Summary of Randomized Trials of Angiotensin Converting Enzyme Inhibitors

Angiotensin converting enzyme (ACE) inhibitors have been shown to reduce the risk of death, worsening heart failure and recurrent infarction in patients with left ventricular dysfunction and heart failure. They have also been shown to reduce mortality in the acute phase of myocardial infarction. They have been demonstrated to reduce major vascular events and progression of renal disease in diabetes with hypertension, compared to placebo and to calcium channel blockers. Current trials are evaluating their role in preventing major vascular events in patients with coronary artery disease, strokes and Type II diabetes who are normotensive.     

Sodium-Glucose Cotransporter-2 Inhibitors in Vascular Biology: Cellular and Molecular Mechanisms

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are new antidiabetic drugs that reduce hyperglycemia by inhibiting the glucose reabsorption in renal proximal tubules. Clinical studies have shown that SGLT2 inhibitors not only improve glycemic control but also reduce major adverse cardiovascular events (MACE, cardiovascular and total mortality, fatal or nonfatal myocardial infarction or stroke) and hospitalization for heart failure (HF), and improve outcome in chronic kidney disease. These cardiovascular and renal benefits have now been confirmed in both diabetes and non-diabetes patients. The precise mechanism(s) responsible for the protective effects are under intensive investigation. This review examines current evidence on the cardiovascular benefits of SGLT2 inhibitors, with a special emphasis on the vascular actions and their potential mechanisms.

     

Tissue angiotensin‐converting enzyme inhibitors: Are they more effective than serum angiotensin‐converting enzyme inhibitors?

Since their discovery in the 1980s, angiotensin-converting enzyme (ACE) inhibitors have been shown to decrease angiotensin formation, prevent breakdown of bradykinin, and may also act on peptides of the renin-angiotensin system. They are effective in reducing the risk of heart failure, myocardial infarction, and death from cardiovascular causes in patients with left ventricular systolic dysfunction or heart failure, and have been shown to reduce atherosclerotic complications in patients who have vascular disease without heart failure. They may preserve endothelial function and counteract initiation and progression of atherosclerosis. Broadly, ACE inhibitors can be divided into tissue specific or serum ACE inhibitors. Tissue-specific ACE inhibitors as a group are not superior to serum ACE inhibitors in the treatment of coronary artery disease. Pending direct comparator clinical trials between a tissue ACE inhibitor and a plasma ACE inhibitor, both ramipril and perindopril can be recommended for secondary risk prevention, based on the evidence.     

Clinical trial data on the cardioprotective effects of beta-blockade

In most patients with heart failure the underlying cause is coronary artery disease (CAD). They have a poor prognosis and die slowly from deteriorating cardiac function or suddenly from ventricular fibrillation or atheromatous plaque rupture. Two key aims of treatment, therefore, are to slow the progression of underlying CAD and the resulting heart failure and to reduce the risk of sudden death. The impact of drugs on CAD and sudden death can be assessed most effectively in patients who have recovered from a myocardial infarction (post-MI patients). Beta-blockers have been studied in at least 25 trials in post-MI patients and their capacity to reduce mortality and re-infarction has been well documented. About 50% of those who die in post-MI trials die suddenly and beta-blockers particularly propranolol, timolol and metoprolol have been shown to reduce the risk of sudden death significantly. Further evidence that beta-blockers are cardioprotective in post-MI patients can be obtained from trials of other drugs by noting the mortality rates in those patients who were also on a beta-blocker. In three trials of antiarrhythmic drugs and two trials of ACE inhibitors, those on beta-blockers had a better prognosis. There is therefore good evidence that in a patient population known to have serious CAD, beta-blockers can effectively reduce the risk of major coronary events and are particularly effective in reducing the risk of sudden death.     

Fighting against sudden death: A single or multidisciplinary approach

There are many causes of sudden death ranging from accidents and suicide to vascular events and arrhythmias. Most sudden deaths will occur in people who have not been diagnosed with a serious heart condition but at a very low annual rate. Many of these events are probably vascular and might be prevented by reducing the risk of developing coronary disease. Only a minority of sudden deaths occur in people with established cardiac disease, but in patients with major structural heart disease, the annual rate is high. The causes of sudden death are many in this clinical setting also, but dominated by ventricular arrhythmias and vascular events. There is good evidence that conventional treatments for heart failure, including ACE inhibitors, beta-blockers, aldosterone antagonists and cardiac resynchronisation devices reduce the risk of sudden death. Evidence that statins, aspirin or revascularisation are safe or effective in patients with heart failure is currently lacking. Implantable defibrillators confer a small but definite additional survival advantage by treating arrhythmias that have not been prevented.     

