B P6 C49 Diagnosis and Management of Acute Heart Failure Flashcards
1
Q
The prevalence of HF is projected to continue to increase over time due to a convergence of several epidemiologic trends:
A
(1) The aging of the population, given the age-related incidence of HF
(2) The reduction in hypertension-related mortality and the greatly improved survival after myocardial infarction (MI), resulting in more patients living with chronic heart failure
(3) The availability of effective therapy for prevention of sudden death
2
Q
On the basis of available registry data, _____% of patients hospi- talized have heart failure with preserved ejection fraction (HFpEF).
A
40-50%
3
Q
The in-hospital mortality of patients with HFpEF appears to be lower com- pared with that of patients with HFrEF, but post-discharge rehospitalization rates and long-term mortality after hospitalization are similarly high for _____.
A
Both
4
Q
Patients with AHF and HFpEF are more likely to be rehospitalized for and to die from non-CV causes than patients with AHF and HFrEF, reflecting their _____.
A
More advanced age and greater burden of comorbidity
5
Q
There are significant differences in the epidemiology of AHF based on age, race, and gender. AHF disproportionally affects older people, with a mean age of _____ years in large registries
A
75 years
6
Q
In the ADHERE registry women admitted for AHF were older than men (74 vs. 70 years), and more frequently had _____ systolic function (51% vs. 28%).
A
Preserved
7
Q
Differences in ethnic groups have been studied most extensively in the United States and have focused primarily on differences between African American and white patients. In the _____ registry, African American patients admitted with AHF were younger (64 vs. 75 years), more likely to have left ventricular (LV) systolic dysfunction (57% vs. 51%) with a lower mean EF (35% vs. 40%), hypertensive cause for heart failure (39% vs.19%), renal dysfunction, and diabetes compared to the non–African American group.
A
Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF)
8
Q
_____ is the most prevalent concurrent condition, present in approximately two-thirds of the patients, whereas _____ is present in about half and _____ in over one-third.
A
Hypertension: 2/3
CAD: 1/2
Dyslipidemia: 1/3
9
Q
The interaction between heart failure status and diabetes has been a subject of substantial interest, given the evolving data that some classes of anti-diabetic drugs, specifically the _____, have a favorable impact on heart failure outcomes
A
Sodium-glucose co-transporter-2 (SGLT-2) inhibitors
Glucagon-like peptide-1 (GLP-1) agonists
10
Q
Alternatively, some patients may have no prior history of HF but abnormal substrate (e.g., stage B patients with asymptomatic LV dysfunction) with a first presentation of heart failure (_____ heart failure)
A
De Novo Heart Failure
11
Q
For patients with normal substrate (normal myocardium),a substantial insult to cardiac performance (e.g.,_____) is generally required to lead to the clinical presentation of AHF.
A
Acute myocarditis
12
Q
For patients with abnormal substrate at baseline (asymptomatic LV dysfunction), smaller perturbations (e.g., _____) may precipitate an AHF episode.
A
Poorly controlled hypertension
Atrial fibrillation
Ischemia
13
Q
For patients with a substrate of compensated or stable chronic HF, _____, are all common triggers for decompensation.
A
Medical or dietary nonadherence
Drugs: NSAIDs or thiazolidinediones
Infectious processes
14
Q
Regardless of the substrate or initiating factors, a variety of “amplifying mechanisms” perpetuate and contribute to the episode of decompensation.These include _____, all of which may contribute to the propagation and worsening of the AHF episode.
A
(1) Neurohormonal and inflammatory activation
(2) Ongoing myocardial injury with progressive myocardial dysfunction
(3) Worsening renal function
(4) Interactions with the peripheral vasculature
15
Q
Systemic or pulmonary congestion often due to a _____ dominates the clinical presentation of most patients hospitalized for AHF
A
High ventricular diastolic pressure
16
Q
_____can be seen as a final common pathway producing clinical symptoms leading to hospitalization
A
Congestion
17
Q
An oversimplified view of AHF pathophysiology is that _____ lead to symptoms of congestion and clinical presentation, and normalization of volume status with diuretic therapy results in restoration of homeostasis
A
Gradual increases in intravascular volume
18
Q
Although patients present with signs and symptoms of systemic congestion such as dyspnea, rales, elevated jugular venous pressure (JVP), and edema, this state is often preceded by “_____ congestion,” defined as high ventricular diastolic pressures without overt clinical signs.
A
Hemodynamic congestion
19
Q
It has been postulated that hemodynamic congestion may contribute to the progression of HF because it may result in increased wall stress as well as in renin- angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) activation.
This may trigger a variety of molecular responses in the myocardium, including _____.
A
Myocyte loss and increased fibrosis
20
Q
In addition, elevated diastolic filling pressures may decrease _____, resulting in sub-endocardial ischemia that may further exacerbate cardiac dysfunction.
A
Coronary perfusion pressure
21
Q
Increased LV filling pressures can also lead to acute changes in ventricular architecture (more spherical shape),contributing to worsening _____.
A
Mitral regurgitation
22
Q
Changes in systolic function and decreased arterial filling can initiate a cascade of effects that are adaptive in the short term but maladaptive when elevated chronically, including stimulation of the SNS and RAAS. Activation of these neurohormonal axes leads to _____.
A
Vasoconstriction
Sodium and water retention
Volume redistribution from other vascular beds
Increases in diastolic filling pressures
Clinical symptoms
23
Q
In patients with underlying ischemic heart disease, initial defects in systolic function may initiate a vicious cycle of _____.Increased LV filling pressures and changes in LV geometry can worsen functional mitral regurgitation, further decreasing cardiac output.
A
Decreasing coronary perfusion
Increased myocardial wall stress
Progressively worsening cardiac performance
24
Q
Importantly, abnormalities in diastolic function are present in heart failure patients regardless of EF. The impairment of the diastolic phase may be related to _____.
A
Passive stiffness
Abnormal active relaxation of the left ventricle
Both
25
Hypertension, tachycardia, and myocardial ischemia (even in the absence of CAD) can further impair diastolic filling. All of these mechanisms contribute to higher LV end-diastolic pressures, which are reflected back to the _____.
Pulmonary capillary circulation
26
One underappreciated aspect of myocardial function in AHF relates to the interdependence of the left and right ventricles. Because of the constraints of the pericardial space, distention of either ventricle due to increased filling pressures can result in direct impingement of _____ of the other ventricle
Diastolic filling
27
In a representative analysis of data from the _____ study using a highly sensitive assay, 90% of patients enrolled had a troponin T level above the 99th percentile upper reference limit at baseline, and troponin elevation was associated with post-discharge outcomes out to 180 days
RELAX-AHF
28
The precise mechanisms mediating myocardial injury in AHF are poorly defined, but _____ may all contribute to myocyte injury even in the absence of epicardial CAD
Increased myocardial wall stress
Decreased coronary perfusion pressure
Increased myocardial oxygen demand
Endothelial dysfunction
Activation of the neurohormonal and inflammatory pathways
Platelet activation
Altered calcium handling
29
Specific therapeutic interventions that may increase myocardial oxygen demand (such as _____) or decrease coronary artery perfusion pressure (such as some _____) may exacerbate myocardial injury and further contribute to the cycle of decompensation
Increase O2 demand: positive inotropic agents
Decrease CaPP: Vasodilators
30
The kidney plays two fundamental roles relative to the pathophysiology of HF:
(1) It modulates loading conditions of the heart by controlling intravascular volume
(2) it is responsible for neurohormonal outputs (i.e.,the RAAS system)
31
Although often assumed to be related to low cardiac output and renal blood flow, careful hemodynamic studies have repeatedly confirmed that the strongest predictor of worsening renal function in heart failure patients relates to _____, which is reflected back to the renal veins and leads directly to changes in GFR.
