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The extent and impact of under-prescribing of evidence-based pharmacological therapies among heart failure patients with reduced ejection fraction (HFREF) in contemporary practice is unclear. We sought to examine the prescribing patterns of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), β-blockers (BBs) and mineralocorticoid receptor antagonists (MRAs), and to quantify the estimated ‘treatment gap’ among HFREF patients in the ‘real-world’ setting. The MEDLINE, PubMed, EMBASE, CINAHL and CENTRAL databases were searched for registry- or survey-based studies which examined the prescribing rates of ACE inhibitors, ARBs, BBs and MRAs among HFREF patients. Searches were limited to those published in the years 2000–2015. A total of 23 reports, including 83,605 patients, were evaluated. Overall, ACE inhibitors/ARBs, BBs and MRAs were prescribed to 79.8, 81.4 and 36.4 % of patients, respectively. The estimated treatment gaps in the overall population were 13.1 % for ACE inhibitors/ARBs, 3.9 % for BBs and 16.8 % for MRAs. The proportion of patients who received ≥50 % of the guideline-recommended target doses was 72 % for ACE inhibitors, 51 % for ARBs, 49 % for BBs, 53 % for the combination of ACE inhibitors/ARBs and BBs and 83 % for MRAs. Prescribing these drugs according to contemporary guidelines was associated with lower mortality risk. Patients who were elderly, female and with comorbidities were less likely to receive optimal treatment as recommended by the guidelines. ACE inhibitors, ARBs, BBs and MRAs are under-prescribed in eligible HFREF patients. Efforts should be made to improve approaches to closing the treatment gap at both systems of care and individual levels.  相似文献   

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Eligible outpatients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF) frequently do not receive target doses of HF medications. The Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF) evaluated the effect of a practice-based performance improvement intervention on treatment of outpatients with LVEF ≤35%. Specific agent and dose were collected at baseline and 24?months for angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), β-blockers, and aldosterone antagonists. Changes in dosing over time were analyzed for each medication class. Data were available for 7605 patients. At baseline, target dose treatment rates were 36.1%, 20.5%, and 74.4%, respectively. Absolute and relative improvements of 9.8% and 47.7% (?P<.001) were achieved for β-blocker dosing at 24?months. The IMPROVE HF intervention was associated with significantly increased treatment of eligible patients with target doses of β-blockers but not ACE inhibitors/ARBs or aldosterone antagonists. Additional research to determine barriers to use of target doses of HF medications may be necessary.  相似文献   

4.
Reducing the effects of angiotensin II by blockade of AT1-receptors may be superior to inhibition of angiotensin II formation by angiotensin converting enzyme (ACE) inhibitors in chronic heart failure (CHF) patients. However, the results of several trials did not fulfil this expectation. In both ELITE II with symptomatic CHF patients and in OPTIMAAL involving high risk patients after acute myocardial infarction, angiotensin II type I (AT1) receptor blocker (ARB) losartan did not prove to be superior to captopril. There are several potential reasons, why ARBs did not fare better than ACE inhibitors. Although AT1-receptor blockade may block the effects of non-ACE pathways of tissue angiotensin II formation, no clinical evidence is available that a more powerful inhibition of the tissue renin-angiotensin system brings improved survival. The choice of patients for clinical trials of HF therapy is not based on the level of neurohumoral activation. Thus, the more effective attenuation of angiotensin II action with ARBs may not bring additional benefits. The potential antiremodeling effect of ARBs through the stimulation of AT2 receptors by angiotensin II could be counterbalanced by a failure of AT1-receptor blockers to enhance bradykinin, nitric oxide and prostacyclin formation with antigrowth properties. Although ACE-inhibitors seem to have slightly better results at present than AT1 blockers in the battle on heart failure patient, future trials will decide which is the definitive winner.  相似文献   

5.
The neurohormonal hypothesis for the pathogenesis of heart failure found an early champion in the angiotensinconverting enzyme (ACE) inhibitors. More recently, the β-blockers and aldosterone receptor antagonists have provided significant support by demonstrating marked additive clinical benefit. Within this context, angiotensin receptor blockers (ARBs) were specifically designed to antagonize one of the most potent contributors to the development and progression of heart failure, angiotensin. This review discusses the recent evidence for the addition of ARBs to standard therapy with ACE inhibitors and suggests how this evidence may be used to care for patients.  相似文献   

