Sacubitril increases the concentrations of these peptides by inhibiting neprilysin, and peptides antagonize the opposite action of neurohormonal overactivation [ ]. Experimental studies have suggested that simultaneous inhibition of the renin-angiotensin system and neprilysin can more effectively decrease neurohormonal activation, which aggravates HF.
While there have been steady developments regarding pharmacological treatment for use in patients with HFrEF, no drugs have shown clear mortality benefits in patients with HFpEF. At present, drug therapy in HFpEF is focused on controlling symptoms and treating risk factors and comorbidities [ 12 ]. The SGLT-2 inhibitors represent a novel class of antihyperglycemic agents that increase urinary excretion of glucose in the renal tubules [ ]. Empagliflozin reduced HF hospitalization and cardiovascular death in patients with type 2 diabetes, with a consistent benefit in patients with HF.
The serious adverse event rate of empagliflozin was similar, but the rate of genital infection was higher than placebo [ 63 ]. Canagliflozin also reduced the risk of cardiovascular death and hospitalization due to HF in patients with type 2 diabetes and elevated risk of cardiovascular disease Canagliflozin Cardiovascular Assessment Study [CANVAS] trial. However, administration of canagliflozin increased the incidence of volume depletion, fracture, and amputation compared with placebo [ 65 ]. SGLT-2 inhibitors induce glycosuria and diuresis, which can be expected to reduce blood pressure, improve glycemic control, result in weight loss, and improve insulin sensitivity [ ].
In addition, it has been reported that SGLT-2 inhibitors have cardioprotective effects by improving cardiac metabolism. A study in a murine model showed that empagliflozin increases cardiac adenosine triphosphate ATP production by activating cardiac oxidation of glucose and fatty acids [ ], although the precise underlying mechanism is not fully understood yet. Large-scale cardiovascular outcome studies using other SGLT-2 inhibitors are underway [ ], and a multinational observational study, including South Korea, is currently in progress [ , ].
Moreover, the benefit of SGLT-2 inhibitors may persist regardless of the presence of diabetes. Empagliflozin significantly reduced the rate of cardiac deterioration in HF without diabetes in a murine model [ ]. Liraglutide, a glucagon-like peptide 1 analog, showed decreased all-cause mortality and cardiovascular death compared with placebo in a large-scale RCT [ 64 ].
As the U. Food and Drug Administration requires cardiovascular safety data for any new antidiabetic medications before approval, novel antidiabetic medications with additional cardiovascular benefits are likely to be developed in the future as well. New drugs that act on cardiac myosin have been developed and tested for efficacy in specific diseases.
Mavacamten, which acts as an inhibitor of cardiac myosin ATPase and reduces cardiac contractility, is under investigation in patients with obstructive HCM [ ]. In a pilot study performed in 11 patients with symptomatic obstructive HCM, significant decreases in both post-exercise peak and resting LV outflow tract gradient were observed in patients with mavacamten treatment [ ]. In contrast to mavacamten, omecamtiv mecarbil OM is a selective cardiac myosin activator that increases myocardial systolic function.
Fibrillogenesis in amyloid cardiomyopathy occurs when the tetrameric structure of the transthyretin protein dissociates into intermediates, which misassemble into amyloid fibrils. Tafamidis binds to the thyroxine-binding sites of transthyretin with high affinity and selectivity, and inhibits dissociation of tetramers into monomers.
In this multicenter, double-blind RCT, tafamidis showed reductions in all-cause mortality and cardiovascular-related hospitalization rates and reduced the decline in functional capacity compared with placebo [ 68 ]. Various cytokines have been shown to play important roles in determining cardiac function under pathophysiological conditions. There have been many clinical trials to improve cardiac pathology by blocking these cytokines, but most have failed to demonstrate clinical efficacy [ ].
However, because canakinumab caused serious infectious complications, the all-cause mortality rate was not different from the placebo group Canakinumab Anti-inflammatory Thrombosis Outcome Study [CANTOS] trial [ 66 ]. The IL-1 receptor antagonist, anakinra, is another potential candidate for anti-inflammatory therapy. Cardiac gene therapy, involving the production of proteins with curative efficacy by transferring specific exogenous genes, was proposed as an important alternative therapeutic approach [ ].
Despite disappointing results, gene therapy still has potential and further studies are required. One of the major obstacles to gene therapy is the delivery method of the therapeutic materials into the target cells. As intravenous injection did not show sufficient effect to transduce the myocardium, intracoronary injection, myocardial injection, and pericardial injection have been suggested according to the condition of the patient, the type of vector, and the target gene.
Further advances in vectors and delivery methods will be essential for the clinical application of gene therapy [ ]. As there is no alternative way to regenerate or replace damaged cardiomyocytes, there has been a great deal of interest in the development of stem cell therapy [ ]. Numerous studies yielded optimistic results using stem cells to improve myocardial function and ventricular remodeling, but the results were inconsistent [ ]. Human pluripotent stem cells hPSCs have emerged to replace embryonic stem cells, which maintain the similarity to embryonic stem cells but without the ethical issues or risks of rejection [ ].
The efficiency of differentiation from hPSCs to cardiomyocytes and bioengineering technology to improve the therapeutic effects of hPSC-derived cardiomyocytes have improved over the past several decades. However, cellular heterogeneity, immaturity, arrhythmogenicity, and tumorigenicity are problems that remain to be resolved [ ].
Many pioneering landmark trials from the s have confirmed the efficacy of implantable cardioverter-defibrillator ICD and cardiac resynchronization therapy CRT for improving cardiovascular outcome in HF patients Table 1 , Fig. The detailed indications are slightly different according to the specific cardiomyopathy in patients Table 2 [ 1 , , ]. However, as more than half of the patients received optimal medical therapy and CRT in both groups, this may have influenced the lack of significant results associated with prophylactic ICD.