Elevated central venous pressure (CVP)
32
_____ renal function in the setting of ongoing clinical improvement is generally reflective of successful decongestion and does not portend a poor prognosis
Worsening renal function
33
Abnormalities of endothelial function related to _____ dependent regulation of vascular tone are well described in heart failure.
Nitric oxide
34
_____, which is related to but distinct from blood pressure, increases cardiac loading conditions and is associated with incident heart failure and worse outcomes.
Arterial stiffness
35
_____ in the setting of AHF redistributes blood centrally, increasing pulmonary venous congestion and edema.
Peripheral vasoconstriction
36
As noted earlier, elevated CVP reduces _____, resulting in greater fluid retention, which further elevates venous pressures
Renal function
37
Abnormal vascular compliance also predisposes these patients to marked blood pressure liability with relatively minor changes in intravascular volume, causing _____.The effects of this vascular abnormality are amplified by LV diastolic dysfunction.
Precipitous increases in afterload and ultimately in LV filling pressures resulting in pulmonary congestion
37
Peripheral arterial vasoconstriction increases _____ resulting in worsening of pulmonary edema and dyspnea.
Afterload
LV filling pressures
Post-capillary pulmonary venous pressures
38
The clinical observation that vasodilator treatment can improve dyspnea in many acutely hypertensive patients without significant diuresis has led to the concept that _____ mismatch can lead to increased diastolic filling pressures in the setting of minimal total body volume changes
Afterload-contractility mismatch
39
Increased plasma concentrations of _____ have all been reported in patients with AHF—all of these axes are associated with vasoconstriction and volume retention, which could contribute to myocardial ischemia and congestion,thus exacerbating cardiac decompensation
Norepinephrine
Plasma renin activity
Aldosterone
Endothelin-1 (ET-1)
40
Pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 are elevated in patients with AHF and have direct _____ effects on the myocardium as well as increasing capillary permeability and inducing endothelial dysfunction
Negative inotropic effects ( TNFa and IL-6)
41
The initial evaluation of the patient with AHF focuses on the following critical aspects:
(1) establishing a definitive diagnosis of AHF as rapidly and efficiently as possible;
(2) emergent treatment for potentially life- threatening conditions (e.g., shock, respiratory failure);
(3) identifying and addressing any relevant clinical triggers or other condition requiring specific treatment (e.g.,acute coronary syndrome [ACS],acute pulmonary embolism, etc.);
(4) risk stratification in order to triage patient to appropriate level of care (e.g., intensive care unit [ICU], telemetry unit, observation unit);
(5) defining the clinical profile of the patient (based on blood pressure, volume status, and renal function) in order to rapidly implement the most appropriate therapy
42
In suspected patients with AHF, these constitutes the immediate phase (initial 60-120 mins)
C - acute Coronary syndrome
H - Hypertensive emergency
A - Arrhythmia
M - acute Mechanical cause
P - Pulmonary embolism
43
In suspected patients with AHF, these constitutes the urgent phase after first medical contact
Check for cardiogenic shock and respiratory failure
44
There are several relevant domains to consider in classifying patients with AHF. These include:
(1) Substrate (i.e., whether there is a prior history of structural heart disease or a background of chronic HF)
(2) Severity (from mild symptoms to cardiogenic shock)
(3) Acuity (gradual onset vs. sudden/acute onset)
(4) Triggers (which may be readily apparent or unknown)
45
_____ makes up about 20% of hospitalizations for AHF. These patients may have no prior history of cardiovascular disease or risk factors (e.g.,acute myocarditis),but more commonly,t hey have a background of risk factors for HF (stage A heart failure according to the American College of Cardiology/American Heart Association [ACC/AHA] guidelines) or preexisting structural heart disease (stage B heart failure according to the ACC/AHA guidelines)
New-onset or de novo heart failure
46
Cardiogenic shock is relatively uncommon (_____% of AHFS presentations in EuroHeart Failure Survey II [EHFS II]) in broad community registries but more common in tertiary care settings.
4%
47
The fact that many patients may have slowly developing symptoms over days to weeks presents the possibility that early intervention with _____ may prevent some hospitalizations
Intensified therapy
48
AHF may be triggered by very clear precipitants or alternatively the reason for decompensation may be obscure.In the OPTIMIZE-HF registry, 61% of enrolled subjects had an identifiable clinical precipitant, with _____ being the most common.
Pulmonary processes (15%)
Myocardial ischemia (15%)
Arrhythmias (14%)
49
More than one precipitant was identified in a substantial minority of the study population. Of the identified triggers, _____ was associated with the highest in-hospital mortality (8%), whereas _____ had a much better prognosis (<2% in-hospital mortality for each)
Worsening renal function: Highest in-hospital mortality
Better prognosis: nonadherence to diet or medication or uncontrolled hypertension
50
Dyspnea is the most common symptom and is present in over _____% of patients presenting with AHF.
90%
51
_____, or the sensation of dyspnea on bending over, is a commonly reported symptom that has recently been validated experimentally
Bendopnea
52
SBP is typically normal or elevated in patients with AHF, with almost 50% presenting with SBP greater than _____ mm Hg
140 mm Hg
53
The combination of _____ can result in elevations of SBP consistent with hypertensive urgencies or emergencies (12% of patients had an SBP over 180 mm Hg on admission).
Underlying hypertension
Marked increase in sympathetic stimulation that accompanies AHF
54
Patients with very low SBP are uncommon, with only _____% of patients in ADHERE presenting with an SBP less than 90 mm Hg.
2%
55
A high pulse pressure may alert the physician to a high output state including the possibility of _____.
Unrecognized thyrotoxicosis
Aortic regurgitation
Anemia
55
_____ is a useful measure that is an indirect marker of cardiac output
Pulse pressure (the difference between systolic and diastolic blood pressure)
55
The _____ is a barometer of systemic venous hypertension and is the single most useful physical examination finding in the assessment of patients with AHF
JVP
56
A low pulse pressure is a marker of a _____ and confers an increased risk in patients admitted with AHF.
Low cardiac output
57
The accurate assessment of the JVP is highly dependent on examiner skill.The JVP reflects the _____, which typically (although not always) is an indirect measure of LV filling pressures.
RAP
58
59
59
59
60
61
_____ are the most common physical examination finding and have been noted in 66% to 87% of patients admitted for AHF
Rales or inspiratory crackles
61
JVP may not reflect LV filling pressures in _____ can complicate the assessment of the JVP because the large “CV wave” of tricuspid regurgitation can lead to its overestimation.