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A hard look at angiotensin receptor blockers in heart failure   总被引:1,自引:0,他引:1  
Multiple trials over the past several years have examined indications for angiotensin receptor blockers (ARBs) in the treatment of left ventricular dysfunction, both acutely after myocardial infarction and in chronic heart failure. Yet despite these data, there is still confusion regarding the efficacy of ARBs as monotherapy in these patient populations, as well as the specific indications for combination ARB/angiotensin-converting enzyme (ACE) inhibitor therapy. We examine the key differences among the trials-including the ACE inhibitor dose, the ARB and its dose, blood pressure reduction, and patient populations-to present our perspective on ARB use, alone or in combination with ACE inhibitors, in patients with chronic heart failure and post-myocardial infarction left ventricular dysfunction. We conclude that ACE inhibitors remain the first-line therapy for left ventricular dysfunction. Angiotensin receptor blockers should be reserved for monotherapy in ACE intolerant patients and for combination therapy in symptomatic class II/III patients with chronic heart failure.  相似文献   

8.
INTRODUCTION: The beneficial effects of ACE inhibitors are generally ascribed to blockade of neurohormonal activation. However, especially in chronic heart failure (CHF) patients plasma angiotensin II and aldosterone levels can be elevated despite ACE inhibition, the so-called ACE escape. In the present study, we aimed to identify the frequency and determinants of ACE escape in CHF patients. METHODS: We studied 99 stable chronic heart failure patients (NYHA class III and IV, 66% ischemic etiology) receiving long-term therapy with ACE inhibitors. In all patients, cardiac, renal, and neurohormonal parameters were measured. ACE escape was defined as plasma angiotensin level > or = 16 pmol/L. RESULTS: Mean (+/- SD) left ventricular ejection fraction of our 99 patients (79 men and 20 women, age 69 +/- 12 years) was 28 +/- 10%. In addition to an ACE inhibitor, 93% of patients received diuretics, 71% a beta-blocker, and 49% spironolactone. None of the patients used an angiotensin receptor blocker. In our population, 45% of the patients had an angiotensin II plasma concentration higher than 16 pmol/L (median concentration was 14.1 pmol/L). Spironolactone use was an independent predictor of elevated plasma angiotensin II levels. Furthermore, spironolactone users had significantly higher plasma active renin protein and aldosterone levels. Plasma angiotensin II concentration was positively correlated to active renin, plasma angiotensin I and plasma aldosterone. No correlation was found between plasma angiotensin II levels and serum ACE activity, dose of ACE inhibitor, or duration of use. CONCLUSION: In a group of severe chronic heart failure patients, 45% had elevated plasma angiotensin II levels independent of serum ACE activity despite long-term ACE inhibitor use. Although a causal link could not be proven, an association was found between spironolactone use and active renin protein, angiotensin II and aldosterone levels, suggesting that escape from ACE is mainly caused by a feedback mechanism.  相似文献   

9.
The benefits of angiotensin-converting enzyme (ACE) inhibitors for the treatment of congestive heart failure (CHF) are well-established. A newer class of medications, angiotensin II receptor blockers (ARBs), may be a suitable replacement for ACE inhibitors as a result of a more complete inhibition of angiotensin II and better tolerability among patients. To examine the current literature on the efficacy and safety of ARBs in the setting of CHF, a Medline search was conducted of the English language literature for the years 1987 to 2005. Clinical trials that reported data on cardiac outcomes were reviewed. The earlier trials were direct ARB to ACE inhibitor comparisons (ELITE I and ELITE II). These studies indicated that ARBs do not confer an improvement in cardiac outcomes over ACE inhibitors. RESOLVD, Val-HeFT, and the 3 separate trials of the CHARM program investigated the addition of an ARB to standard therapy. The RESOLVD trial showed no significant differences in clinical events among ACE inhibitor, ARB, and their combination. Although no mortality benefit was evident in the Val-HeFT trial, a substantial reduction in CHF rehospitalizations was reported among patients who were not receiving ACE inhibitor therapy. The CHARM-Overall program demonstrated a significant benefit in cardiovascular death and hospital admissions for CHF with the addition of ARB to standard therapy, a benefit that was more pronounced in patients with depressed left ventricular ejection fraction. In the setting of CHF, rates of cardiac outcomes do not differ substantially between ARBs and ACE inhibitors. However, their combination may improve outcomes for patients with CHF.  相似文献   

