dysfunction in one organ induces acute or chronic dysfunction in the other organ.
2. Management of CRS is challenging and involves diuretics, ACE inhibitors, beta blockers, and dialysis. However, treatment outcomes remain poor, with high mortality and rates of rehospitalization.
3. While advances have been made, CRS continues to significantly impact morbidity and mortality. Early multidisciplinary management may help improve outcomes, but effective new therapies are still needed to better treat and prevent this challenging condition.
CARDIAC COMPLICATIONS & ITS MANAGEMENT OF CKDMohd Tariq Ali
Uremic cardiomyopathy is the primary manifestation of cardiac complications in patients with chronic kidney disease. It results from the combined effects of pressure and volume overload on the heart from conditions like hypertension as well as the uremic state itself. This leads to left ventricular hypertrophy initially as an adaptive response but later maladaptive changes like cardiomyocyte death, fibrosis, and dilated cardiomyopathy if left unmanaged. Early initiation of hemodialysis, preferably non-conventional daily or nocturnal dialysis, can help halt progression of uremic cardiomyopathy while kidney transplantation has been shown to reverse it.
This study investigated the effects of adding eplerenone to evidence-based heart failure therapies in patients with mild systolic heart failure symptoms. The study randomized 2,737 patients to receive either eplerenone or placebo. The primary outcome of death from cardiovascular causes or hospitalization for heart failure occurred in 18.3% of the eplerenone group compared to 25.9% of the placebo group, demonstrating that eplerenone reduced risks. The trial was stopped early due to these benefits after a median follow up of 21 months. Eplerenone was found to provide cardiovascular protection in patients with heart failure compared to placebo.
The FIGARO-DKD trial evaluated the efficacy and safety of finerenone in reducing major adverse cardiovascular events in adults with type 2 diabetes and chronic kidney disease. Over 5300 patients were randomized 1:1 to receive finerenone or placebo on top of standard renin-angiotensin-aldosterone system inhibitor therapy. Finerenone showed a statistically significant 18% relative risk reduction in the primary composite outcome of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure compared to placebo. Hyperkalemia was the most common adverse effect but occurred at a lower rate than other mineralocorticoid receptor antagonists.
Aspirin in the primary and secondary prevention of vascular diseases. ppt.pptxKyawMyoHtet10
Aspirin alone or in combination with other antiplatelet therapies reduces the risk of cardiovascular events like heart attack and stroke. However, dual antiplatelet therapy also increases the risk of major bleeding compared to single antiplatelet therapy. The benefits and risks of different antiplatelet regimens depend on the individual patient's risk factors and require consideration in determining the optimal treatment strategy.
This document analyzes the benefits of aldosterone receptor antagonists (ARAs) in treating heart failure based on evidence from major clinical trials. ARAs such as spironolactone and eplerenone, when added to standard heart failure therapies, were shown to significantly reduce mortality and hospitalization rates compared to placebo in patients with NYHA class II-IV symptoms and reduced ejection fraction. However, ARAs remain underutilized in practice due to concerns about side effects like hyperkalemia. Ongoing research is exploring more selective next-generation ARAs that may have fewer safety issues.
Impact of statins and beta-blocker therapy on mortality after coronary artery...Paul Schoenhagen
Abstract
Background: We conducted a retrospective cohort study of patients after first-time isolated coronary artery bypass graft surgery (CABG) and assessed the impact of a discharge regimen including beta-blockers and statin therapy and their relationship to long-term all cause mortality and major adverse cardiovascular events (MACE).
Methods: We identified patients age >18 years, undergoing first time isolated CABG from 1993 to 2005. Patients were identified using the Cardiovascular Information Registry (CVIR). We collected follow-up information at 30, 60, 90 days and yearly follow-up. The registry is approved for use in research by the institutional review broad.