Isolated RV failure (e.g., from pulmonary hypertension or RV infarct)
Significant tricuspid regurgitation
62
However, rales are often not heard in patients with a background of chronic heart failure and pulmonary venous hypertension, due to _____, reinforcing the important clinical pearl that the absence of rales does not necessarily imply normal LV filling pressures
Increased lymphatic drainage
63
Cool extremities with palpable peripheral pulses suggest _____ consistent with a marginal cardiac index, marked vasoconstriction, or both
Decreased peripheral perfusion
64
Symptoms related to fluid overload
Dyspnea (exertional, paroxysmal nocturnal dyspnea, orthopnea, or at rest); cough; wheezing
Foot and leg discomfort
Abdominal discomfort/bloating; early satiety or anorexia
65
Signs related to fluid overload
Rales, pleural effusion
Peripheral edema (legs, sacral)
Ascites/increased abdominal girth; right upper quadrant pain or discomfort; hepatomegaly/ splenomegaly; scleral icterus
Increased weight
Elevated jugular venous pressure, abdominojugular reflux
Increasing S3, accentuated P2
66
Symptoms related to Hypoperfusion
Fatigue
Altered mental status, daytime drowsiness, confusion, or difficulty concentrating
Dizziness, pre-syncope, or syncope
67
Signs related to Hypoperfusion
Cool extremities
Pallor, dusky skin discoloration, Hypotension
Pulse pressure (narrow)/proportional pulse pressure (low)
Pulsus alternans
68
Peripheral edema is present in up to ___% of patients admitted with AHF and is less common in patients presenting with predominantly low-output heart failure or cardiogenic shock
65%
69
As with rales, the presence of _____ has a reasonable positive predictive value for AHF but a low sensitivity, so its absence does not exclude that diagnosis
Edema
70
Edema due to AHF is usually dependent, symmetric, and pitting. It is estimated that a minimum of _____ liters of extracellular fluid is accumulated to produce clinically detectable edema.
4L
71
In diagnostic testing, natriuretic peptides have greater _____ predictive value (i.e., the ability to rule out heart failure as a cause of dyspnea) than _____ predictive value (i.e.,the ability to definitively identify a diagnosis of heart failure as the cause of dyspnea)
Negative
Positive
72
Assessment of cardiac troponin in patients with AHF is now a Class I recommendation in clinical guidelines and serves to both establish prognosis as well as inform the likelihood of concurrent ACS. It is important to note that elevation of troponin in the context of a typical AHF hospitalization without clinical evidence of ACS is NOT synonymous with a Type ____ MI based on the updated fourth universal MI definition.
Type II MI
73
_____ is more directly related to the severity of AHF than creatinine, as it integrates both renal function and neurohormonal activation in AHF.
Blood urea nitrogen (BUN)
74
In the ADHERE registry, 90% of patients underwent chest radiography during hospitalization and there was evidence of congestion in over __% of these patients.
80%
75
Arrhythmias are also a common trigger for AHF, and atrial fibrillation is present in _____%.
20-30%
76
An _____ is generally the single most useful test in evaluating the cause in the patient with AHF.
Echocardiogram
77
The tissue Doppler ratio of peak early diastolic trans-mitral blood flow velocity (E) to the peak early diastolic mitral annular tissue velocity (Ea) (E:Ea ratio) has been shown to be additive to BNP measures in diagnosing AHF patients presenting with dyspnea. An E:Ea ratio of greater than _____ predicts a pulmonary capillary wedge pressure (PCWP) greater than _____ mm Hg and has been demonstrated to be accurate in the emergency room and intensive care settings.
E:Ea >15 = PCWP 15 mm Hg
78
The initial goals in the management of a patient presenting with AHF are to _____.
(1) Expeditiously establish the diagnosis
(2) Treat life-threatening abnormalities
(3) Initiate therapies to provide symptom relief
(4) Identify the cause and precipitating triggers for the episode of AHF
79
In patients with hypoxemia (SaO2 < ___%), oxygen administration is recommended.
<90%
80
Although oxygen saturation on presentation is inversely
related to short-term mortality, inhaled oxygen (FiO2 >/= ____) may cause detrimental hemodynamic effects (such hyperoxia-induced vasoconstriction) in patients with systolic dysfunction, therefore it is not routinely recommended for patients without hypoxemia
> /= 40%
81
The _____trial enrolled 1069 patients with pulmonary edema who were randomized to standard oxygen therapy, CPAP, or NIPPV. NIV with CPAP or NIPPV was associated with greater improvement in patient-reported dyspnea, heart rate, acidosis, and hypercapnea after 1 hour of therapy, although it was not associated with a 7-day mortal- ity benefit nor a decreased need for intubation when compared with standard oxygen therapy
Three Interventions in Cardiogenic Pulmonary Oedema (3CPO)
82
_____ are the most frequently administered pharmacologic therapy for AHF; over 75% of patients in the emergency department receive intravenous diuretics, with a mean door to first intravenous administration time of 2.2 hours in ADHERE.
IV Loop diuretics
83
Whereas some patients with volume redistribution rather than hypervolemia may derive benefit from vasodilators alone, symptomatic patients with objective evidence of congestion consistent with pulmonary or systemic venous hypertension or edema should generally receive urgent diuretic therapy for relief of symptoms related to congestion. Initial therapy is typically a bolus injection with a dose between _____ times the patient’s oral loop diuretic dose for patients on chronic diuretic therapy
1 and 2.5x
84
In the absence of hypotension, vasodilators may have a role in the initial therapy of patients with pulmonary edema and poor oxygenation. A treatment strategy of early initiation of _____ therapy in patients with severe cardiogenic pulmonary edema has been shown to reduce the need for mechanical ventilation and the frequency of MI
IV nitrate therapy
85
In general, hospitalization is recommended for patients with _____.
(1) Evidence of significant decompensated heart failure, including hypotension, worsening renal function, or altered mentation;
(2) Significant hypoxemia
(3) Hemodynamically significant arrhythmia (most commonly atrial fibrillation either with rapid ventricular response or new onset)
(4) ACS
86
Hospitalization should be considered in patients with worsened congestion, even in the absence of dyspnea and often reflected by _____.
(1) Significant weight gain (5 kg)
(2) Other signs or symptoms of pulmonary or systemic congestion
(3) Newly diagnosed heart failure
(4) Complications of heart failure therapy (such as electrolyte disturbances
(5) Frequent implantable cardioverter-defibrillator [ICD] firings)
(6) Other associated comorbid condition
87
_____ is the most common tachyarrhythmia requiring treatment in patients with AHF.
Atrial fibrillation with rapid ventricular response
88
In patients with AF with RVR and systolic dysfunction, _____ may be used. _____ and other agents that suppress ventricular function should be avoided in patients with significant systolic dysfunction but may be effective in patients with preserved function.
Intravenous digoxin (in the absence of an accessory pathway), cautious use of beta blocker therapy, or amiodarone
Diltiazem
89
The most common cause of RV HF in AHF is _____.
Left-sided failure
90
Isolated RV HF is relatively rare and is generally due to _____.
Acute RV infarction
Acute pulmonary embolism
Severe pulmonary hypertension
91
Isolated RV HF caused by an acute RV infarction is best treated with _____, whereas hemodynamically significant pulmonary embolism may be treated with thrombolytics.
RV infarction: Early reperfusion
HS PE: Thrombolytics
92
Hemodynamic stabilization by optimizing CVPs via carefully monitored fluid loading (target CVP approximately ____ mm Hg) and increasing RV systolic function with intravenous inotropic support under invasive hemodynamic guidance may also be necessary
Target CVP 10-12 mm Hg
93
Selective pulmonary artery vasodilation by _____ agents may improve RV function through decreased afterload.