The foundation role of beta blockers across the cardiovascular disease spectrum: a year 2009 update

Hypertension is a risk factor for myocardial infarction (MI), stroke, and heart failure and precedes heart failure in 91% of cases. This becomes even more important considering that the number of Americans with hypertension increased from 65 million in 2005 to 72 million in 2007. If blood pressure is effectively controlled this risk can be minimized-blood pressure reductions as small as 2 mm Hg have been shown to reduce the risk of cardiovascular events by up to 10%. There is also strong evidence that blood pressure targets for populations at high risk of cardiovascular disease, including those with diabetes, coronary artery disease, and chronic kidney disease, should be lower than 140/90 mm Hg. The number and type of antihypertensive drugs have increased dramatically from 28 diuretics in 1972 to over 125 agents today, including fixed dose combination dosage forms. Beta blockers have been available for the treatment of hypertension since the 1960s. However, there has been resistance to using these agents in patients with diabetes and renal failure because of metabolic side effects, and in other patients because of tolerability concerns such as depression, weight gain, and impotence. Two newer beta blockers with vasodilatory effects (carvedilol and nebivolol) have proven efficacy and tolerability in patients with hypertension and appear to lack the adverse effects associated with older beta blockers. Carvedilol causes vasodilation by alpha blockade, and nebivolol via nitric oxide mechanisms. Both of these agents reduce peripheral vascular resistance and maintain cardiac output. Clinical trial evidence to date leads to the conclusion that beta blockers are strongly indicated post-MI and in all patients with left ventricular dysfunction regardless of symptoms. Their beneficial abilities include improvement of oxygen supply and demand (which can reduce myocardial ischemia), anti-arrhythmic properties, and beneficial effects on cardiac remodeling.     

Evidence for benefits of angiotensin receptor blockade beyond blood pressure control

Elevated levels of angiotensin II result in oxidative stress and endothelial dysfunction, which initiate atherogenic pathologic processes that are important in cardiovascular disease development. Angiotensin II induces its deleterious effects primarily through the type 1 receptor; these effects are inhibited by angiotensin II receptor blockers (ARBs) directly at the receptor level. Angiotensin II may potentiate protective mechanisms through stimulation of the type 2 receptor, which is not blocked by ARBs. Accumulating data suggest that blockade of angiotensin II production or activity provides vascular and cardioprotective benefits, such as reduction of atrial fibrillation, acute myocardial infarction, and heart failure events. Moreover, blockade of the renin-angiotensin system has been shown to offer renal protection in subjects with and without diabetes mellitus and to reduce the risk of new-onset diabetes.     

Diabetes and heart failure in the post-myocardial infarction patient

Diabetes mellitus, a disease which is increasing in prevalence, is a major risk factor for coronary heart disease. In patients following acute myocardial infarction, the presence of diabetes is a powerful risk factor for the development of heart failure, and this intersection of heart failure and diabetes following myocardial infarction carries substantial risk. The poor prognosis associated with heart failure in diabetic patients following myocardial infarction is likely multifactorial. Aggressive strategies for prevention and treatment of heart failure are crucial to reducing the risk associated with diabetes and heart failure following myocardial infarction. This review summarizes epidemiologic, pathophysiologic, and therapeutic data related to diabetes and heart failure in the post-myocardial infarction setting.     

Aspirin use in chronic heart failure: what should we recommend to the practitioner?

There has been ongoing controversy as to whether aspirin should be used in patients with chronic heart failure (CHF). The argument for aspirin is that many patients have underlying coronary disease, and aspirin prevents reinfarction and other vascular events. Arguments against the routine use of aspirin are that many CHF patients do not have underlying coronary disease, and that the benefit of aspirin lessens after the first 6 to 12 months after infarction. Also, several analyses suggest that aspirin may actually worsen outcomes in CHF patients, possibly because it inhibits prostaglandins, with resulting adverse hemodynamic and renal effects. Two recent prospective randomized studies have found that aspirin is associated with more frequent hospitalizations for worsening heart failure, although it did not have an adverse effect on vascular events. These results suggest that aspirin should not be routinely used in CHF patients and be avoided in those with refractory CHF, but that it may be beneficial in patients with recent infarction or multiple vascular risk factors.     