Results: We identified 5,205 patients who underwent single isolated CABG between January 1993 and December 2005. The mean age was 64.5±9.7 years and over 70% were male. There was a significant difference in the low density lipoproteins (LDL) concentration between those with or without statin medications (134±41.9 mg/dL) (no statin) vs. 126±44.8 mg/dL (with statin), P=0.001. A discharge regimen with statin therapy was associated with and overall reduction in 30 day, 1 year and long-term mortality. In addition, overall the triple ischemic endpoint of death, myocardial infarction (MI) and stroke was also significantly lower in the statin vs. no-statin group. In addition, statin and beta-blockers exerted synergistic effect on overall mortality outcomes short-term and in the long-term. We note that the predictors of overall death include no therapy with statin therapy and age [hazard ratios (HR) 1.1, 95% CI: 1.04-1.078, P<0.001] and presence of renal failure (HR 2.0, P=0.005). The estimated 11-year Kaplan Meier curves for mortality between the two groups starts to diverge immediately post discharge after single isolated CABG and continue to diverge through out the follow-up period.
Conclusions: A post-discharge regimen of statins independently reduces overall and 1 year mortality. These results confirm those of earlier studies within a contemporary surgical population and support the current clinical guidelines.
Impact of statins and beta-blocker therapy on mortality after coronary artery...Paul Schoenhagen
Background: We conducted a retrospective cohort study of patients after first-time isolated coronary artery bypass graft surgery (CABG) and assessed the impact of a discharge regimen including beta-blockers and statin therapy and their relationship to long-term all cause mortality and major adverse cardiovascular events (MACE).
Methods: We identified patients age >18 years, undergoing first time isolated CABG from 1993 to 2005. Patients were identified using the Cardiovascular Information Registry (CVIR). We collected follow-up information at 30, 60, 90 days and yearly follow-up. The registry is approved for use in research by the institutional review broad.
Results: We identified 5,205 patients who underwent single isolated CABG between January 1993 and December 2005. The mean age was 64.5±9.7 years and over 70% were male. There was a significant difference in the low density lipoproteins (LDL) concentration between those with or without statin medications (134±41.9 mg/dL) (no statin) vs. 126±44.8 mg/dL (with statin), P=0.001. A discharge regimen with statin therapy was associated with and overall reduction in 30 day, 1 year and long-term mortality. In addition, overall the triple ischemic endpoint of death, myocardial infarction (MI) and stroke was also significantly lower in the statin vs. no-statin group. In addition, statin and beta-blockers exerted synergistic effect on overall mortality outcomes short-term and in the long-term. We note that the predictors of overall death include no therapy with statin therapy and age [hazard ratios (HR) 1.1, 95% CI: 1.04-1.078, P<0.001] and presence of renal failure (HR 2.0, P=0.005). The estimated 11-year Kaplan Meier curves for mortality between the two groups starts to diverge immediately post discharge after single isolated CABG and continue to diverge through out the follow-up period.
Conclusions: A post-discharge regimen of statins independently reduces overall and 1 year mortality. These results confirm those of earlier studies within a contemporary surgical population and support the current clinical guidelines.
This document discusses the relationship between lipids and cerebrovascular diseases. It finds that higher cholesterol levels are associated with increased risk of ischemic stroke, while lower cholesterol levels are associated with increased risk of hemorrhagic stroke. Statins have been shown to reduce stroke risk by lowering LDL cholesterol levels. The document reviews several clinical trials that demonstrate the efficacy of statin therapy in both primary and secondary stroke prevention.
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Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
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Cell Therapy Expansion and Challenges in Autoimmune DiseaseHealth Advances
There is increasing confidence that cell therapies will soon play a role in the treatment of autoimmune disorders, but the extent of this impact remains to be seen. Early readouts on autologous CAR-Ts in lupus are encouraging, but manufacturing and cost limitations are likely to restrict access to highly refractory patients. Allogeneic CAR-Ts have the potential to broaden access to earlier lines of treatment due to their inherent cost benefits, however they will need to demonstrate comparable or improved efficacy to established modalities.
In addition to infrastructure and capacity constraints, CAR-Ts face a very different risk-benefit dynamic in autoimmune compared to oncology, highlighting the need for tolerable therapies with low adverse event risk. CAR-NK and Treg-based therapies are also being developed in certain autoimmune disorders and may demonstrate favorable safety profiles. Several novel non-cell therapies such as bispecific antibodies, nanobodies, and RNAi drugs, may also offer future alternative competitive solutions with variable value propositions.