Therefore, the role of prophylactic ICD implantation to reduce mortality in HF patients may be reestablished with the further development of HF therapy. Current class I indications of cardiac implantable electronic devices in patients with heart failure. In Korea, there has been a rapid increase in the implantation of cardiac implantable electronic devices Fig.
Temporal trends of cardiac implantable electronic device implantation in Korea. Recent studies have focused on determining ways to achieve a high response rate in patients with CRT implants. The targeted LV lead placement group showed a higher portion of CRT responders and lower rate of combined endpoint compared with the control group [ ].
The combination of multimodality imaging, including nuclear imaging and radial strain, demonstrated a higher response rate compared with the control group, but the clinical outcomes were similar between the two groups [ ]. AF is the most common type of arrhythmia in HF populations, and it can cause deterioration of LV function as well as symptoms of HF [ ].
Rate control and anticoagulation are the mainstays of AF treatment. In this RCT, patients who received AF ablation therapy showed lower rates of all-cause mortality, worsening or hospitalization for HF, and cardiovascular death after about 3 years [ ]. The composite primary endpoints consisting of death, disabling stroke, serious bleeding, or cardiac arrest at 5 years were similar between ablation and drug therapy groups hazard ratio, 0. If a patient has HF and symptomatic AF but is not a candidate for AF ablation or has failed to respond to this treatment, atrioventricular junction ablation followed by CRT may be a useful treatment option.
Remote monitoring has become one of the most active fields in the management of HF. Due to the importance of volume status in HF patients, there have been efforts to estimate and use hemodynamics as a guide for treatment. Jude Medical, St. Large amounts of information are available from patients with a preexisting cardiac implantable electronic device, including heart rate, lead profile, battery status and arrhythmic events.
However, a meta-analysis including nine RCTs of remote monitoring showed no additional benefit with regard to survival or patient safety [ ]. The diagnostics included in implantable devices show good predictive capability for impending HF decompensation using device-specific algorithms, such as OptiVol Medtronic, Minneapolis, MN, USA [ ]. As methodologies for remote monitoring using implantable devices can be extended, we expect better results in the near future.
Functional or secondary mitral regurgitation MR , frequently accompanied by HFrEF, is a meaningful predictor of mortality after adjusting for clinical, echocardiographic, or laboratory variables [ ]. However, surgical treatment of moderate ischemic MR in addition to coronary artery bypass surgery failed to show LV reverse remodeling and mortality improvement [ ].
As the benefit of surgery for functional MR is questionable, the American guidelines for valvular heart disease published in recommended mitral valve surgery for secondary MR only in patients with symptomatic severe MR or moderate MR undergoing other cardiac surgery [ ]. Percutaneous approaches to correct secondary MR in HF patients are actively studied because the devices for percutaneous treatment of MR have been advanced throughout repair, annuloplasty, and replacement of the mitral valve [ ], and the surgical risk of HFrEF combined with MR is high.
On the other hand, in the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation COAPT trial performed in symptomatic patients with HF and moderate-to-severe secondary MR despite maximal medical therapy, the addition of percutaneous mitral repair with MitraClip to medical therapy was associated with lower rates of HF hospitalization and all-cause mortality than medical therapy alone within 2 years of follow-up [ ].
Other percutaneous approaches to improve the outcomes of functional MR are also under investigation. The outcomes with the Cardioband system, a device for percutaneous mitral annuloplasty, were reported recently. Most patients showed moderate or less residual MR and improved symptoms at 1 year [ ]. Various devices for percutaneous mitral valve replacement are also under investigation but are still at the level of early feasibility studies at present [ , ].
Several forward-looking device therapies are under development. The device significantly reduced post-exercise pulmonary capillary wedge pressure at 1 month [ ] and showed similar safety outcome at 1 year [ ]. As autonomic imbalance is important in the pathophysiology of HF, vagus nerve stimulation is thought to be a potential treatment target [ ]. Although renal denervation has been suggested as an alternative treatment option for resistant hypertension, the results of RCTs were disappointing [ , ].
However, another RCT indicated the possibility of revival. As hypertension is one of the most important etiologies of HF, renal denervation may be a promising technology if these trials succeed. These devices were initially used as a bridge to transplantation, but are now also commonly used as destination therapy. Advances in mechanical technology and surgical techniques have greatly increased the success rate and duration of ventricular assist devices. This device is highly miniaturized to facilitate minimally invasive surgery and reduce surgical complications [ ].
HVAD showed good clinical outcome and safety in the real-world registry data. Vigorous anticoagulation therapy and adequate blood pressure control play important roles in reducing the incidence of stroke [ ]. There have also been improvements in minimally invasive techniques to reduce surgical complications Fig. Adverse events of left ventricular assist devices. The data of HeartWare ventricular assist device HVAD and Heartmate 3 HM 3 were quoted from different clinical trials, so direct comparison of adverse event rates is inappropriate.
GI, gastrointestinal. Heartmate II, another LVAD, also showed acceptable clinical outcomes and safety for destination therapy [ 84 ] as well as use as a bridge to transplantation [ 83 ]. The newly developed Heartmate 3 is equipped with a fully magnetically levitated centrifugal flow pump, and showed a survival rate of This is an improvement compared with Although the survival rate is improving, many patients with Heartmate 3 implants still experience a range of complications, including bleeding, infection, stroke, right HF, and arrhythmias Fig.
Food and Drug Administration, provides the most definitive treatment options for patients with biventricular failure who are not candidates for isolated LVAD placement [ ]. The SynCardia system has recently developed a smaller 50 cc TAH that was designed to accommodate patients with low body surface area.