Inhaled (nitric oxide, prostacyclin analogs)
OR
Intravenous (prostacyclin analogs, sildenafil)
94
If the patient is mechanically ventilated, normoxia and hypocarbia should be goals using moderate tidal volumes (approximately _____ mL/kg) and as low a PEEP as possible (<___ cm H2O) to maintain moderate plateau pressures.
TV 8 mL/kg
PEEP < 12 cm H2O
95
Cardiogenic shock is characterized by marked hypotension (SBP <___ mm Hg) lasting more than 30 minutes, associated with severe reduction of cardiac index (usually <___ L/min/m2) in spite of adequate LV filling pressure (PCWP >___ mm Hg), resulting in organ hypoperfusion.
SBP < 80 mm Hg more than 30 mins
CI < 1.8 L/min/m2
PCWB > 18 mm Hg
96
The goals for the management of a patient with AHF during the hospitalization phase are to _____.
(1) Complete the diagnostic and acute therapeutic processes that were initiated at the time of initial presentation
(2) Optimize the patient’s hemodynamic profile, volume status, and clinical symptoms
(3) Initiate or optimize chronic heart failure therapy
97
Dietary sodium restriction (__ g daily) and fluid restriction (__ liters daily) may be useful to help treat congestion, although the utility of sodium and fluid restriction in this setting has increasingly been called into question
Dietary Na: 2g/day
Fluids: 2L/day
98
The increased risk of venous thromboembolism in heart failure is exacerbated by the _____ of hospitalized patients with AHF and venous thromboembolism prophylaxis is indicated in all patients unless there is a clear contraindication.
Decreased mobility
99
Patients admitted on _____ have a lower occurrence of ventricular arrhythmias, a shorter length of stay, and reduced 6-month mortality compared to those not receiving them
Beta blockers
100
Patients who had beta blockers withdrawn had significantly lower outpatient use of beta blockers and higher in-hospital mortality, short-term mortality, and combined short-term rehospitalization and mortality, even after adjustments for potential confounders. Therefore, patients should continue beta blocker therapy during the admission for AHF, unless _____ are present
Significant hypotension or cardiogenic shock
101
Recent data from the PIONEER trial suggest that hospitalization is an ideal time to transition to _____ therapy in appropriate patients rather than defer this to the outpatient setting.
Sacubitril-valsartan
102
_____ is often described as the clinical state where the volume overload of heart failure is resistant or refractory to treatment due to progressive renal insufficiency.
Cardio-renal syndrome
103
A commonly used practical definition of cardio-renal syndrome is an increase in serum creatinine of greater than _____ mg/dL (or ___% decreases in GFR) despite evidence of persistent clinical or hemodynamic congestion
>0.3 mg/dL increase in creatinine
or
25% decrease in GFR
103
This definition of the cardio-renal syndrome emphasizes the importance of persistent congestion, as multiple studies have suggested that changes in renal function during successful decongestion therapy are usually _____.
Transient and may not be associated with adverse outcomes
104
Progressive deterioration of renal
function (BUN >_____ mg/dL and creatinine >___ mg/dL) or _____ may
necessitate discontinuation of RAAS
inhibitors, although use of other vasodilators should be considered, either
intravenous (i.e., nitroglycerin or nitroprusside) or oral (isosorbide dinitrate and hydralazine)
BUN > 80 mg/dL
Creatinine >3.0 mg/dL
Hyperkalemia
105
Both terminology and specific definitions of WHF have varied between studies, leading to widely varying estimates of prevalence from 5% to 42%. In general, the development of WHF during inpatient AHF therapy is associated with both longer length of inpatient stay (by approximately _____ days in a recent pooled analysis) and adverse post-discharge outcomes (approximately 50% to 100% increase in 30 or 60 day death or HF rehospitalization
5 days
105
The pre-discharge phase focuses on the goals of _____..
Evaluating readiness for discharge, optimizing chronic oral therapy, minimizing the side effects of treatments, and ultimately preventing early readmission and improving symptoms and survival
106
Similarly, elevations of discharge ___ level have been shown to be associated with risk for rehospitalization post-discharge.6
BNP
107
Pharmacologic therapies known to improve long-term outcomes in chronic heart failure, such as beta blockers, ACE inhibitors or ARBs, ARNIs,and mineralocorticoid receptor antagonists,should be initiated _____ in hemodynamically stable, appropriate patients.
As soon as reasonable during the hospitalization and prior to discharge
107
A series of studies have also investigated the benefits of post-discharge support, especially patient-centered discharge instructions, transition coaches, follow-up telephone calls, and early physician follow-up, although results of these studies have been mixed in terms of impact on out- comes.
108
A follow-up appointment is optimally scheduled within approximately ____ post-discharge, but closer follow-up (in less than a week) should be considered for patients with high-risk features.
7 to 10 days
109
Considerations Prior to Discharge after Acute Heart Failure Hospitalization
110
The current general therapeutic approach focuses on the successful treatment of clinical and hemodynamic congestion,while limiting untoward effects on myocardial or end-organ function, identifying addressable triggers, and optimizing proven long-term therapies.
111
___ reflects the interaction between vascular tone and myocardial pump function and is one of the most important prognos- tic indicators in AHF
Blood pressure
112
____ may decrease preload by reversing venous vasoconstriction and the related central volume redistribu- tion from the peripheral and splanchnic venous systems, and reduce afterload by decreasing arterial vasoconstriction with a resultant improvement in cardiac and renal function
Vasodilators
113
____ are the primary therapy for AHF with **pulmonary edema**,and for **non-hypotensive patients with low cardiac output (poor peripheral or central perfusion with SBPs above 85 to 100 mm Hg).**
Vasodilators
114
However, in an international registry of 4953 patients admitted for AHF (ALARM-HF; 75% admitted to ICU/ CCU care settings), analysis of a propensity-based matched cohort of 1007 matched pairs demonstrated improved in-hospital survival in patients treated with vasodilators and diuretics compared to patients only treated with diuretics with 7.8% compared to 11.0% in-hospital mortality,respectively(P=0.016).
Interestingly, this, difference in survival was particularly evident in patients with SBP less than ___
120 mm Hg
115
Hypotension (SBP below 85 to 90 mm Hg) or signs of peripheral hypoperfusion are poor prognostic signs in patients with AHF
116
If there is clear evidence of hypovolemia, carefully monitored “fluid challenges” may be attempted, although rapid intravenous fluid boluses can precipitate congestive symptoms.
____ , as an isolated finding in the absence of congestion and poor peripheral or central perfusion, does not require emergent treatment.
Inotropic therapy may be indicated for persistent symptomatic hypotension or evidence of hypoperfusion in the set- ting of advanced systolic dysfunction
Asymptomatic hypotension
117
An analysis of 954 propensity- matched pairs of patients from the ALARM-HF registry suggested that IV catecholamine use was associated with 1.5-fold increase in in-hospital mortality for dopamine or dobutamine use and a greater than 2.5-fold increase for norepinephrine or epinephrine use.70 Spe- cific inotropic agents vary by country and local clinical practice
118
The use of vasoconstrictors, such as high-dose dopamine, phenylephrine, epinephrine, and norepinephrine, should generally be avoided unless absolutely necessary for refractory symptomatic hypo- tension or hypoperfusion
119
Most patients with AHF have evidence of volume overload and for patients in whom this is the dominant presenting feature,such as those with significant peripheral edema or ascites, ___ remain the foundation of AHF therapy.