Widespread adoption of cell therapies will not only require strong efficacy and safety data, but also adapted pricing and access strategies. At oncology-based price points, CAR-Ts are unlikely to achieve broad market access in autoimmune disorders, with eligible patient populations that are potentially orders of magnitude greater than the number of currently addressable cancer patients. Developers have made strides towards reducing cell therapy COGS while improving manufacturing efficiency, but payors will inevitably restrict access until more sustainable pricing is achieved.
Despite these headwinds, industry leaders and investors remain confident that cell therapies are poised to address significant unmet need in patients suffering from autoimmune disorders. However, the extent of this impact on the treatment landscape remains to be seen, as the industry rapidly approaches an inflection point.
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Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
2. Hoogwerf/Renin–Angiotensin System Blockade and Cardiovascular and Renal Protection 31A
Figure 1. Incidence of cardiovascular events (cardiovascular death, myocardial infarction, stroke, all-cause mortality, hospitalization for congestive heart
failure) according to degree of albuminuria, expressed as deciles of the albumin-to-creatinine ratio. (Reprinted with permission from JAMA.11)
and 12.1% in those with elevated plasma creatinine or renal athy (urinary protein excretion 500 mg/day; serum creat-
replacement therapy (p 0.0001 for trend). Similarly, the inine 221 mol/L). During a median of 3 years’ follow-
proportion of all deaths that were attributable to CVD in- up, the risk of a doubling of serum creatinine was reduced
creased from 51% in patients without nephropathy to 66% by 48% (95% CI, 16 – 69%; p 0.007) among captopril-
in those with microalbuminuria and 75% in those with treated patients compared with the placebo group, and the
macroalbuminuria.10 risk of death, dialysis, or transplantation was reduced by
An analysis of data from the HOPE study, which in- 50% (95% CI, 18 –70%, p 0.006).
volved 3,498 patients with and 5,545 without diabetes, with In a further study, 94 normotensive patients with type 2
objective evidence of vascular disease, plus 1 other risk diabetes and microalbuminuria (30 –300 mg per 24 hours)
factor, showed that the relation between albuminuria and were treated with enalapril 10 mg or placebo for 5 years.14
cardiovascular risk is continuous and graded, both in indi- Enalapril treatment was associated with an initial decrease
viduals with and without diabetes (Figure 1).11 After adjust- in albuminuria, which was followed by a slow increase,
ment for other risk factors, the relative risk of major car- such that urine albumin concentrations after 5 years were
diovascular events (cardiovascular death, MI, or stroke) similar to those at the start of the study. By contrast, in
associated with microalbuminuria was 1.83 (95% confi- placebo-treated patients, albuminuria progressed throughout
dence interval [CI], 1.64 –2.05), and that for hospitalization the study, resulting in a significant (p 0.005) difference in
for congestive heart failure was 3.23 (95% CI, 2.54 – 4.10). urine albumin concentrations between the groups at 5 years.
The relative risk of major cardiovascular events increased Renal function, expressed as the mean reciprocal of serum
with the degree of nephropathy. Compared with the lowest creatinine, decreased by 13% in the placebo group and
quartile of urinary albumin-to-creatinine ratio (UACR), the remained stable (mean change – 1%) in the enalapril group
relative risks of major cardiovascular events in the second, (p 0.05).