Events in the cardiac arrhythmia suppression trial: baseline predictors of mortality in placebo-treated patients

Patients randomized to placebo in the encainide and flecainide arms of the Cardiac Arrhythmia Suppression Trial (CAST) have been found to have a relatively low 1-year mortality rate of 3.9% in comparison with previous studies of patients in the postmyocardial infarction period. To determine the comparability of CAST with previous studies, baseline variables were examined in the 743 patients randomized to placebo in the flecainide and encainide arms of CAST. Twenty-three baseline characteristics were correlated with major outcome events: arrhythmic death (16 events), total mortality (26 events) and congestive heart failure (51 events). On multivariate analysis the risk of new or worsening congestive heart failure was significantly associated with diuretic use, diabetes, high New York Heart Association functional class, age, prolonged QRS duration and low ejection fraction. The risk of arrhythmic death or resuscitated cardiac arrest was significantly associated with an index Q wave myocardial infarction, history of heart failure, use of digitalis, diabetes and prolonged QRS duration. Total mortality or resuscitated cardiac arrest was significantly associated with an index Q wave myocardial infarction, diabetes, ST segment depression, high functional class, prolonged QRS duration and low ejection fraction. The variables at baseline associated with mortality from all causes or arrhythmic death or resuscitated cardiac arrest and heart failure in the CAST placebo-treated patients are similar to those identified in previous postmyocardial infarction studies. Thus, the observation of increased mortality in CAST associated with the administration of encainide and flecainide for suppression of ventricular premature depolarizations is probably applicable to any comparably defined group of patients in the postmyocardial infarction period.     

SGLT2 Inhibitors: Benefit/Risk Balance

Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycemia by increasing urinary glucose excretion. They have been evaluated in patients with type 2 diabetes treated with diet/exercise, metformin, dual oral therapy or insulin. Three agents are available in Europe and the USA (canagliflozin, dapagliflozin, empagliflozin) and others are commercialized in Japan or in clinical development. SGLT2 inhibitors reduce glycated hemoglobin, with a minimal risk of hypoglycemia. They exert favorable effects beyond glucose control with consistent body weight, blood pressure, and serum uric acid reductions. Empagliflozin showed remarkable reductions in cardiovascular/all-cause mortality and in hospitalization for heart failure in patients with previous cardiovascular disease. Positive renal outcomes were also shown with empagliflozin. Mostly reported adverse events are genital mycotic infections, while urinary tract infections and events linked to volume depletion are rather rare. Concern about a risk of ketoacidosis and bone fractures has been recently raised, which deserves caution and further evaluation.     

Glucagon-Like Peptide-1 and its Cardiovascular Effects

Recently, the crucial role of GLP-1 in cardiovascular disease has been suggested by both preclinical and clinical studies. In vivo and in vitro studies have demonstrated cardio-protective effects of GLP-1 by activating cell survival signal pathways, which have greatly reduced ischemia/reperfusion injury and also cardiac dysfunction in various congestive heart failure animal models. Clinically, beneficial effects of GLP-1 have been shown in patients with myocardial infarction, hypertension, and heart failure, and 2 classes of incretin enhancers, GLP-1 receptor agonists and DPP-4 inhibitors, are currently available for the treatment of type 2 diabetes mellitus. In this review, we will summarize the role of incretins in various cardiovascular events such as hypertension and heart failure and postprandial lipoprotein secretion, and discuss their molecular mechanisms and potentials as a new therapeutic as well as preventive drug type for reducing cardiovascular events in both diabetic and nondiabetic patients.     

Stage B: What is the Evidence for Treatment of Asymptomatic Left Ventricular Dysfunction?