Intravenous diuretics
120
Patients with clinically evident congestion typically have ___ of excess volume and amount greater than 10 liters are not uncommon
4 to 5 liters
121
Diuresis addresses the underlying abnormality and frequently improves symptoms and signs of elevated filling pressures. However, ____ therapy may provide more rapid relief in highly symptomatic patients with evidence of pulmonary congestion.
Intravenous vasodilator
Patients receiving intravenous fluids had increased rates of subsequent critical care admission, intubation, renal replacement therapy, and hospital death compared with those who received only diuretics
Hospital discharge before hemodynamic congestion is fully treated appears to be a common cause of rehospitalization
122
The use of PAC in the routine management of AHF has been a subject of controversy.The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) was a randomized controlled trial of 433 patients with severe symptomatic heart failure despite recommended therapies randomized to receive therapy guided by clinical assessment and PAC or by clinical assessment alone.73 In ESCAPE, use of PAC did not significantly affect the days alive and out of hospital during the first 6 months (133 vs. 135 days), mortality (43 vs. 38 deaths), or the number of days hospitalized (8.7 vs. 8.3 days) compared to clinical assessment alone. Based on the results of the ESCAPE trial, the use of PAC in AHF management has declined—in EHFS II, only 5% of patients had a PAC during AHF hospitalization.
123
Invasive hemodynamic assessment with PAC may still play an important role in selected patients, especially those with shock or other severe hemodynamic compromise, with oliguria or anuria, or with unclear hemodynamics and poor response to therapy
124
In patients with advanced heart failure in whom PAC is used to tailor therapy, guve targets?
PCWP of less than 16 mm Hg
Rght atrial pressure less than 8 mm Hg
Systemic vascular resistance between 1000 and 1200 dynes sec cm−5
125
The first point of contact at the admitting hospital for most patients (80%) is the emergency department.
126
Hospital discharge before congestion is adequately treated appears to be a common cause of early readmission.
127
Early post-discharge follow-up has also been associated with lower rehospitalization rates in retro- spective registry data.68 A variety of other interventions centered on telemedicine, disease monitoring, and disease management remain under active investigation.
128
____ are the primary pharmacologic treatment for volume overload in patients with AHF, and typically result in rapid symptom relief in most patients.
Loop diuretics
129
Loop diuretics (furosemide, torsemide, bumetanide, and ethac- rynic acid) can lead to excretion of up to 25% of the filtered sodium and intravenous administration avoids variable bioavailability and allows for rapid onset of action (typically within ___).
Nonsteroidal anti-inflammatory drugs can greatly reduce the efficacy of diuretics by reducing renal synthesis of vasodilatory ____, and these agents should be avoided.
30 to 60 minutes
Prostaglandins
130
Based on the results of the DOSE study described below, initial doses of approximately ___ times the outpatient dose should be considered for patients on chronic oral diuretic therapy, with underlying renal dysfunction, or with severe volume overload.
2.5x
131
The ____ was a randomized, double-blind study that prospectively compared diuretic strategies in AHF.86 Using a 2 × 2 factorial design, 308 patients were randomized to treatment with IV furosemide using either twice-daily bolus dosing or a continuous infusion and to either a low (equivalent to the numerical value of the oral outpatient dose given IV) or high (2.5 times the oral dose given IV) dose strategy.
There was no significant difference in either of the co-primary endpoints of global assessment of symptoms or change in creatinine at 72 hours with administration by bolus compared to infusion or with the low- versus high-dose strategy.
The high-dose strategy was associated with greater relief of dyspnea and net fluid loss at 72 hours, although more patients in the high-dose group had a transient increase in creatinine greater than 0.3 mg/dL,which resolved by the time of hospital discharge.
DOSE trial
The significance of this finding is unclear; although there were no apparent differences in hospital length of stay or days alive out of the hospital, the study was not powered for long-term clinical outcomes.
Overall, there were no differences in results between the continuous infusion and intermittent bolus strategies in the clinical trial setting of DOSE,suggesting that whichever approach is most likely to reliably produce the desired diuresis in the particular local clin- ical practice should be used.
132
In the setting of diuretic resistance, administration of a thiazide- like diuretic that blocks the distal tubule can provide significant aug- mentation of the diuretic effect.
Intravenous _____ or oral _____ given prior to the loop diuretic are effective agents, although care must be taken to monitor for hypotension, worsening renal function, and electrolyte abnormalities, which may be profound.
IV Chlorothiazide (500 to 1000 mg)
PO Metolazone (2.5 to 10 mg)
132
If hypokalemia is a persistent problem with replacement requirements, administration of a potassium-sparing diuretic,such as ___, should be considered, and may also provide synergistic diuretic effects,especially at higher doses, as well as long-term bene- ficial effects on outcomes
Spironolactone or eplerenone
133
In the absence of hypotension, ______ can be used as first-line therapy in combination with diuretics in the management of AHF patients to improve congestive symptoms
Vasodilators
134
However, in practice vasodilators appear to provide symptom relief in these patients. Vasodilators can be classified as:
(1) predominantly venous dilators, with consequent reduction in ____;
(2) arterial dilators, leading to a decrease in ____
(3) balanced vasodilators,with combined action on both the venous and the arterial system
Preload
Afterload
134
Currently available vasodilators include the organic nitrates (nitroglycerin and isosorbide dinitrate), sodium nitroprusside (SNP), and nesiritide. All of these drugs act by activating soluble guanylate cyclase (sGC) in the smooth muscle cells, leading to higher intracel- lular concentrations of cGMP and consequent vessel relaxation.
They should be used with caution in patients who are preload or afteroad dependent (e.g., ____), because they may cause severe hypotension.
BP should be monitored frequently and the drug discontinued if symp- tomatic hypotension develops.
Ssevere diastolic dysfunction, aortic stenosis, and CAD
135
Organic nitrates are one of the oldest therapies for AHF. These agents are potent venodilators, producing rapid decreases in pulmonary venous and ventricular filling pressures and improvement in pulmonary congestion, dyspnea, and myocardial oxygen demand at low doses. At slightly higher doses and in the presence of vasoconstriction, nitrates are also arteriolar vasodilators, reducing afterload and increasing car- diac output.
136
137
Nitrates are relatively selective for ____, compared to intramyocardial, coronary arteries, resulting in increased coronary blood flow and making them useful for patients with concomitant active myocardial ischemia
Epicardial
138
The starting dose of nitroglycerin is usu- ally 20 μg/min with rapid up-titration occurring every 5 to 15 minutes in either 20 μg/min increments or doubling of the dose.The dose may initially be titrated to the goal of immediate symptom relief,but a blood pressure reduction of at least 10 mm Hg in mean arterial pressure with a SBP greater than 100 mm Hg may be preferable
139
The nitrate dose may need to be reduced if SBP is 90 to 100 mm Hg and will often need to be discontinued with SBP less than 90 mm Hg
140
Early administration of high-dose intravenous nitrates is beneficial in improv- ing arterial oxygenation and potentially preventing some consequences of AHF (MI, need for mechanical ventilation), compared to furosemide alone47 or NIV,92 although these studies were small and not blinded.
141
The major limitation of organic nitrates is the tolerance that typically develops within 24 hours.
___ is the most common adverse effect (20% within 24 hours). Symptomatic hypotension (5%) may also be noted, but generally resolves when nitrate therapy is discontinued.