This technical improvement should allow the device to be implanted in women and children, and it might be particularly useful in growing adolescents with palliated congenital heart disease [ ]. Heart transplantation HT has become the standard treatment for selected patients with end-stage HF. Improvements in immunosuppressants, donor procurement, surgical techniques, and post-HT care have resulted in a substantial decrease in the incidence of acute allograft rejection, which had previously significantly limited survival of HT recipients.
However, there are limitations to long-term allograft survival, including rejection, infection, coronary allograft vasculopathy, and malignancy Fig. Careful balance of immunosuppressive therapy and vigilant surveillance for complications can further improve long-term outcomes of HT recipients. Most transplant recipients have been treated with a combination of a calcineurin inhibitor, mycophenolate mofetil, and steroids [ ]. To monitor the effects of immunosuppressive drugs and adjust the dose, physicians check the serum concentration of immunosuppressant.
However, the serum concentration does not accurately reflect the degree of immunosuppression in a specific patient. Immune monitoring assay Immuknow, Cylex, Columbia, MD, USA , a peripheral blood test, helps physicians to determine the degree of immunosuppression in patients by measuring the amount of ATP released from activated lymphocytes [ ]. In a study to determine the efficacy of immune monitoring assay, patients with infectious complications had a low immune monitoring score, and some patients with rejection had a high score [ ]. Further large-scale studies with more sophisticated measurements of immune monitoring methods are needed to achieve personalized immunosuppression.
Adverse events of heart transplantation: within 1 year and after 5 years. The dd-cfDNA is detectable in both blood and urine of transplant recipients. When a rejection event occurs, dd-cfDNA could increase up to 5-fold from the baseline value in the blood [ ]. The dd-cfDNA is a potential candidate as a noninvasive tool for diagnosis of graft rejection, as the degree of dd-cfDNA elevation has been shown to be correlated with acute cellular rejection events, as determined by endomyocardial biopsy in early studies [ ].
As the number of the donors is very small compared to patients requiring HT, there have been continuing efforts to expand the donor pool. To maximize the number of patients receiving HT, some transplantation centers now use extended criteria donor ECD hearts in high-risk recipients, and the outcomes seem to be acceptable.
The ECD program has had little impact on the outcome of transplanted patients and seems to accomplish the purpose of expanding the donor pool [ ]. The concept of donation after circulatory death DCD was introduced as part of the efforts to expand the donor pool. To minimize the damage due to ischemic time in DCD organs, trials to utilize ex vivo perfusion systems were performed.
The ex vivo heart perfusion system maintains the heart in a beating and metabolically active state by supplying warm, oxygenated, and nutrient-enriched donor blood. Recently, ex vivo perfusion systems have been reported to show non-inferiority with regard to outcome compared with standard cold storage methods, and further trials are currently underway [ 89 ]. It is a life-threatening medical condition requiring urgent evaluation and treatment, typically leading to urgent hospital admission [ 1 ].
The outcome of hospitalized HF patients in Korea has shown a modest improving trend over time, although treatment of AHF has not changed for several decades [ 3 ]. Clinical characteristics and outcomes of AHF registry according to different countries are summarized in Table 3 [ 46 , - ].
Many novel drugs have shown no clinical improvement [ 1 ]. This is because AHF syndrome is an event in the context of underlying HF, and not a disease entity per se [ ]. Notably, the mid- or long-term outcome of AHF may not depend on treatment at the acute stage, but on the underlying disease status causing decompensation [ 46 , ].
In addition, the classification of AHF is not clear [ - ]. Inadequate phenotyping is also responsible for the failure of treatments to improve outcomes in AHF. In this section, we focus on new treatment strategies and the attempt to reduce readmission to hospital Table 4. Diuretics are the mainstay of pharmacological treatment in AHF to improve symptoms [ ]. Recently, the time-to-diuretics concept was proposed for AHF. In contrast, another observational study failed to show any associations between clinical outcomes and short door-to-diuretics time [ ].
Newly developed intravenous vasodilators failed to improve outcomes in AHF. Serelaxin, i. The inodilator, levosimendan, was associated with reduction of short- and long-term mortality rates compared with placebo in LV dysfunction patients with acute MI [ ]. However, there was no mortality benefit of levosimendan in comparison with dobutamine [ ]. The initiation of sacubitril- valsartan therapy led to a greater reduction of NT-proBNP concentration than enalapril therapy, with no significant difference in rate of adverse events, such as deteriorating renal function, hypotension, hyperkalemia, and angioedema [ ].
As outlined above, the treatment strategy for AHF has not changed markedly over the last several years. To reduce the healthcare costs associated with AHF, the hospital readmission reduction program was introduced in the USA, which awarded a penalty to hospitals with high day readmission rates.
However, the results have been disappointing. The day and 1-year readmission rates decreased, while the mortality rate tended to increase [ ]. In addition, the quality of care and clinical outcome were similar between hospitals with high and low risk-adjusted day HF readmission rates [ ], and the mortality rate was lower in the higher hospital-level day episode payment [ ]. It is possible that some hospitals attempted to improve the index rather than the true outcome by adopting methods, such as increased admission period, delaying readmission after 30 days, etc.
Remote monitoring mentioned in the previous section can be utilized for the early detection of deterioration and the prevention of readmission in AHF patients. Digital healthcare has received much attention recently. As the amounts of information from diverse sources, such as electronic medical records, wearable devices, and genomic data, are increasing rapidly, artificial intelligence and machine learning are essential to collect, manage, and apply these data appropriately [ ]. Ahmad et al. The use of artificial intelligence and clinical decision support systems is not suitable for clinical application.
However, it may help physicians to make decisions by organizing large amounts of data and building delicate prognostic models in the near future. HF is becoming an increasingly important disease entity with the aging of society. According to its increasing prevalence, many new drugs and devices have been studied to improve clinical outcome in terms of mortality and quality of life in HF patients.