10.
Hospitalized patients with heart failure and decreased ejection fraction are at substantial risk for mortality and rehospitalization, yet no acute therapies are proven to decrease this risk. Therefore, in-hospital use of medications proved to decrease long-term mortality is a critical strategy to improve outcomes. Although endorsed in guidelines, predictors of initiation and continuation of angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), β blockers, and aldosterone antagonists have not been well studied. We assessed noncontraindicated use patterns for the 3 medications using the Get With the Guidelines-Heart Failure (GWTG-HF) registry from February 2009 through March 2010. Medication continuation was defined as treatment on admission and discharge. Multivariable logistic regression using generalized estimating equations was used to determine factors associated with discharge use. In total 9,474 patients were enrolled during the study period. Of those treated before hospitalization, overall continuation rates were 88.5% for ACE inhibitors/ARBs, 91.6% for β blockers, and 71.9% for aldosterone-antagonists. Of patients untreated before admission, 87.4% had ACE inhibitors/ARBs and 90.1% had β blocker initiated during hospitalization or at discharge, whereas only 25.2% were started on an aldosterone antagonist. In multivariate analysis, admission therapy was most strongly associated with discharge use (adjusted odds ratios 7.4, 6.0, and 20.9 for ACE inhibitors/ARBs, β blockers, and aldosterone antagonists, respectively). Western region, younger age, and academic affiliation were also associated with higher discharge use. Although ACE inhibitor/ARB and β-blocker continuation rates were high, aldosterone antagonist use was lower despite potential eligibility. In conclusion, being admitted on evidence-based medications is the most powerful, independent predictor of discharge use.  相似文献   

11.
Clinical and basic science research has repeatedly confirmed the importance of the renin-angiotensin-aldosterone system in the pathophysiology of chronic heart failure. Accordingly, blockade of this system by angiotensin-converting enzyme (ACE) inhibitors has assumed a central role in the treatment of heart failure. Recently, angiotensin II receptor blockers (ARBs) have gained prominence as a possible substitute for ACE inhibitors in therapy for heart failure. However, clinical data compiled on this use of ARBs have shown them to be useful only as alternative therapy in ACE inhibitor-intolerant patients. Continuing large-scale clinical investigations may lead to an expansion of their role in therapy for various cardiovascular diseases.  相似文献   

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Angioedema is a rare, potentially life-threatening adverse event of renin-angiotensin system inhibitors. The objective of the present study was to determine the risk of angioedema from randomized clinical trials. A PubMed/CENTRAL/EMBASE search was made for randomized clinical trials from 1980 to October 2011 in patients on angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or direct renin inhibitor (DRI). Trials with a total number of patients ≥100 and a duration of ≥8 weeks were included for analysis. Incidence of angioedema was pooled by weighing the incident rate of each trial by the inverse of the variance. Twenty-six trials with 74,857 patients in the ACE inhibitor arm with 232,523 person-years of follow-up, 19 trials with 35,479 patients on ARB with 122,293 person-years of follow-up, and 2 trials with 5,141 patients on DRI with 1,735 person-years of follow-up met the inclusion criteria and were included in the analysis. In head-to-head comparison in 7 trials, risk of angioedema with ACE inhibitors was 2.2 times higher than with ARBs (95% confidence interval [CI] 1.5 to 3.3). With ACE inhibitors and ARBs, incidence of angioedema was higher in heart failure trials compared to hypertension or coronary artery disease trials without heart failure (p <0.0001). Weighted incidence of angioedema with ACE inhibitors was 0.30% (95% CI 0.28 to 0.32) compared to 0.11% (95% CI 0.09 to 0.13) with ARBs, 0.13% (95% CI 0.08 to 0.19) with DRIs, and 0.07% with placebo (95% CI 0.05 to 0.09). In conclusion, incidence of angioedema with ARBs and DRI was <1/2 than that with ACE inhibitors and not significantly different from placebo. Incidence of angioedema was higher in patients with heart failure compared to those without heart failure with ACE inhibitors and ARBs.  相似文献   

