Best of heart failure

15 been hospitalized with heart failure in the past 12 months. Ivabradine significantly reduced the relative risk of hospital- ization for worsening HF or CV death (RRR 18%, p < 0.0001); the significance is driven mostly by a reduction of rehospitalization. HFNEF describes a heterogeneous pool of patients that make about 50% of HF patients with a unique set of patho- physiologic mechanisms. These patients are typically older with hypertension, obesity, renal failure, anemia, and atrial fibrillation and are more likely to be females. There is also a high incidence of diabetes and coronary artery disease in these patients [ 7 ]. In contrast to patients with impaired left ventricular EF, HFNEF patients have non-dilated left ven- tricular cavity size, concentric instead of eccentric left ven- tricular hypertrophy, and a normal EF [ 34 ]. It is controversial whether LV systolic function is truly normal in patients with HFNEF because EF is an imprecise measure of left ventricular systolic function. However, inva- sive conductance studies suggested from pressure–volume loops that end-systolic pressure–volume relationship is steeper or normal in HFNEF suggesting a normal systolic function. On the other hand, end-diastolic pressure–volume relationship is shifted leftward and upward indicating dia- stolic dysfunction [ 35 , 36 ]. Diastolic dysfunction is not uncommon among elderly patients estimated at about 5.6%, but only 1% has HFNEF [ 37 ]. In one study, the product of left ventricular mass index and left atrial volume has the highest predictive accuracy for HFNEF [ 38 ]. In addition to ventricular stiffness, arterial stiffness has also been suggested to contribute to HFNEF, and the combined ventricular–arterial stiffness leads to an exaggerated hypertensive response after small increases in LV end-diastolic volume [ 7 ]. 24.3 ACC/AHA Classification of Congestive Heart Failure The current ACC/AHA classification for CHF [ 3 ] is comple- mentary to the New York Heart Classification (NYHC) [ 39 ] and helps define the evolution of symptoms of patients with CHF. In addition, the ACC/AHA classification focuses on the risk factors for CHF by identifying patients who have risk factors for CHF. This classification includes four stages of CHF: Stage A: Asymptomatic patients with no left ventricular dys- function but are at risk of developing CHF including patients with coronary artery disease, hypertension, dia- betes mellitus, family history of cardiomyopathy, and the metabolic syndrome. Stage A is not represented in the NYHC. Stage B : Asymptomatic patients with left ventricular dys- function. This is equivalent to Class I of the NYHC. Stage C : Symptom ventricular dysf Class II and Clas ple in the United Stage D : Symptom Class IV of the in the United Sta 24.4 Pharma Heart Fa 24.4.1 Heart Fai Fraction Dysfunct As noted above, o nisms of HFNEF is with diastolic dysf patients with HF a HFNEF. “True” H nary artery disease, strictive cardiomyo and right-sided fail mia, thyrotoxicosis carditis, or intracar Diastolic dysfun ditions including cor lar disease, age [ 4 secondary to intrace [ 42 ], and hypertrop ARB (losartan) has but did not change l Isolated diastolic identified in 11.5% ease with the use o atrial size and N-t (NT-proBNP) appe function [ 45 ]. Also, are seen with differe Recently an algo posed by the work Cardiology [ 47 ]. In toms of HF, normal with evidence of a distensibility, and d of HFNEF if one of PCWP > 12 mmHg ing, E/E ′ > 15 by ti DopplerwithaBNP mL or BNP > 200 and LVH or atrial mal pulmonary ven 24 Evidence-Based Management of the Patient with Congestive Heart Failure 455 24.4.6 Aldosterone Blockers Angiotensin II is a dominant stimulus of aldosterone secre- tion [ 94 ]. Aldosterone secretion, however, continues to escape ACEI or ARB [ 27 , 95 , 96 ]. A reduction, however, in aldosterone plasma level is seen with angiotensin blockers [ 97 ]. Recent data confirms that aldosterone blockers are important to improve morbidity and mortality in patients with CHF and reduced left ventricular systolic function. Aldosterone blockade reduces myocardial fibrosis and ven- tricular remodeling and has important effects on autonomic balance, fibrinolysis, oxidative stress, and activation of the NF-kappaB and AP-1 signaling pathways [ 98 ]. The Randomized Aldactone Evaluation Study (RALES) [ 28 ] randomized patients ( n = 1663) with advanced CHF and EF ≤ 35% to spironolactone 25 mg daily ( n = 822) or pla- cebo ( n = 841) including ACEI, digoxin, and diuretics. After