New Drugs for the Treatment of Heart Failure
Although few studies showed encouraging results, researchers are attempting to find subgroups in whom certain medications or devices could be most effective, new methods for better diagnosis and prediction of prognosis in HF patients, and new tools for treating HF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No potential conflict of interest relevant to this article was reported. National Center for Biotechnology Information , U. Korean J Intern Med. Published online Dec Author information Article notes Copyright and License information Disclaimer.
Received Nov 28; Accepted Dec 9. This article has been corrected. See Korean J Intern Med. This article has been cited by other articles in PMC. Abstract Heart failure HF is an important cardiovascular disease because of its increasing prevalence, significant morbidity, high mortality, and rapidly expanding health care cost. Keywords: Heart failure, Diagnosis, Management, Prognosis. Open in a separate window. Figure 1. Figure 2. Diagnosis In the initial evaluation of HF, it is necessary to examine natriuretic peptides NPs and to perform echocardiography [ 1 ].
Right ventricular strain The RV has a complex structure that causes difficulty in the estimation of systolic function. Novel biomarkers and genetic testing Biomarkers As there is a considerable body of evidence for NP biomarkers, they have already been incorporated into the American expert consensus for HF [ 33 ]. Genetic testing Inherited cardiomyopathies account for a small portion of HF cases. Figure 3. Table 1. Landmark pharmacological and non-pharmacological studies of heart failure.
Emerging pharmacological treatment SGLT-2 inhibitor and glucagon-like peptide 1 agonist The SGLT-2 inhibitors represent a novel class of antihyperglycemic agents that increase urinary excretion of glucose in the renal tubules [ ]. New drugs in specific cardiomyopathy fields New drugs that act on cardiac myosin have been developed and tested for efficacy in specific diseases. Anti-inflammatory therapy Various cytokines have been shown to play important roles in determining cardiac function under pathophysiological conditions.
Gene therapy Cardiac gene therapy, involving the production of proteins with curative efficacy by transferring specific exogenous genes, was proposed as an important alternative therapeutic approach [ ]. Stem cell therapy As there is no alternative way to regenerate or replace damaged cardiomyocytes, there has been a great deal of interest in the development of stem cell therapy [ ].
Table 2. Figure 4. Remote monitoring Remote monitoring has become one of the most active fields in the management of HF. Percutaneous correction of functional mitral regurgitation Functional or secondary mitral regurgitation MR , frequently accompanied by HFrEF, is a meaningful predictor of mortality after adjusting for clinical, echocardiographic, or laboratory variables [ ].
Other interventions: inter-atrial shunting, vagus nerve stimulation, and others Several forward-looking device therapies are under development. Figure 5. Heart transplantation Heart transplantation HT has become the standard treatment for selected patients with end-stage HF. Figure 6. Expanding the donor pool As the number of the donors is very small compared to patients requiring HT, there have been continuing efforts to expand the donor pool.
Table 3. Clinical characteristics and outcomes of acute heart failure registry. Table 4. Recent evidence regarding mortality in treatment of acute heart failure. Topic Study Year Author No. KorAHF Park et al. Footnotes No potential conflict of interest relevant to this article was reported. Eur Heart J. Korean guidelines for diagnosis and management of chronic heart failure. Korean Circ J. Temporal trends of hospitalized patients with heart failure in Korea.
Epidemiology, pathophysiology and clinical outcomes for heart failure patients with a mid-range ejection fraction. Eur J Heart Fail. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. Epidemiology of heart failure in Korea: present and future. The diagnostic accuracy of the natriuretic peptides in heart failure: systematic review and diagnostic meta-analysis in the acute care setting.
A randomized trial of intensive versus standard blood-pressure control. The association of left ventricular ejection fraction, mortality, and cause of death in stable outpatients with heart failure. J Am Coll Cardiol. Zakeri R, Cowie MR. Heart failure with preserved ejection fraction: controversies, challenges and future directions. Potter E, Marwick TH. Assessment of left ventricular function by echocardiography: the case for routinely adding global longitudinal strain to ejection fraction. Global longitudinal strain to predict mortality in patients with acute heart failure.
Prediction of all-cause mortality and heart failure admissions from global left ventricular longitudinal strain in patients with acute myocardial infarction and preserved left ventricular ejection fraction. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
J Am Soc Echocardiogr. Greyson CR. Pathophysiology of right ventricular failure.
Crit Care Med. Right ventricular systolic function in heart failure: a long story but still the same question. Arch Cardiovasc Dis. Right ventricular strain in heart failure: clinical perspective. Right ventricular longitudinal strain measures independently predict chronic heart failure mortality. Prognostic value of biventricular strain in risk stratifying in patients with acute heart failure.
J Am Heart Assoc. State of the art: clinical applications of cardiac T1 mapping. Cardiac magnetic resonance postcontrast T1 time is associated with outcome in patients with heart failure and preserved ejection fraction. Circ Cardiovasc Imaging. Contrast-enhanced T1 mapping-based extracellular volume fraction independently predicts clinical outcome in patients with non-ischemic dilated cardiomyopathy: a prospective cohort study. Eur Radiol. Native T1 mapping in differentiation of normal myocardium from diffuse disease in hypertrophic and dilated cardiomyopathy.
T1-mapping and outcome in nonischemic cardiomyopathy: allcause mortality and heart failure. Myocardial extracellular volume fraction with dual-energy equilibrium contrast-enhanced cardiac CT in nonischemic cardiomyopathy: a prospective comparison with cardiac MR imaging. Assessment of myocardial delayed enhancement with cardiac computed tomography in cardiomyopathies: a prospective comparison with delayed enhancement cardiac magnetic resonance imaging.