13.
Patterns of antihypertensive drug use, the cost of this care and potential savings with changes of treatment patterns, were studied for all hypertensives treated at US Veterans Affairs (VA) medical facilities for fiscal years 1995 and 1996. Data was aggregated by individual medication as well as by antihypertensive drug class. Cost estimates were based on median cost and number of units for each dosage form of each medication dispensed at all facilities. Potential savings were estimated by substituting β-blockers or diuretics for calcium antagonists. In a subset of patients the prevalence of hypertension, and among hypertensives the prevalence of coronary artery disease, congestive heart failure, and diabetes mellitus, was determined. For these patients, patterns of treatment by antihypertensive drug class was examined.For all VA facilities, of the 10 most frequently prescribed antihypertensives in 1995, four were calcium antagonists, two angiotensin converting enzyme (ACE) inhibitors, two β-blockers, and two diuretics. In 1996, this was changed by the addition of an ACE inhibitor and the subtraction of a diuretic combination. Calcium antagonists accounted for 37% of treatment days in 1995 and 35% in 1996, ACE inhibitor use went from 34% to 36%, β-blockers from 17% to 18%, and diuretic use remained at 12%. In 1996, approximately 86.6 million dollars were spent on calcium antagonists, 51.8 million on ACE inhibitors, 7.9 million on β-blockers, and 3.6 million on diuretics. The estimated annual cost savings for each 1% conversion of calcium antagonists to β-blockers would be $713,000 and to diuretics $758,000. In a subset of 7526 hypertensive patients with known comorbid conditions, calcium antagonists and ACE inhibitors were also the most commonly used drug classes for all categories of patients, including those without coronary artery disease, congestive heart failure, and diabetes mellitus.Calcium antagonists and ACE inhibitors were the most commonly dispensed antihypertensives at VA facilities for both 1995 and 1996, with a small decrease in calcium antagonist use from 1995 to 1996. The cost implications of these practice patterns as compared with the primary use of diuretics and β-blockers are enormous.  相似文献   

14.
Evidence from large, randomized, controlled clinical trials supports the use of angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and spironolactone to reduce mortality and morbidity. Despite these effective therapies, event rates related to heart failure remain high. Although ACE inhibitors reduce angiotensin II production, they do not fully suppress the increased angiotensin II production in heart failure. Angiotensin II receptor blockers (ARBs) directly block the effect of angiotensin II, derived from any source, at the receptor level and have the potential to be as effective or even more effective than ACE inhibitors. The results of a number of clinical studies have demonstrated ARBs are effective and well tolerated. However, no studies have demonstrated a convincing decrease in mortality with ARB use, although a decrease has been observed for heart failure hospitalization. The results from further studies are awaited to clarify the role of ARBs in the treatment of heart failure.  相似文献   

15.
We enrolled 347 hypertensive patients, randomly allocated them to different first-line treatments, and followed-up for 24 months. Persistence on treatment was significantly higher in patients treated with ARBs (68.5%) and ACE inhibitors (64.5%) vs. CCBs (51.6%), β-blockers (44.8%), and diuretics (34.4%). No ARB, ACE inhibitor, β-blocker, or diuretic was associated with a greater persistence in therapy as compared with the other molecules used in each therapeutic class. The rate of persistence was significantly higher in patients treated with lercanidipine vs. other CCBs (59.3% vs. 46.6%). Systolic and diastolic BP decreased more in patients treated with ARBs (-11.2/-5.8 mmHg), ACE inhibitors (-10.5/-5.1 mmHg), and CCBs (-8.5/-4.6 mmHg) when compared to ß-blockers (-4.0/-2.3 mmHg) and diuretics (-2.3/-2.1 mmHg).  相似文献   