third, and fourth quartiles were 1.11 (95% CI, 0.95–1.30), In the HOPE study, ramipril treatment significantly re-
1.38 (95% CI, 1.19 –1.60), and 1.97 (95% CI, 1.73–2.25), duced the high cardiovascular risk associated with renal
respectively (p 0.001 for trend); for every 0.4-mg/mmol impairment.12 The hazard ratio for the combined risk of
increase in the UACR, the adjusted risk of major cardio- cardiovascular death, MI, or stroke in ramipril-treated pa-
vascular events increased by 5.9% (95% CI, 4.9 –7.0%). A
tients with renal insufficiency compared to placebo-treated
further analysis showed that the cumulative incidence of
patients was 0.80 (95% CI, 0.59 –1.09), whereas in patients
cardiovascular death, MI, or stroke was significantly
without renal impairment, the corresponding figure was
higher in patients with mild renal insufficiency (serum
0.79 (95% CI, 0.70 – 0.88, p 0.2 for heterogeneity of
creatinine 124 mol/L) than in those without (22.2% vs
hazard ratios).12
15.1%, p 0.001), and increased with the serum creati-
Several studies have also investigated the effects of ARB
nine concentration.12
therapy in patients with diabetic nephropathy. In the Irbe-
Effects of RAAS inhibition on diabetic nephropa- sartan Diabetic Nephropathy Trial (IDNT),15 1,715 hyper-
thy: In a landmark study, Lewis et al13 compared the effects tensive patients with type 2 diabetes and nephropathy (se-
of the ACE inhibitor captopril and placebo on renal function rum creatinine, 106 –265 mol/L in men and 88 –265
in 409 patients with type 1 diabetes and diabetic nephrop- mol/L in women) were randomized to receive irbesartan
3. 32A The American Journal of Cardiology (www.AJConline.org) Vol 105 (1A) January 4, 2010
300 mg, amlodipine 10 mg, or placebo, and studied for a sive patients (n 163).19 Similar findings were observed in
mean of 2.6 years. Irbesartan significantly reduced the risk A Trial to Compare Telmisartan 40 mg Titrated to 80 mg
of the primary end point (a composite of doubling of serum Versus Losartan 100 mg in Hypertensive Type 2 Diabetic
creatinine, development of end-stage renal disease, or death Patients with Overt Nephropathy (AMADEO); a larger,
from any cause) compared with both amlodipine (p 52-week study of 860 patients with diabetic nephropathy
0.006) and placebo (p 0.02), but had no effect on the risk (serum creatinine 3 mg/dL [women] and 3.2 mg/dL
of cardiovascular events (cardiovascular death, nonfatal MI, [men]) and blood pressure 130/80 mm Hg.20 In this study,
hospitalization for heart failure, permanent neurologic def- the reduction in the UACR from baseline was significantly
icit result from cerebrovascular disease, or lower limb am- greater for telmisartan than losartan (Figure 2), despite com-
putation above the ankle); however, the study was not ad- parable reductions in blood pressure.
equately powered to detect significant changes in these end More recently, the ONTARGET trial, which was among
points. the first large-scale trials to compare an ACE inhibitor with
The Reduction of Endpoints in NIDDM with the Angio- ramipril in 25,620 high-risk patients, showed that the inci-
tensin II Antagonist Losartan (RENAAL) study16 compared dence of the primary renal outcome (a composite of dialysis,
the effects of losartan 50 –100 mg and placebo in 1,513 doubling of serum creatinine, and death) was comparable
patients with type 2 diabetes and nephropathy (defined as an between telmisartan and ramipril during a median follow-up
early morning UACR 300, or a urinary albumin excretion of 56 months (13.4% vs 13.5%, respectively).20 The increase
0.5 g/day and serum creatinine of 115–265 mol/L) who in urinary albumin excretion rate was significantly less with
were already receiving standard antihypertensive therapy. telmisartan than ramipril (p 0.04) but the decrease in the
Again, ARB therapy significantly reduced the progression estimated glomerular filtration rate was lower for ramipril than
of nephropathy compared with placebo but had no signifi- telmisartan ( 2.82 mL/min per 1.73 m2 vs 4.12 mL/min per
cant effect on cardiovascular outcomes, except for a 32% 1.73 m2). However, the overall yearly estimated glomerular
(p 0.005) reduction in hospitalizations for heart failure. filtration rate decrease in ONTARGET was 1 mL/yr, which
Similarly, in the Irbesartan in Patients with Type 2 Diabetes is the level observed in a healthy, age-matched population.21
and MicroAlbuminuria–2 (IRMA-2) study,17 which in-
volved 590 patients with hypertension with type 2 diabetes
and microalbuminuria, ARB therapy significantly delayed Heart Disease Risk
the development of diabetic nephropathy compared with
placebo, but it had no effect on cardiovascular outcomes. Several large trials, including the HOPE study,8 the Euro-
The incidence of nonfatal cardiovascular events was higher pean Trial on Reduction of Cardiac Events with Perindopril
in the placebo group than in the group receiving irbesartan in Stable Coronary Artery Disease (EUROPA),22 and the
300 mg (8.7% vs 4.5%), but the difference was not statis- Prevention of Events with Angiotensin Converting Enzyme
tically significant (p 0.11). It should be noted that none of Inhibitors (PEACE) study,23 have shown that ACE inhibitor
these nephropathy trials using ARB therapy showed a re- therapy significantly reduces the risk of coronary artery
duction in cardiovascular risk; however, none of them had disease (CAD) in various at-risk patient populations. How-
sufficient numbers of subjects or study duration to have ever, the available evidence suggests that combination ther-
sufficient statistical power to demonstrate any benefit on apy with ACE inhibitors and ARBs may not offer signifi-
CVD outcomes. cant benefits in this setting.