Int J Cardiovasc Imaging. Utility of dual-energy CTbased monochromatic imaging in the assessment of myocardial delayed enhancement in patients with cardiomyopathy. Dual-energy CT of the heart. Incremental value of biomarkers to clinical variables for mortality prediction in acutely decompensated heart failure: the Multinational Observational Cohort on Acute Heart Failure MOCA study. Int J Cardiol. Heart failure therapy-induced early ST2 changes may offer longterm therapy guidance.
J Card Fail. Soluble ST2 serum concentration and renal function in heart failure. Role of soluble ST2 as a prognostic marker in patients with acute heart failure and renal insufficiency. J Korean Med Sci. Galectin-3 in heart failure: an update of the last 3 years. Heart Fail Clin. Braunwald E. Biomarkers in heart failure.
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The incremental prognostic and clinical value of multiple novel biomarkers in heart failure. Januzzi JL, Troughton R. Are serial BNP measurements useful in heart failure management? Serial natriuretic peptide measurements are useful in heart failure management. Natriuretic peptide-guided therapy in chronic heart failure: a meta-analysis of 2, patients in 12 randomized trials. PLoS One. Effect of natriuretic peptide-guided therapy on hospitalization or cardiovascular mortality in high-risk patients with heart failure and reduced ejection fraction: a randomized clinical trial.
Use of guideline-directed medications for heart failure before cardioverter-defibrillator implantation. Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document. Orphanet J Rare Dis. Judge DP. Use of genetics in the clinical evaluation of cardiomyopathy. Genetics and heart failure: a concise guide for the clinician. Curr Cardiol Rev. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study.
Angiotensin-neprilysin inhibition versus enalapril in heart failure. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. Carvedilol Heart Failure Study Group. The effect of spironolactone on morbidity and mortality in patients with severe heart failure.
Randomized Aldactone Evaluation Study Investigators. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial.
Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. Liraglutide and cardiovascular outcomes in type 2 diabetes. Canagliflozin and cardiovascular and renal events in type 2 diabetes. Antiinflammatory therapy with canakinumab for atherosclerotic disease. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.
Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction.
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Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. Defibrillator implantation in patients with nonischemic systolic heart failure.
Wearable cardioverter-defibrillator after myocardial infarction. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. The effect of cardiac resynchronization on morbidity and mortality in heart failure. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms.
Cardiac-resynchronization therapy for the prevention of heart-failure events. Cardiac-resynchronization therapy for mild-to-moderate heart failure. Bisoprolol, carvedilol, and metoprolol have been shown to reduce the risk for death and improve symptoms, clinical status, and quality of life in patients with chronic heart failure with or without CAD , , Evidence supports the cardiovascular protective effects of ACE inhibitors and their role in reducing the risks for future ischemic events, such as acute MI and unstable angina , , Although the available ACE inhibitors differ with respect to structure, bioavailability, potency, receptor-binding characteristics, tissue distribution, metabolism, and excretion properties, there is little evidence that these differences are associated with therapeutic advantages.
Because the benefits of ACE inhibitors appear to reflect a class effect, the selection of a particular agent should be based on such factors as availability in local formularies, cost, and tolerability. Angiotensin-receptor blockers also play an important role in vascular protection by decreasing blood pressure and reducing LV mass, stroke incidence, and improving outcomes in heart failure , , — Influenza is associated with increased mortality and hospitalizations in patients with cardiovascular disease.
All 3 classes of calcium-channel blockers improve myocardial oxygen supply and are effective in several angina presentations — The choice between various calcium-channel blockers depends on individual characteristics of patients, potential drug interactions, and adverse events. Overall, calcium-channel blockers are well-tolerated and adverse effects are generally related to systemic hypotension. Diltiazem is usually the best tolerated of the 3 classes dihydropyridines, phenylalkylamines, and benzothiazepines. Calcium-channel blockers should be used with caution in patients who are taking cyclosporine, carbamazepine, lithium carbonate, amiodarone, or digoxin because of potential drug interactions.
Nitrates are effective in the treatment of all forms of angina and exert their effects through vasodilatation , contributing to coronary blood flow redistribution , and antithrombotic and antiplatelet effects , Long-term nitrate therapy in patients with stable IHD results in improvement in anginal tolerance. All patients should be prescribed sublingual nitroglycerin tablets or nitroglycerin spray for immediate relief of angina.
Most patients respond within 5 minutes of taking 1 to 2 sublingual dose or doses of 0. If additional doses are necessary, they should be taken at 5-minute intervals, but no more than 1. These products are also effective for prevention of effort-induced angina when administered 5 to 10 minutes before the angina-inducing action, with relief lasting approximately 30 to 40 minutes The most common side effects are headache, flushing, and hypotension.
All short-acting nitrate preparations may result in hypotension, sometimes severe, and headaches that limit continued patient adherence with these agents. Nitrates are relatively well-tolerated if a titration schedule is used at initiation and with discontinuation. Ranolazine inhibits the late inward sodium current, indirectly reducing the sodium-dependent calcium current during ischemic conditions, and leading to improvement in ventricular diastolic tension and oxygen consumption.
The extended-release preparation reduces the frequency of angina, improves exercise performance, and delays the development of exercise-induced angina and ST-segment depression — Among patients with acute coronary syndromes, ranolazine did not reduce the incidence of MI or death Ranolazine is contraindicated in combination with potent inhibitors of the CYP3A4 pathway, including ketoconazole 3.
The major adverse effects are constipation, nausea, dizziness, and headache. Revascularization by coronary artery bypass grafting CABG or percutaneous coronary intervention PCI is performed to improve survival, symptoms, or both. The decision to perform revascularization should be undertaken in consultation with a multidisciplinary heart team, including an interventional cardiologist and a cardiac surgeon. This team reviews relevant clinical data, determines whether revascularization using PCI or CABG is technically feasible and reasonable, and helps the patient select among available options — Studies performed over the past 3 decades have established that in a select subgroup of patients, patients who have undergone CABG have lower mortality than patients treated medically.