16.
遵循指南优化药物治疗明显改善心力衰竭患者预后   总被引:8,自引:0,他引:8  
目的 评价遵循指南对慢性心力衰竭(心衰)患者进行优化药物治疗的可行性和有效性,强调遵循指南治疗、改善心衰预后的重要意义.方法 连续入组2001年1月至2009年6月间就诊的231例左室射血分数≤40%的门诊心衰患者,按指南推荐给予优化药物治疗,随访至2009年12月31日.计算该组人群的病死率及再住院率,评价治疗前后心脏结构及功能的改变.结果 (1)217例患者完成随访,中位随访时间为35(6~108)个月,血管紧张素转换酶抑制剂和B受体阻滞剂达到指南推荐靶剂量的比率分别为50.7%及37.3%.(2)该研究总病死率11.5%,年平均病死率3.9%;随访期间再住院率27.6%.(3)治疗后左室舒张末期内径显著减小(68.2 mm与62.2 mm,P<0.01),恢复至正常及接近正常大小(男≤60 mm,女≤55 mm)者共为43.2%.治疗后左室射血分数显著提高(29.8%与43.3%,P<0.01),>40%者为60.4%,≤40%但较治疗前提高≥10%者为22.9%.结论 遵循指南对心衰患者进行优化药物治疗可以显著改善心脏重构和心功能、降低病死率.
Abstract:
Objective To evaluate the effects of optimal pharmacotherapy according to guideline on treating chronic heart failure(CHF)in real world clinical practice. Methods A total of 231 consecutive outpatients with reduced left ventricular ejection fraction(LVEF≤40%)and enlarged left ventricular end diastolic diameter(male >55 mm, female >60 mm)were recruited from January 2001 to June 2009. All patients were treated with optimal pharmacotherapy according to guideline recommendations and followed up to December 31,2009. Mortality, rehospitalization and changes of heart size and cardiac function at baseline and at the end of follow-up period were analyzed. Results(1)14 patients were lost during follow-up (6. 1%), and follow-up was complete in 217 patients(93.9%). 97.2% and 98.2% patients were prescribed angiotensin converting enzyme(ACE)inhibitors and β-blockers(βB). Combined of ACE inhibitors and BB use was applied in 95.3% patients. The target dose of ACE inhibitors and βB were reached in 50. 7% and 37.3% patients.(2)Lower mortality and re-hospitalization rates were observed in this cohort: all-cause morality, average annual mortality was 11.5% and 3.9% respectively. Rehospitalization rate was 27.6%.(3)Left ventricular end-diastolic diameter(LVEDD)decreased from (68.2 ±7.2)mm to(62. 2 ±9. 6)mm. LVEDD value was normal or near normal(male≤60 mm, female ≤55 mm)in 43.2% patients. LVEF improved form(29. 8 ±7. 5)% to(43. 3 ± 11.8)%, LVEF was >40% in 60.4% patients, LVEF was ≤ 40% but increased ≥ 10% after treatment in 22.9%patients. Conclusion Optimal pharmacotherapy according to guideline can improve prognosis of outpatients with CHF.  相似文献   

17.
Most guidelines for the management of patients with cardiovascular disease recommend angiotensin-converting enzyme (ACE) inhibitors as first-choice therapy, whereas angiotensin receptor blockers (ARBs) are merely considered an alternative for ACE inhibitor–intolerant patients. The aim of this review was to compare outcomes and adverse events between ACE inhibitors and ARBs in patients. In patients with hypertension and hypertension with compelling indications, we found no difference in efficacy between ARBs and ACE inhibitors with regard to the surrogate endpoint of blood pressure and outcomes of all-cause mortality, cardiovascular mortality, myocardial infarction, heart failure, stroke, and end-stage renal disease. However, ACE inhibitors remain associated with cough and a very low risk of angioedema and fatalities. Overall withdrawal rates because of adverse events are lower with ARBs than with ACE inhibitors. Given the equal outcome efficacy but fewer adverse events with ARBs, risk-to-benefit analysis in aggregate indicates that at present there is little, if any, reason to use ACE inhibitors for the treatment of hypertension or its compelling indications.  相似文献   