The Incipient to Overt: Angiotensin II Blocker, Telm- For example, the Valsartan in Acute Myocardial Infarc-
isartan, Investigation on Type 2 Diabetic Nephropathy tion Trial (VALIANT) compared the effects of captopril
(INNOVATION) study was a randomized, multicenter, dou- alone and in combination with valsartan in 14,703 patients
ble-blind, placebo-controlled study in which 527 normoten- with acute MI.24 Although there were some questions about
sive and hypertensive Japanese patients with microalbumin- the dosages of interventions used in the trial, there was no
uria (UACR of 100 300 mg/g creatinine) were randomized significant difference in overall mortality between patients
to telmisartan 40 mg or telmisartan 80 mg for 52 weeks.18 receiving valsartan or captopril monotherapy and those re-
The transition to overt diabetic nephropathy was signifi- ceiving combination treatment. The hazard ratio for all-
cantly lower in the telmisartan 80 mg and telmisartan 40 mg cause mortality in the combination therapy group compared
groups compared with placebo (16.7% and 22.6% vs 49.9%, with the captopril monotherapy group was 0.98 (97.5% CI,
respectively; p 0.0001) over a 30-month follow-up period. 0.89 –1.09; p 0.73). Valsartan and captopril monothera-
In addition, 12.8% of the telmisartan 40 mg group and pies were found to be comparable in terms of all-cause
21.2% of the telmisartan 80 mg group also had microalbu- mortality and a composite end point of fatal and nonfatal
minuria remission (UACR 30 mg/g) compared with 1.2% cardiovascular events. A subsequent analysis25 showed that
in the placebo group (p 0.001). In a post hoc analysis of the incidence of MI was slightly lower in patients receiving
the INNOVATION study, telmisartan 40 or 80 mg was also combination therapy than in either of the monotherapy
shown to reduce the transition from microalbuminuria to groups, although the difference was not statistically signif-
overt nephropathy compared with placebo in the normoten- icant (p 0.187 vs captopril).
4. Hoogwerf/Renin–Angiotensin System Blockade and Cardiovascular and Renal Protection 33A
Figure 2. The change in the urinary protein-to-creatinine (UPC) ratio for telmisartan- and losartan-treated patients (p 0.027). The values represent mean
(SD) at each time point over 52 weeks. (Reprinted with permission from Kidney Int.20)
Until ONTARGET was published, there were no large CI, 0.74 – 0.85) and 0.78 (95% CI, 0.73– 0.84), respectively.
studies on the effects of ARBs on CAD risk in patients Similar findings were obtained when the data were stratified
without heart failure. In this trial, 25,620 patients with according to the antihypertensive therapy received by pa-
vascular disease or high-risk diabetes without heart failure tients in the control groups.26 In the HOPE study, ramipril
were randomized to treatment with telmisartan, ramipril, or was associated with a 34% reduction in the risk of new-
the combination.9 At a median follow-up of 56 months, the onset diabetes (relative risk, 0.66; 95% CI, 0.51– 0.85;
incidence of the primary composite end point (death from p 0.001) compared with placebo in all patient sub-
cardiovascular causes, MI, stroke, or hospitalization for groups.27 Importantly, a follow-up trial, HOPE–The Ongo-
heart failure) was comparable between telmisartan (16.7%) ing Outcomes (HOPE-TOO), showed that this protective
and ramipril (16.5%). The occurrence of any heart failure effect was maintained during long-term follow-up for a
event was also comparable between telmisartan and ramipril mean of 7.2 years (Figure 3).28 The relative risk for the
(6.7% vs 6.9%, respectively). ONTARGET also showed that development of new-onset diabetes among patients in the
the combination of telmisartan and ramipril did not offer ad- ramipril group during this period was 0.66 (95% CI, 0.46 –
ditional benefits in terms of cardiovascular protection. 0.95); the overall relative risk during both HOPE and
HOPE-TOO was 0.69 (95% CI, 0.56 – 0.86; p 0.0006).