Given the risk of severe hypotension with potentially catastrophic consequences, the recent use of ____ should be ruled out prior to administration of nitrates.
Headache
Phosphodiesterase 5 inhibitors (sildenafil, tadalafil, vardenafil, etc.)
142
___ induces a balanced reduction in afterload and preload that is exquisitely titratable, due to a very short half-life (seconds to a few minutes) and is particularly effective in the setting of markedly ele- vated afterload (e.g., hypertensive AHF) and moderate-severe mitral regurgitation
Sodium Nitroprusside
143
Nitroprusside, a pro-drug that is rapidly metabolized to nitric oxide and cyanide, has no inherent arrhythmogenic properties, may improve myo- cardial oxygen demand by reducing afterload and wall stress, creates no significant electrolyte disturbances, and is rarely toxic. Despite its potency, severe hypotension is unusual and rapidly resolves
However, significant vasodilation of the intramyocardial vasculature has been noted, possibly producing a ____, and consequently, nitroprusside is not recommended for patients with active ____.
Coronary steal phenomenon
Myocardial ischemia
144
The most common complaints with nitroprusside are related to the ____, including nausea, abdominal discom- fort, dissociative feelings, and dysphoria.
Cyanide metabolite
145
Cyanide rarely accumulates in patients, but impaired hepatic function and doses of greater than 250 μg/min for over 48 hours increase this risk. The thiocyanate metabolite can accumulate in patients with moderate to severe renal insufficiency when exposed to prolonged infusions of high doses (usually >400 μg/min) over days and is usually not relevant in the treatment of AHF. Cya- nide levels may be measured, but rarely return in a timely fashion to be useful.
146
There are no randomized studies of nitroprusside in patients with AHF, although multiple studies demonstrated dramatic reduction in PCWP (15 mm Hg) and marked increases in cardiac output, associated with increases in diuresis, natriuresis, and decreased neurohormonal activa- tion.
147
______, a (recombinant human B-type natriuretic peptide) is identical to endogenous BNP and causes potent vasodilation in the venous and arterial vasculatures, resulting in significant reductions in venous and ventricular filling pressures and mild increases in cardiac output.
Nesiritide
148
An optional bolus of 2 μg/kg followed by a 0.01 μg/kg/min infusion is the recommended starting dose for nesiritide
149
The Vaso- dilation in the Management of Acute CHF (VMAC) trial randomized 489 patients with decompensated CHF and dyspnea at rest to placebo, nitroglycerin, or nesiritide.93 After 3 hours, patients receiving nesir- itide had a significantly greater decrease in PCWP compared to both nitroglycerin and placebo, and improvement in dyspnea compared to placebo (no difference from nitroglycerin).
150
To address these issues, the _____ trial ran- domized 7141 patients with AHF to nesiritide or placebo for 24 to 168 hours.96 At 30 days, there was no difference between patients receiv- ing nesiritide and those receiving placebo with regard to the compos- ite endpoint of death or rehospitalization for heart failure. The clinical effects on dyspnea were relatively modest and have generally not been felt to be clinically important compared to placebo. Use of nesiritide had no impact on worsening renal function but was associated with an increase in the rate of hypotension
ASCEND-HF Trial
151
Another small study (ROSE-AHF) enrolled 360 patients admitted for AHF to specifically assess the effect of low-dose nesiritide on congestion and renal function.97 In this study, nesiritide had no beneficial effect on urine output or cystatin-C, nor on any of the other secondary endpoints reflective of decongestion, renal function, or clinical outcomes, although it was associated with more symptomatic hypotension.
152
The use of these drugs (inotropes and inodilators) should be limited to patients with reduced EF, who present with low SBP (<90 mm Hg) or low measured cardiac output in the presence of signs of congestion and organ hypoperfusion such as decreased mentation or reduced urine output
153
_____is the most commonly used positive inotrope in Europe and the United States, despite evidence that it increases mortality.
Dobutamine
154
Dobutamine at doses of ____ μg/kg/min may improve renal perfusion in patients with cardiogenic shock, although higher doses (_____ μg/ kg/min) may be necessary for more profound hypoperfusion
1-2 ug/kg/min
5-10 ug/kg/min
155
In general, _____ is the preferred inotrope in patients with significant hypotension and in the setting of significant renal dysfunction, given the renal excretion of milrinone.
dobutamine (or dopamine)
156
Concomitant _____ therapy will result in competitive antagonism of the effects of dobutamine and higher doses of dobuamine (10 to 20 μg/kg/min) may be required to obtain the desired hemodynamic effects.
Beta blocker
157
At low doses of dobutamine, stimulation of _____ receptors causes vasodilation, resulting in decreased aortic impedance and systemic vascular resistance with reduction in afterload and indirect increases in cardiac output
Beta2 and Alpha receptors
158
Although there are some methodologic concerns, the _____ study demonstrated significantly increased mortality with dobutamine compared to placebo, consistent with the results of other studies of this class of agents.
CAlcium Sensitizer or Inotrope or NOne in low output heart failure (CASINO)
159
Dopamine should be gradually weaned from these doses down to 3 to 5 μg/kg/min and then discontinued to avoid potential ____ effects of low-dose dopamine.
Hypotensive
160
Low-dose dopamine (_____ μg/kg/min) has been proposed to cause specific dilation of renal, splanchnic, and cerebral arteries, potentially increasing renal blood flow in a selective manner
161
The _____ study of 60 patients admitted for AHF suggested that a combination of low-dose furosemide and low-dose dopamine resulted in comparable urine output and dyspnea relief, but improved renal function profile and potassium homeostasis compared to high-dose furosemide.
DAH-HF
162
However, the _____ study of 161 patients found no beneficial effect of the addition of low-dose dopamine to furosemide
DAD-HF II
163
In the _____ study of 360 patients hospitalized with AHF, low-dose dopamine did not increase urine volume during 72 hours, did not improve cystatin C concentrations, but did reduce hypotension and increased tachycardia compared to placebo. Therefore, there does not appear to be an indication for low-dose dopamine therapy to improve renal function.
ROSE-AHF
164
_____ -dose dopamine (_____ μg/kg/min) results in enhanced norepinephrine release, stimulating cardiac receptors with an increase in inotropy and mild stimulation of peripheral vasoconstricting receptors. Because the positive inotropic effect is largely dependent upon myocardial catecholamine stores, which are often depleted in patients with advanced heart failure, dopamine is a poor inotrope in patients with severe systolic dysfunction.
Intermediate (2-10 ug/kg/min)
165
_____ -dose dopamine (_____ μg/kg/min) causes peripheral and pulmonary artery vasoconstriction, mediated by direct agonist effects on alpha1 adrenergic receptors. These doses pose a significant risk of precipitating limb and end-organ ischemia and should be used cautiously.
High-dose dopamine (10 to 20 μg/kg/min)
166
Epinephrine is a full _____ -receptor agonist and a potent inotropic agent with balanced vasodilator and vasoconstrictor effects.The direct effect of epinephrine on increasing inotropy independent of myocardial catecholamine stores makes epinephrine a useful agent in the treatment of _____.
Beta-receptor
Transplant patients with denervated hearts
167
Many specific inhibitors of PDE IIIa, such as milrinone and enoximone, have been developed to provide organ-specific improvements in hemodynamics through _____.