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BACKGROUND: Angiotensin II exerts a number of harmful effects in patients with chronic heart failure (CHF) and, through an increase in oxidative stress, is thought to be critical in the development of endothelial dysfunction. Angiotensin II may be elevated in CHF despite treatment with angiotensin converting enzyme (ACE) inhibitors, producing a rationale for adjunctive angiotensin receptor blockade. We investigated whether the addition of angiotensin antagonism to ACE inhibition would reduce oxidative stress and improve endothelial function and exercise tolerance in patients with chronic heart failure. METHODS AND RESULTS: Twenty-eight heart failure patients, who were on stable ACE inhibitor therapy, were randomised to receive adjunctive therapy with candesartan or placebo. Plasma lipid-derived free radicals, TBARS and neutrophil O2-generation, markers of oxidative stress, were measured in venous blood. Arterial endothelial function was assessed as the response of the brachial artery to flow-related shear stress. Exercise capacity was determined by cardiopulmonary exercise testing. Compared with placebo, candesartan had no effect on changes in lipid derived free radicals (-0.1+/-1.2 vs. -0.1+/-1.0 units, respectively, P=NS), TBARS (-2.2+/-1.1 vs. -2.6+/-2.2 micromol/l, respectively, P=NS) or neutrophil O2-generating capacity (-7.3+/-5.1 vs. -8.4+/-7.9 mV/5x10(5) neutrophils, respectively, P=NS). There was no effect on changes in brachial artery flow-mediated dilatation (0.5+/-1.0 vs. 0.8+/-1.3%, respectively, P=NS) nor peak VO2 (1.6+/-0.7 ml/kg per min vs. 1.8+/-0.6 ml/kg per min; P=NS). CONCLUSION: The addition of the candesartan to ACE inhibitor therapy had no effect on oxidative stress and did not improve endothelial function or exercise capacity in patients with CHF.  相似文献   

19.
Heart failure treatment centers on antagonism of the renin-angiotensin-aldosterone system and adrenergic nervous system. Angiotensin-converting enzyme (ACE) inhibitors have been shown to benefit patients with left ventricular systolic dysfunction irrespective of symptoms. Despite ACE inhibitor use, left ventricular dysfunction continues to progress in most patients. In addition, ACE inhibitors are substantially underused in patients who would benefit, in large part due to physician concern over potential adverse effects. Angiotensin receptor blockers (ARBs) have been proposed as either potential substitutes for ACE inhibitors or as additive therapy for heart failure patients. The authors will review the importance of the renin-angiotensin-aldosterone system in the progression of heart failure, as well as the mechanisms by which ACE inhibitors and ARBs counteract this effect. The clinical evidence to date supporting the use of ARBs in heart failure also will be reviewed. Based on current trials, ARBs are suitable substitutes for ACE inhibitors in patients who have true ACE inhibitor intolerance, but ACE inhibitors should still be considered first-line therapy in the treatment of left ventricular systolic dysfunction and heart failure. ARBs are a reasonable additive therapy in patients on maximal ACE inhibitor therapy who remain symptomatic, especially in patients unable to tolerate beta blockade.  相似文献   

20.
Objective Heart failure is an epidemic in the elderly, but there is a striking lack of data in this clinically important patient population. We investigated the demographics, cardiac performance, and medication management of a segment of the hospital popula- tion in at least their eighth decade of life. Methods We retrospectively reviewed 75 records of heart failure patients who were 80 years of age or older. Records were reviewed for demographic information, presence or absence of diastolic dysfunction, evaluation of ejection fraction, and medication usage including angiotensin-concerting enzyme (ACE) inhibitors, angiotensin receptor antagonists (ARBs), beta-adrenergic blockers, digoxin, and aldosterone antagonists. Assessment for contra-indications to ACE inhibitor or ARBs use was also performed to assess co-morbidities that limit treatment of heart failure. Results The population of very elderly with heart failure is heterogeneous. We found a higher proportion of females as well as higher rates of diastolic dysfunction in patients aged ≥ 90 years compared to patients between the ages of 80-89 years. Usage of ACE inhibitors, ARBs and beta-adrenergic blockers was strikingly low throughout the very elderly population. While co-morbid conditions limited use of agents in many cases, there was a lack of explicit contra-indication in most patients not on an ACE inhibitor or an ARB. Conclusions Heart failure is not a single disease processes, but a continuum of disease processes that vary with age. The elderly with heart failure are an undertreated population, in part due to the multitude of co-morbidities that affect them. Further prospective studies are needed to better understand the physiology and ideal treatment regiment in this growing population.  相似文献   

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