Because surgical techniques and the effectiveness of medical therapy have both improved over time, however, it is not entirely clear that the earliest studies remain fully applicable. In general, the anatomical or clinical features that are associated with substantial ischemia and the extent of ischemia on noninvasive testing are predictors for subsequent adverse outcomes.
In the most contemporary studies, however, no significant overall improvement in survival has been observed between patients randomly assigned to revascularization and those assigned to GDMT, even among patients who might be regarded as high risk. In patients with stable IHD who do not meet these criteria, there is only limited evidence, derived from observational studies, that revascularization influences survival.
As opposed to patients with acute coronary syndromes, there is no compelling evidence that PCI improves survival for any group of patients with stable IHD. Moreover, PCI may increase the short-term risk for MI 28, — but does not decrease the long-term risk 28, , , , , Even in patients who are unlikely to experience improvement in survival, revascularization is often performed to relieve anginal symptoms. In general, however, an adequate trial of GDMT should be undertaken before revascularization is contemplated.
The COURAGE Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation trial demonstrated that this strategy is effective in the majority of patients with anginal symptoms, including those with considerable ischemia on noninvasive testing. Such patients can be evaluated for revascularization of significant lesions if GDMT is ineffective, poorly tolerated, or contraindicated, and deferring revascularization in this fashion was not associated with any detectable increase in mortality.
These latter lesions require additional evidence of physiologic significance, from either stress testing or intracoronary flow testing such as fractional flow reserve , to establish their clinical significance — Clinical correlation between the patient's symptoms, stress test results, and coronary anatomy is essential. In general, the greater the extent and severity of ischemia on noninvasive stress testing, the greater the benefit to be derived from revascularization compared with medical therapy , — Naturally, patient preferences play an important role in determining the preferred course of therapy, particular in deciding whether to consider revascularization.
To effectively participate in decision making, patients must be furnished with accurate information about the relative risks, benefits, and costs of all therapeutic options. When revascularization is the preferred strategy, the choice between CABG and PCI should be based on a variety of factors, including coronary anatomy, coexisting medical conditions, local expertise, likelihood of achieving complete revascularization, and patient preferences.
Procedural strokes were more common after CABG 1. Repeat coronary revascularization was less frequent at 1 year after CABG 3. See Figure 2 in the Executive Summary for an algorithm on revascularization to improve survival of patients with stable IHD and Figure 3 in the Executive Summary for an algorithm on revascularization to improve symptoms of patients with stable IHD. Although differences exist in incidence of disease and approaches to diagnosis, the general approach in this guideline would be to apply the recommendations consistently among groups.
Women generally have a lower incidence of IHD than men until older age. In younger women, microvascular disease is more common, and obstructive epicardial CAD is less prevalent. Stable angina is the most frequent initial manifestation of IHD in women, as opposed to acute MI and sudden death in men , Atypical chest pain and anginal equivalent symptoms, such as dyspnea, are more common in women, although women still present with similar patterns, duration, and frequency of symptoms. Contrary to earlier perceptions, the prognosis of women with chest pain and nonobstructive disease is not necessarily better , , and their outcomes after an MI are worse — The lower prevalence of obstructive disease in conjunction with technical challenges makes the interpretation of ischemia on imaging studies somewhat more difficult.
Younger women have higher false-positive rates on stress testing and nuclear imaging studies, which may be due, in part, to attenuation from breast tissue. This trend may have improved in recent years and after accounting for the higher incidence of diabetes and hypertension in women The risk for procedural complications also appears to be significantly higher in women On the basis of these observations, the initial approach to therapy for women with stable IHD should be to prescribe a full regimen of GDMT and to consider revascularization only for patients who do not obtain a satisfactory response or who experience unacceptable adverse effects.
On the basis of the higher risk associated with PCI in women, it may be reasonable to adopt an even more conservative approach to this procedure than in men. Common coexisting conditions of pulmonary, gastrointestinal, and musculoskeletal systems can cause chest pain, making diagnosis more difficult, even in patients with documented IHD. Physiologic changes in older adults, including alterations in cardiac output through various mechanisms, muscle loss and deconditioning, neuropathies, lung disease, and degenerative joint disease, make stress testing more difficult.
The higher prevalence of stable IHD disease in older adults leads to more false-negative test results. Although the prognostic value of the Duke treadmill score in older adults may be limited , exercise stress testing still provides good information for management For patients who are unable to exercise, pharmacologic stress imaging is indicated and yields a similar degree of accuracy compared with testing in younger individuals who present with suspicion for IHD — Despite the complexities and concerns related to evaluating and treating elderly patients with stable IHD, findings from the COURAGE and TIME Trial of Invasive versus Medical therapy in Elderly patients trials indicated that initial therapy with medical therapy was not significantly less effective than medical therapy plus PCI in relieving angina during a month period.
Current status of heart failure in China Cui X, Hu K, Ge J - Cardiol Plus
Moreover, considerable evidence indicates that elderly patients have 2- to 7-fold higher odds of mortality after PCI and CABG than do younger patients and that the risk appears to increase monotonically after age 65 years , —, — It is recommended that management using GDMT be the initial approach in most elderly patients. Given concerns about higher mortality, particularly in patients older than 75 or 80 years, decisions to recommend revascularization should be undertaken only after careful consideration of patient preferences, functional capacity, quality of life, and end-of-life issues Diabetes types 1 and 2 is an important risk factor for stable IHD.