a mean follow-up of 24 months, the trial was stopped early. Spironolactone reduced the primary endpoint of mortality by 30% (46% versus 35%, p < 0.001) primarily due to reduction of progression of CHF and sudden cardiac death. In addition, spironolactone significantly improved New York Heart Association functional class ( p < 0.001) and reduced rehos- pitalization due to worsening CHF by 35% ( p < 0.001). Spironolactone also increases the risk of hyperkalemia [ 99 ], which accounted for an increase in hospitalization from 2.4 per 1000 patients in 1994 to 11.0 per 1000 patients in 2001 ( p < 0.001) and a mortality increase from 0.3 per 1000 to 2.0 per 1000 patients ( p < 0.001). Therefore, close follow-up of patients for serum potassium levels is needed when spirono- lactone is initiated. Avoiding spironolactone in patients with elevated potassium levels (>5 mEq/L) and high baseline cre- atinine (>2.0) is advised to avoid serious hyperkalemia problem. Another recent trial, Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS) [ 29 ], randomized patients with CHF and an EF < 40%, 3–14 days post-MI, to eplerenone (25–50 mg daily) or placebo. At a mean follow- up of 27 months, eplerenone reduced total mortality by 15% ( p = 0.008), cardiovascular mortality or cardiovascular hos- pitalizations by 13% ( p = 0.002), and sudden cardiac death by 21% ( p = 0.03). The EPHESUS established the impor- tance of aldosterone antagonism in post-MI patients with reduced left ventricular function irrespective of the degree of heart failure. 24.4.7 β (Beta) Blockade in Heart Failure Multiple β (beta) blockers have been shown to reduce mortal- ity and morbidity in patients with heart failure and reduced left ventricular systolic function. Current guidelines support the use of carvedilol, metoprolol, and bisoprolol to treat patients with CHF. Beta blockers reduce ortality by approximately 35% when added to standard therapy in mild- to-moderate [ 100 – 102 ] or advanced CHF [ 103 ] and reduced hospitalizations by 33–38% [ 100 , 101 , 104 ]. Beta blockers have a positive impact on positive remodeling by reducing cavity size and improving ejection fraction [ 105 ]. In the US Carvedilol Heart Failure Study [ 100 ] (Fig. 24.3 ), 1094 patients were enrolled in a double-blind, placebo- controlled, stratified program in which they received one of four treatment protocols based on their exercise capacity. Patients with heart failure were randomized to placebo ( n = 398) or carvedilol ( n = 696) in addition to conventional therapy. The overall mortality at 6-month follow-up was reduced by 65% ( p < 0.001) and rehospitalization by 27% with carvedilol ( p = 0.036). This effect was s en in both black and non-black pati nts [ 106 ]. Carvedilol also reduced length of hospital stay and length of stay in the intensive care unit lead- ing to a 57% reduction in inpatient care costs for cardiovascular admissions ( p = 0.016) and 81% lower for heart failure admis- sions ( p = 0.022) [ 104 ]. Finally, severe heart failure (EF < 22%, markedly reduced 6-min corridor walk test, and severe impair- ment of quality of life) had an improvement in EF with carvedilol ( p = 0.004) [ 107 ]. In the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study group [ 108 ], 2289 patients with severe heart failure symptoms were randomly assigned to receive carvedilol ( n = 1156) or pla- cebo ( n = 1133). The carvedilol group experienced no increase in cardiovascular risk and had fewer patients who died (19 ver- sus 25; hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.41–1.35) and were hospitalized (134 versus 153; HR 0.85; 95%CI 0.67–1.07). Carvedilol was well tolerated in euvolemic patients with fewer patients withdrawn from treatment than placebo. 1.0 0.9 Probability of event-free survival 0.7 0.8 0.0 0 100 Placebo ( n = 398) 65% ↓ US Carvedilol trials Carvedilol ( n = 696) 200 300 Days 400 Fig. 24.3 US C vedil l trials showing a significa t reduction in mortality with carvedilol compared to placebo in patients with left ventricular systolic dysfunction 24 Evidence-Based Management of the Patient with Congestive Heart Failure A e ue n m e L S or t - o . t w ne e- u o β - u ed a p i H r uc i x l dde t o-m [ d o pi , h a m n o d ng v an n n [ I a i r F il r d ) 4 t nt o i do l n e o t i e i f r o o e P t i a mi e a w a p 03 ) i f t d o k p e i i g % t e o a d s o ) d 1 w h is [ 1 n 2 y e - rr lk e i u n m w rve p d iz S v r nd r - 3). c en no e ova r ent d e 1 v s h d r ti 0 5; o i ] 3 C –1 0 d p t h n f n o 7 e l 3 v i l s n fi