Increasing myocardial and vascular smooth muscle cell cAMP concentrations
168
Most commonly used PDEI
Milrinone
169
Milrinone therapy may be initiated with a _____ μg/kg bolus over 10 to 20 min, although in clinical practice the bolus dose is usually omitted. Infusions are typically started at _____ μg/kg/min and may be up-titrated to hemodynamic effect
Bolus: 25-75 ug/kg bolus over 10-20 min
Infusion: 0.10-0.25 ug/kg/min
170
Also due to these pharmacodynamics, patients who have had prolonged administration of milrinone may have delayed deterioration, so they should be observed for at least _____ hours after cessation.
48 hours
171
In _____ trial, 951 patients admitted with exacerbation of systolic heart failure not requiring intravenous inotropic support were randomized to milrinone or placebo infusion. There was no difference in the primary endpoint of days hospitalized for cardiovascular causes with 60 days, but significant increases in sustained hypotension and new atrial arrhythmias were noted in the milrinone-treated patients. In addition, a post-hoc sub-group analysis demonstrated increased mortality in patients with an ischemic cause of heart failure who received milrinone. This study reinforces the caution that must be exercised in selecting these agents for the treatment of patients with AHF.
OPTIME-CHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure)
172
_____ is a novel agent that increases myocardial contractility and produces peripheral vasodilation, through cardiac myofilament calcium sensitization by calcium-dependent (systolic) troponin C binding and activation of vascular smooth muscle potassium channels, respectively.
Levosimendan
173
Although Levosimendan may be given with a bolus of _____ μg/ kg over 10 minutes, many clinicians directly initiate a continuous infusion at a rate of _____ μg/kg/min, which may be up-titrated to 0.2 μg/kg/min.
Bolus: 12 to 24 μg/ kg
Infusion: 0.05 to 0.10 μg/kg/min uptitrate to 0.2 ug/kg/min
174
In clinical trials, levosimendan has been shown to significantly increase cardiac output, reduce PCWP and afterload, and improve dyspnea. The potent vasodilating effects of levosimendan can cause significant _____, the risk of which may be reduced by maintaining filling pressures.
Hypotension
175
Levosimendan has an active, acetylated metabolite with a half-life of over _____ hours, allowing it to have hemodynamic effects days after discontinuation of the infusion.
80 hours
176
_____, a recent study of 600 patients, demonstrated significant improvement in the clinical status, serial BNP, and hospital length of stay with levosimendan treatment compared to standard care, but there were also more episodes of hypotension, atrial fibrillation, and ventricular ectopy, as well as a nonsignificant increase in early deaths at 14 to 90 days.
REVIVE-II (Randomized multicenter evaluation of intravenous levosimendan efficacy versus placebo in the short term treatment of decompensated heart failure)
177
_____ randomized 1327 patients with systolic dysfunction, evidence of low cardiac output, and dyspnea at rest despite diuretics and vasodilators to either levosimendan or dobutamine. An early reduction in mortality was not sustained through 180 days, but levosimendan was associated with a greater incidence of atrial fibrillation and lower incidence of WHF compared to dobutamine
SURVIVE (Survival of patients with AHF in need of intravenous inotropic support trial)
178
_____ will redistribute cardiac output centrally at the expense of peripheral perfusion
and increased afterload.
Vasopressors
179
Norepinephrine is a potent agonist of the _____
and the _____ receptors, but is a weaker agonist of _____ receptors, resulting in marked vasoconstriction.
Beta1
Alpha1
Beta2
180
In general, it is the preferred vasopressor for cardiogenic shock
Norepinephrine
181
In the _____ trial, 1679 patients with
shock were randomized to either dopamine or norepinephrine with a nonstatistical difference increase in mortality with dopamine associated with a significant increase in arrhythmic events. In a subgroup analysis including the 280 patients with cardiogenic shock, norepinephrine had improved survival compared to dopamine.
SOAP II
182
Phenylephrine is a selective ____ receptor agonist with potent direct arterial vasoconstrictor effects.
This agent may be used in case of severe hypotension, particularly when the hypotension is related to systemic vasodilation, rather than to a decrease in cardiac output.
Alpha1
183
_____ rapidly improves hemodynamics without increasing heart rate or decreasing BP and may be considered in patients with a low BP due to a low cardiac output.
Digoxin
184
Digoxin may be used intravenously with an ini- tial bolus of _____ mg IV. It should be given slowly because a rapid administration may cause systemic vasoconstriction. The initial bolus should be followed by an oral or IV dose of _____ mg at least 12 hours after the initial dose.
0.5 mg IV
after 12 hours, 0.25mg
185
In patients who continue to have signs and symptoms of HF, digoxin therapy should be continued in addition to other therapies, with a dose resulting in a trough serum concentration of less than ___ ng/mL
< 1 ng/mL
186
_____ may increase the likelihood of developing digitalis intoxication, even at the therapeutic doses.
Ischemia
Hypokalemia
Hypomagnesemia
187
Digoxin should not be used in patients with _____.
Moderate to severe renal impairment
Ongoing ischemia
Advanced AV block
188
_____, also known as antidiuretic hormone, is the main regulator of plasma osmolality.
Arginine vasopressin (AVP)
189
In particular, vasopressin appears to be the major contributor to the development of the _____ observed in patients with HF.
Hyponatremia
190
In patients with AHF, volume overload, and persistent hyponatremia at risk for or having active cognitive symptoms, therapy with a _____ for short-term improvement in serum sodium concentration may be considered.
Vasopressin antagonist
191
Currently available vasopressin antagonists are tolvaptan (an oral, selective V2 receptor antagonist) and conivaptan (a V1a/V2 receptor antagonist for IV use). Although both agents have been approved for the treatment of clinically significant _____, they have not been shown to improve long-term outcomes in heart failure and are not currently approved for this indication.
Hypervolemic and euvolemic hyponatremia
192
_____ was an international trial that evaluated more than 4000 patients admitted with AHF and reduced EF. Tolvaptan added to standard therapy for AHF modestly improved signs and symptoms during hospitalization and modestly reduced body weight without affecting renal function, HR, or BP, but post-discharge survival and readmission rate were not affected by chronic post-discharge therapy with tolvaptan
The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST)
193
A recent small double blind study of short-term (48 hours) therapy with tolvaptan vs placebo in AHF, the _____ study, did not show a clinically important benefit of tolvaptan therapy in this setting
TACTICS-HF
194
_____ without significant myocardial depressant effects, such as nicardipine and clevidipine, may be potentially useful in patients with AHF presenting with severe hypertension refractory to other therapies. In a pilot study of 104 patients with hypertensive AHF who exhibited pulmonary congestion, clevidipine rapidly provided significant blood pressure control associated with improvement in dyspnea compared to standard of care.
Calcium channel blockers (CCBs)
195
The theoretical advantage of ultrafiltration is the removal of _____, resulting in greater and more reliable salt removal, potentially without the neurohormonal activation seen with diuretics
Isotonic fluid
196
Potential limitations of ultrafiltration include the need for _____. Although theoretically attractive, the appropriate use of ultrafiltration in AHF remains uncertain.