Cardiovascular mortality is 3-fold higher in diabetic men and between 2- and 5-fold higher in diabetic women compared with patients without diabetes , Achievement and maintenance of optimal glycemic control and lipid management, along with careful attention to other risk factors such as hypertension, smoking, and obesity are paramount. For patients whose symptoms are inadequately managed or who experience intolerable adverse effects, revascularization should be considered. For diabetic patients with extensive coronary disease and active ischemia, early revascularization may be preferable and should be considered.
Coronary artery bypass grafting may be associated with lower mortality in diabetic patients with multivessel disease than PCI, but this remains uncertain Chronic kidney disease is associated with greater risk for developing stable IHD, for its progression, and for worse outcomes — Physicians should consider creatinine clearance in pharmacotherapy and risk scores for prediction of contrast-induced nephropathy in addition to the use of renal protective strategies to avoid complications related to chronic kidney disease Obese individuals may have limited physical capacity, exaggerated dyspnea on exertion, and excessive breast tissue that impairs imaging, and their weight may exceed the limits of diagnostic equipment — Enhancements to single-photon emission computed tomography, including prone imaging, and use of intravenous contrast with stress echocardiography may improve accuracy — HIV infection and treatment appear to be associated with an increased risk for premature coronary and cerebrovascular atherosclerosis , Acute MI is often the initial manifestation The cause is probably multifactorial and related to both the underlying infection and antiretroviral therapy.
The protease inhibitors amprenavir—fosamprenavir with or without ritonavir and lopinavir with ritonavir have the strongest association with risk for acute MI, whereas saquinavir may not be associated Indinavir, lopinavir—ritonavir, didanosine, and abacavir were associated with increased risk for MI Other agents, such as nonnucleoside reverse transcriptase inhibitors, entry inhibitors, and integrase inhibitors, do not appear to be associated with an increase in risk for IHD.
Despite the increase in prevalence of IHD among patients with HIV, the absolute increase in incidence of acute MI is relatively low, and overall mortality does not appear to be increased , It is likely that this reflects the otherwise enormous benefit conferred by treatment with antiretroviral therapy in the course of HIV infection. Nonetheless, patients receiving antiretroviral therapy should be assessed for cardiovascular risk factors and monitored for signs and symptoms of IHD. It is prudent to recommend a healthy diet, regular physical activity, and avoidance of smoking.
Patients with hypercholesterolemia should be managed in a fashion similar to that used for other patients at risk for IHD Rheumatoid arthritis has been shown to increase inflammation of coronary artery walls and increase frequency of vulnerable plaques The adjusted rate of stable IHD in systemic lupus erythematosus is at least fold higher than in patients without it.
Low socioeconomic status is highly associated with the risk for developing and dying of cardiovascular disease , Moreover, members of an ethnic minority in particular African Americans and Hispanics are less likely to receive a wide variety of diagnostic and therapeutic interventions, including preventive medications, cardiac procedures, and access to cardiologists , Health care providers and systems should strive to eliminate barriers to care for patients who have stable IHD and are of low socioeconomic status or are ethnic minorities.
The evidence is very limited, especially from high-quality studies, on the efficacy of specific strategies on patient outcomes that can be used to follow up with patients with stable IHD. However, this is an important clinical issue for primary care physicians. The clinical follow-up of patients with stable IHD seeks to maximize function and to minimize long-term mortality and morbidity.
Ongoing reassessment of adherence to and effectiveness of the therapeutic regimen, including clinical response, occurrence of adverse effects, and treatment goals, should be based on evolving scientific evidence and preferences of the patient. Coexisting chronic medical conditions that may directly or indirectly affect the clinical course of stable IHD should be managed effectively. Unnecessary testing should be avoided. When appropriate, follow-up exercise testing provides reassessment of the anatomical, functional, and prognostic severity of disease. Patients with stable IHD who have accelerating symptoms or decreasing functional capacity require prompt reassessment, and those who develop acute coronary syndromes should be managed according to established guidelines.
Patients with stable IHD should be evaluated before elective or emergent surgery according to established perioperative guidelines. Standard risk assessment tools for coronary disease that were developed from clinical and laboratory evaluation of ambulatory populations suspected of having IHD as discussed in the guideline on diagnosis of stable IHD included patients with noncardiac causes of presenting symptoms 67, , and probably perform less well in populations of patients with known stable IHD.
Moreover, although mortality and morbidity might intuitively be expected to be higher in patients with documented as opposed to suspected IHD, the former group is more likely to be receiving effective therapy to reduce risk, including revascularization; this could account for the generally low and declining risk for death observed in patients with established but stable IHD , , — Unfortunately, there is no accepted index for assessing ongoing risk by using clinical variables in patients with stable IHD.
Patients with stable IHD should have a follow-up evaluation every 4 to 12 months. This interval should be 4 to 6 months during the first year of therapy. Annual evaluations are reasonable after the first year of therapy if the patient is stable and reliable enough to call or make an appointment when angina symptoms become worse or other symptoms occur. In addition, effective communication between the primary care physician and cardiologist is essential when patients are jointly managed.
In the follow-up of patients with stable IHD, key components of history include any changes in physical activity or symptoms; response to therapy, adverse effects, and adherence; and development of relevant or new conditions or changes in existing conditions. Physical examinations should include weight, blood pressure, and heart rate. Physicians should look for signs of heart failure, such as elevated jugular venous pressure, hepatojugular reflux, pulmonary crackles, new murmurs or gallops, or edema.
The vascular examination should identify any change in peripheral pulses or new bruits. It is reasonable to screen patients not known to have diabetes with a fasting blood glucose measurement every 3 years and to annually measure hemoglobin A 1c levels in patients with established diabetes. Lipid profile assessment 6 to 8 weeks after initiation of lipid-lowering drug therapy and then periodically during the first year of therapy is reasonable Routine measurement of hemoglobin, thyroid function, serum electrolytes, renal function, or oxygen saturation is not beneficial and should be done only when required by the patient's history, physical examination, or clinical course.