The Diabetes Reduction Assessment with Ramipril and
Prevention of Diabetes Mellitus Rosiglitazone Medication (DREAM) study29 investigated
the effect of ramipril on the development of diabetes in
Post hoc analyses of both ACE inhibitor and ARB trials 5,269 patients without CVD but with impaired fasting glu-
strongly suggest that RAAS blockade is associated with a cose or impaired glucose tolerance. Ramipril treatment had
reduction in the incidence of new-onset diabetes. For ex- no significant impact on the risk of death or the develop-
ample, in a recent systematic review that included data from ment of diabetes, compared with placebo (hazard ratio,
13 studies involving approximately 67,000 patients, the 0.91; 95% CI, 0.81–1.03; p 0.15) The DREAM study is
relative risks for the development of new-onset diabetes in discussed in more detail in an article elsewhere in this
patients receiving ACE inhibitors or ARBs were 0.79 (95% supplement.30 In the ONTARGET trial, the development of
5. 34A The American Journal of Cardiology (www.AJConline.org) Vol 105 (1A) January 4, 2010
Figure 3. Kaplan-Meier plot of the risk of new-onset diabetes mellitus during the Heart Outcomes Prevention Evaluation (HOPE) study and the HOPE–The
Ongoing Outcomes (HOPE-TOO) extension study (p 0.0006). (Reprinted with permission from Circulation.29)
new-onset diabetes was largely comparable among the 3 standard care in a broad section of at-risk patients. Both
treatment groups: 6.7% (ramipril), 7.5% (telmisartan), and agents had a comparable effect on the composite primary
6.1% (combination therapy).9 It is difficult to determine outcome, which is indicative of comparative cardioprotec-
whether treatment in ONTARGET was associated with a tive benefits, even in at-risk patients without heart failure at
significant reduction in the risk of diabetes, given the lack of study inclusion. However, further studies of ARBs and ACE
a placebo arm. Further analysis of the baseline characteris- inhibitors are still warranted in patients with metabolic
tics may help to predict the likelihood of progression to syndrome and in the development of new-onset diabetes.
diabetes and other overt conditions in such a high-risk
population if aggressive treatment was not administered.
ONTARGET also indicates that the combination of an ARB
Acknowledgment
and an ACE inhibitor was not associated with further re-
duction in new-onset diabetes. Further studies of the effects
Writing and editorial assistance was provided by Michael
of ARBs and combination therapy on the development of
new-onset diabetes are currently under way. Shaw, PhD, of PAREXEL MMS, which was contracted by
Boehringer Ingelheim for these services. The author(s) meet
criteria for authorship as recommended by the International
Committee of Medical Journal Editors (ICMJE) and were
Conclusion
fully responsible for all content and editorial decisions, and
were involved at all stages of manuscript development. The
Cardiovascular and renal benefits have been shown in both
authors received no compensation related to the develop-
ARB and ACE inhibitor trials. A number of studies have
ment of the manuscript.
shown that these 2 classes are effective in reducing the rate
of renal disease progression in patients with diabetic ne-
phropathy, although more long-term vascular outcome stud-
ies are needed in patients with chronic kidney disease. Both Author Disclosures
the INNOVATION and AMADEO studies showed that the
renoprotective effects achieved with telmisartan were inde- The author who contributed to this article has disclosed the
pendent of blood pressure. ONTARGET is also among the following industry relationship:
first studies to show comparable renoprotective effects be- Byron J. Hoogwerf, MD, has served as a consultant for
tween an ARB (telmisartan) and ramipril on top of usual Boehringer Ingelheim.
6. Hoogwerf/Renin–Angiotensin System Blockade and Cardiovascular and Renal Protection 35A
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