Although patients with American College of Cardiology / American Heart Association (ACC/AHA) Stage B heart failure, or asymptomatic left ventricular dysfunction (ALVD) are at high risk for developing symptomatic heart failure, few manage-ment strategies have been shown to slow disease state progression or improve long-term morbidity and mortality. Of the pharmacologic therapies utilized in patients with symptomatic disease, only angiotensin converting enzyme (ACE) inhibitors (and to a lesser extent, angiotensin receptor blockers, or ARBs) have been shown to improve clinical outcomes among pa-tients with ALVD. Although evidence to support the use of beta blockers in this setting has been primarily derived from ret-rospective studies or subgroup analyses, they are generally recommended in most patients with ALVD, especially those with ischemic etiology. Statins are associated with improvements in both major adverse cardiovascular events and heart failure events among patients with a history of acute myocardial infarction. Finally, in eligible patients, placement of an automatic implantable cardioverter defibrillator (ICD) has been associated with reduced mortality rates among those with ALVD due to ischemic cardiomyopathy, and some subgroups may derive benefit from cardiac resynchronization therapy or biventricular pacing.     

Cardiovascular protection with sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: Does it apply to all patients?

Patients with type 2 diabetes (T2D) are at an increased risk of cardiovascular disease (CVD). Cardiovascular risk in these patients should be considered as a continuum, and comprehensive treatment strategies should aim to target multiple disease risk factors. Large-scale clinical trials of sodium-glucose co-transporter-2 (SGLT2) inhibitors have shown an impact on cardiovascular outcomes, including heart failure hospitalization and cardiovascular death, which appears to be independent of their glucose-lowering efficacy. Reductions in major cardiovascular events appear to be greatest in patients with established CVD, particularly those with prior myocardial infarction, but are independent of heart failure or renal risk. Most large-scale trials of SGLT2 inhibitors predominantly include patients with T2D with pre-existing CVD and high cardiovascular risk at baseline, limiting their applicability to patients typically observed in clinical practice. Real-world evidence from observational studies suggests that there might also be beneficial effects of SGLT2 inhibitors on heart failure hospitalization and all-cause mortality in various cohorts of lower risk patients. The most common adverse events reported in clinical and observational studies are genital infections; however, the overall risk of these events appears to be low and easily managed. Similar safety profiles have been reported for elderly and younger patients. There is still some debate regarding the safety of canagliflozin in patients at high risk of fracture and amputation. Outstanding questions include specific patterns of cardiovascular protection according to baseline risk.     

Anaemia in diabetes: an emerging complication of microvascular disease

Diabetes as the dominant cause of ESRD is also the major cause of renal anaemia. However, most patients with diabetic kidney disease will succumb to co-morbid vascular disease or heart failure before developing severe renal impairment. In these patients, anaemia is also common finding, with a 2-3 times greater prevalence and earlier onset than in patients with renal impairment from other causes. We have recently shown that at least one in five outpatients with type 1 or type 2 diabetes in tertiary referral clinics have anaemia, in whom it constitutes a significant additional burden. Impaired renal erythropoietin release in response to declining haemoglobin levels appears to be the major contributor to anaemia in diabetes. This may be due to the predominance of damage to cells and vascular architecture of the renal tubulointerstitium associated with diabetic nephropathy that may be apparent, like albuminuria, before demonstrable changes in renal function. In addition, systemic inflammation, autonomic neuropathy and reduce red cell survival may also compound anaemia in diabetes. While anaemia may be considered a marker of diabetic kidney disease, reduced haemoglobin levels, even within the normal range, identify diabetic patients with an increased risk of hospitalisation and mortality. Anaemia may also be significant in determining the outcome of heart failure and hypoxia-induced organ damage in patients with diabetes. Upcoming studies will determine whether correction of anaemia in diabetes will lead to improved outcomes in these patients.     

Advanced chronic kidney disease,cardiovascular events and the effect of diabetes: data from the Atherosclerosis and Folic Acid Supplementation Trial

Background: End‐stage kidney disease registry data have reported increased mortality in patients with diabetes as compared with those without. Here we examine whether diabetes is independently associated with an increased risk of major cardiovascular events and death in patients with advanced chronic kidney disease (CKD). Methods: Data from 315 participants with CKD in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) were assessed. Primary end‐points were fatal or non‐fatal cardiovascular events, including myocardial infarction, stroke, unstable angina, coronary revascularisation and peripheral vascular events assessed both jointly and separately using Cox‐proportional hazard models. Results: Twenty‐three per cent reported diabetes. Median follow up was 3.6 years. In those with diabetes, an increased risk for major cardiovascular events was observed, crude hazard ratio (HR) 2.87 (95% confidence interval (CI) 2.11–3.90). After adjustment for age, gender, smoking, systolic blood pressure, body mass index, past ischaemic heart disease and use of preventive therapies, diabetes was associated with an HR of 1.83 (1.28–2.61) for major cardiovascular events. The risk for peripheral vascular events was also increased, adjusted HR 6.31 (2.61–15.25). For all‐cause death, major coronary and stroke events, the risk in those with diabetes was not significantly increased (all‐cause death, adjusted HR 1.31 (95% CI 0.80–2.14); major coronary events, adjusted HR 1.26 (95% CI 0.64–2.49); and major stroke events, adjusted HR 1.28 (95% CI 0.55–2.99)). Conclusions: Diabetes significantly increases the risk of major cardiovascular events, especially peripheral vascular events in patients with advanced CKD. Trials of multifactorial management of cardiovascular risk factors are required to determine if outcomes for this population may be improved.     