Repeated electrocardiography ECG is indicated when 1 medications affecting cardiac conduction are initiated or changed, 2 the anginal pattern changes, 3 symptoms or findings suggestive of a dysrhythmia or conduction abnormality are present, and 4 near or frank syncope occurs. Although periodic recording of standard lead ECG provides a baseline waveform against which tracings taken during symptoms can reasonably be compared, there is no clear evidence showing that routine, periodic ECG is useful in the absence of a change in history or physical examination.
Strategies for the selection and use of noninvasive testing in the evaluation of new or worsening symptoms in patients with documented stable IHD are similar to those in patients with suspected stable IHD. Despite widespread use of follow-up stress testing in patients with stable angina, few published data have established the benefits of this approach. Whenever possible, initial and follow-up testing should be performed using the same stress and imaging techniques so that any interval change can more reliably be attributed to alterations in clinical status rather than merely differences in technique.
In patients with interpretable results on resting ECG who are capable of exercise, treadmill exercise ECG testing remains the first choice. Loss of the ability to exercise on follow-up testing in and of itself suggests deterioration in functional and clinical status. In general, the diagnostic accuracy of stress testing is similar in patients with and without known stable IHD.
A few meta-analyses examining the effect of prior MI on diagnostic accuracy have found that the specificity of exercise ECG was higher in mixed populations , whereas the diagnostic performance of exercise echocardiography was reduced. In contrast, the specificity of exercise single-photon emission computed tomography was increased because of the predictive value of total stress perfusion abnormalities, which includes both the risk for ischemia plus infarcted myocardium As discussed in the ACP guideline on diagnosis of stable IHD, the durability of information gained from a stress test over time varies widely according to the characteristics of the patients and the type of test performed.
A normal stress test result is generally associated with a low risk for adverse cardiac events; however, among patients with negative results on perfusion imaging studies, the risk for cardiac death or MI can increase fairly rapidly over a 2-year follow-up period if a number of clinical risk factors are present.
Among other groups, the risk remains low over 2 years and can be predicted to remain low for an extended period of time. The goals of managing patients with stable IHD include reducing premature cardiovascular death and nonfatal MI while maintaining a level of activity, functional capacity, and quality of life that is satisfactory to the patient.
Despite limited evidence for the efficacy of specific strategies for the follow-up of patients with stable IHD, there is an emerging consensus that patients with a variety of chronic illnesses have improved outcomes when they receive coordinated care. Weight control and maintenance of a body mass index BMI of A stepwise strategy for smoking cessation Ask, Advise, Assess, Assist, Arrange , follow-up, referral to special programs, and pharmacotherapy are recommended Grade: strong recommendation; moderate-quality evidence.
Recommendation The organizations recommend ARBs for patients with stable IHD who have hypertension, diabetes, LV systolic dysfunction, or chronic kidney disease and have indications for, but are intolerant of, ACE inhibitors Grade: strong recommendation; high-quality evidence. Recommendation The organizations recommend that PCI with coronary stenting bare-metal stent or drug-eluting stent should not be performed if the patient is not likely to be able to tolerate and comply with dual antiplatelet therapy for the appropriate duration of treatment based on the type of stent implanted Grade: strong recommendation; moderate-quality evidence.
Recommendation The organizations recommend assessment of LV ejection fraction and segmental wall motion by echocardiography or radionuclide imaging in patients with new or worsening heart failure or evidence of intervening MI by history or ECG Grade: strong recommendation; low-quality evidence. Recommendation The organizations recommend standard exercise ECG in patients with known stable IHD who have new or worsening symptoms not consistent with unstable angina and who have 1 at least moderate physical functioning and no disabling comorbidity and 2 an interpretable ECG Grade: strong recommendation; moderate-quality evidence.
Recommendation The organizations recommend exercise with radionuclide myocardial perfusion imaging or echocardiography in patients with known stable IHD who have new or worsening symptoms not consistent with unstable angina, and who have a at least moderate physical functioning or no disabling comorbidity but b an uninterpretable ECG Grade: strong recommendation; moderate-quality evidence. Recommendation The organizations recommend that pharmacologic stress imaging with radionuclide myocardial perfusion imaging, echocardiography, or cardiac magnetic resonance imaging should not be used in patients with known stable IHD who have new or worsening symptoms not consistent with unstable angina and who are capable of at least moderate physical functioning or have no disabling comorbidity Grade: strong recommendation; low-quality evidence.
Recommendation The organizations recommend that standard exercise ECG testing should not be performed in patients with known stable IHD who have new or worsening symptoms not consistent with unstable angina and who a are incapable of at least moderate physical functioning or have disabling comorbidity or b have an uninterpretable ECG Grade: strong recommendation; low-quality evidence.
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Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Exercise-related cardiac arrest in cardiac rehabilitation. The Johannesburg experience. Safety of medically supervised outpatient cardiac rehabilitation exercise therapy: a year follow-up. Van Camp. Cardiovascular complications of outpatient cardiac rehabilitation programs. Safety of medically supervised exercise in a cardiac rehabilitation center.
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Combination therapy with metoprolol and nifedipine versus monotherapy in patients with stable angina pectoris. Isosorbidemononitrate and atenolol in the treatment of stable exertional angina. Evaluation of the antianginal and anti-ischemic efficacy of slow-release isosorbidemononitrate capsules, bupranolol and their combination, in patients with chronic stable angina pectoris.
The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. Carvedilol Heart Failure Study Group. Cardiac Insufficiency Bisoprolol Study. Comparison of celiprolol and propranolol in stable angina pectoris. Celiprolol International Angina Study Group. Double-blind comparison of once daily betaxolol versus propranolol four times daily in stable angina pectoris.
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chenrekomenni.tk Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial.
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