Cardiovascular Risks of Anemia Correction with Erythrocyte Stimulating Agents: Should Blood Viscosity Be Monitored for Risk Assessment?

To date, all major clinical trials for anemia correction using erythrocyte stimulating agents (ESAs) failed to show improved outcomes for cardiovascular disease (CVD), stroke, and vascular thrombosis. Even moderate elevations in hemoglobin (e.g., to 13 g/dL) using erythropoietin have been associated with significantly increased risk of thrombotic cardiovascular events and heart failure. This review presents a biophysical rationale for increased risk of CVD among certain patients treated with ESAs and suggests a risk management approach based on blood viscosity. Whole blood viscosity is a key determinant of the work of the heart, and elevated blood viscosity appears to be both a strong predictor of cardiovascular disease and an important pathophysiological factor in the development of atherothrombosis. Blood donation has been shown to reduce viscosity. Reflecting these findings, studies in male blood donors and in women of premenopausal age with regular menstruation have shown reduced incidence of cardiovascular events such as myocardial infarction, angina, stroke, and the requirement for procedures such as percutaneous transluminal coronary angioplasty and coronary artery bypass graft compared with non-donors and postmenopausal women, respectively. We propose that blood viscosity monitoring should be considered as part of a cardiovascular risk assessment, whenever an increased cardiovascular risk is detected and particularly in the context of anemia correction.     

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in atherosclerosis

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) effectively interfere with the renin-angiotensin system and exert various beneficial actions on cardiac and vascular structure and function, beyond their blood pressure-lowering effects. Randomized, controlled clinical trials have shown that ACE inhibitors improve endothelial function, cardiac and vascular remodeling, retard the anatomic progression of atherosclerosis, and reduce the risk of myocardial infarction, stroke, and cardiovascular death. Therefore, these agents are recommended in the treatment of a wide range of patients at risk for adverse cardiovascular outcomes, including those with coronary disease, prior stroke, peripheral arterial disease, high-risk diabetes, hypertension, and heart failure. ARBs are effective blood pressure-lowering and renoprotective agents and can be used in heart failure in patients who do not tolerate ACE inhibitors. The role of ARBs in the prevention of atherosclerosis and its sequelae is currently under investigation. The use of combined ACE inhibitor plus ARB therapy offers theoretical advantages over the use of each of these agents alone and is also under investigation in large, randomized clinical trials.     

A Modern Perspective on β-Blocker Use in Hypertension: Clinical Trials and Their Influence on Clinical Practice

National guidelines recommend β-blockers as second step agents after diuretic therapy in patients without compelling indications despite little clinical trial evidence of cardiovascular outcome benefits in uncomplicated essential hypertension. In high-risk patients with hypertension, such as those with a previous myocardial infarction or diabetes, heart failure, or coronary artery disease, β-blockers have been shown to reduce the risk of cardiovascular mortality and to reduce events beyond those ascribed to blood pressure (BP) lowering. The use of a β-blocker-based regimen in patients with diabetes has been shown to reduce cardiovascular mortality, progression of diabetic nephropathy, and stroke. Lowering BP in hypertensive patients is a primary goal, but it is also essential that goal BP be achieved with the fewest adverse consequences (ie, by choosing agents that do not worsen concomitant conditions or cause unacceptable side effects). Physicians must consider issues of possible worsening insulin resistance and dyslipidemia associated with some β-blockers. These metabolic concerns, however, are not an issue for the combined β-/αblocker carvedilol. This review highlights historical data and important clinical trials that underscore the importance of β-blockade in specific patients and delineates situations where β-blockers benefit patients with hypertension and/or cardiovascular disease.