(1) Large-bore venous access
(2) Systemic anticoagulation
(3) Increased complexity of nursing care related to management of the device
197
_____ trial randomized 200 patients with AHF to veno-venous ultrafiltration or standard of care within 24 hours of initial presentation. Patients receiving ultrafiltration demonstrated a greater reduction in body weight at 48 hours, but no improvements in dyspnea and/or renal function. Intriguingly, there was a reduction in post-discharge events at 90 days with ultrafiltration, although the number of events was small
The Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure (UNLOAD)
198
_____ randomized 188 patients with AHF, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic care (intravenous diuretics dosed by the investigator to maintain urine output of 3 to 5 L/day plus intravenous vasodilators or inotropes if needed to achieve target urine output) or ultrafiltration (fluid removal rate 200 mL/hr). Ultrafiltration resulted in similar weight loss (approximately 12 pounds), but resulted in an increase in creatinine levels, compared to standard care, and was associated with more serious adverse events, especially kidney failure, bleeding complications, and intravenous catheter-related complications. This trial enrolled a high-risk population with a composite rate of death or rehospitalization at 60 days of over 50%
The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS)
199
_____ was designed as an 810-patient trial that was terminated early after 224 patients were enrolled. Although underpowered, there were trends suggesting longer time to first HF event and fewer HF and cardiovascular events in the adjustable ultrafiltration group compared to those randomized to adjustable intravenous loop diuretics. There was no difference in renal function, but more patients assigned to ultrafiltration experienced adverse events.
The AVOID-HF study (Aquapheresis Versus Intravenous Diuretics and Hospitalizations for Heart Failure, NCT01474200)
200
Administration of _____ along with high-dose furosemide and sodium and fluid restriction may be associated with greater diuretic and clinical response.
Hypertonic saline (HSS; 3%)
201
The _____ study randomized 1771 patients hospitalized for AHF to a single-blind strategy of hyper- tonic saline solution (150 mL 3% NS) plus furosemide 250 mg intravenous bolus twice daily and sodium restriction to 120 mmol/day versus furosemide 250 mg intravenous bolus twice daily and sodium restriction to 80 mmol/day; both groups received a fluid intake of 1000 mL/day. After discharge, the HSS group continued with 120 mmol Na/day; the second group continued with 80 mmol Na/day. There was a shorter length of stay, increased creatinine clearance at discharge, reduced readmission rate, and improved survival for patients in the hypertonic saline group. These hypothesis-generating data are intriguing, but they are limited by the unblinded study design and the potential confound- ing by post-discharge management.
SMAC-HF
202
_____ was first identified as a major hormone of pregnancy with powerful systemic and renal vascular effects, as well as beneficial effects on cardiac preconditioning and ischemia, inflammation, fibrosis, and apoptosis.
Relaxin
203
Relaxin was first identified as a major hormone of pregnancy with powerful systemic and renal vascular effects, as well as beneficial effects on cardiac preconditioning and ischemia, inflammation, fibrosis, and apoptosis. _____ demonstrated encouraging effects in a dose-finding pilot study of 234 patients with AHF.
Serelaxin (recombinant human relaxin-2)
204
The Phase III _____ trial enrolled 1161 patients within 16 hours of presentation who had dyspnea, congestion, mild-to-moderate renal insufficiency, and SBP greater than 125 mm Hg and randomized them to standard of care with a 48-hour infusion of either serelaxin (30 μg/kg/day) or placebo. The trial demonstrated efficacy of serelaxin in improving dyspnea as quantified by the area under the curve of the change from baseline dyspnea visual analog scale over 5 days, which was associated with improvements in signs of congestion, decreased in-hospital WHF, shorter length of stay, and both cardiovascular and all-cause mortality at 180 days. There were no significant changes in the dyspnea score as assessed by the 7-level Likert scale over the first 24 hours nor any endpoint related to HF rehospitalizations. Serelaxin treatment was also associated with improved markers of end-organ damage or dysfunction, including cardiac, renal, and hepatic markers .There were no serious adverse events of hypotension or other safety signals in the serelaxin-treated patients
RELAX-AHF (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure)
205
Mechanistic studies have confirmed serelaxin’s beneficial effects on hemodynamics125 and renal function. The _____trial, enrolling over 6600 patients admitted for AHF, evaluated the effects of serelaxin compared to placebo on WHF through 5 days and 180-day cardiovascular mortality and showed no significant benefit.
RELAX-AHF-2
206
_____, a modified version of pro-ANP, is a 32-amino-acid hor- mone, synthesized and secreted from the distal tubules of the kidney that regulates renal sodium absorption and water homeostasis via binding to NPR1 receptors and increasing intracellular cGMP levels.
Urodilantin
207
_____, a synthetically produced urodilatin, has demonstrated beneficial effects on hemodynamics and symptom relief in two studies of patients with AHF.
Ularitide
208
The _____ trial (NCT01661634) enrolled 2157 patients with symptomatic AHF and randomized them to a 48- hour infusion of either ularitide (15 ng/kg/min) or placebo. Ularitide did not significantly improve either primary endpoint of the clini- cal composite endpoint through 5 days or cardiovascular mortality during the course of the study. Ularitide had no beneficial effect on any secondary endpoint without evidence of end-organ protection and increased creatinine associated with a doubling of hypotension
TRUE-AHF
209
______ block the first enzymatic step in the RAAS cascade, leading to a profound suppression of this neurohormonal system
Direct renin inhibitors (DRIs)
210
The _____ trial enrolled 1639 hemodynamically stable patients a median 5 days after admission for AHF with EF less than 40%, elevated natriuretic peptides, and signs or symptoms of fluid overload who were randomized to daily oral aliskiren or placebo. Aliskiren treatment was associated with higher rates of hyperkalemia, hypotension, and renal impairment/renal failure compared to placebo after a median follow-up of 11.3 months, but there was no difference in cardiovascular death or heart failure rehospitalization at 6 or 12 months
ASTRONAUT
211
Endothelin receptor antagonists block the actions of _____, the most powerful endogenous vasoconstrictor that is produced by the vascular endothelial cells. It exerts its effects by binding to two receptors, ETA and ETB, located on the vascular smooth muscle cells, resulting in significant systemic arterial vasoconstriction.
ET-1
212
_____, a nonselective ETA-B antagonist, has been shown to improve hemodynamics in patients with AHF
Tezosentan
213
The _____ studied more than 1400 patients admitted with AHF in a large, international trial. The addition of IV tezosentan to standard therapy did not improve symptoms nor decrease WHF or mortality at 7 days after randomization.
Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Study (VERITAS)
214
Another approach to neurohormonal antagonism in AHF included the angiotensin II type I receptor beta-arrestin-biased ligand, _____, which increases signaling of the beta-arrestin mediated pathways stimulating inotropy while simultaneously antagonizing the classic G-protein angiotensin II signaling pathways.
TRV027
215
The _____ study enrolled 621 patients admitted with AHF in a dose-ranging study of a 48 to 96 hour infusion of TRV027 compared to placebo. TRV027 did not confer any benefit over placebo at any dose with regards to the primary composite endpoint or any of the individual components, although there were no significant safety issues.
BLAST-AHF
216
_____ is the first compound in a new class of vasodilators. Their mechanism of action is similar to that of organic nitrates (and their end product NO) because both classes of drugs activate the sGC in smooth muscle cells, thus leading to the synthesis of cGMP and subsequent vasodilation. It has been shown to improve hemodynamics in patients with AHF; however, at high doses, it has been associated with significant hypotension, which resulted in the termination of early clinical studies
Cinaciguat
217
Vericiguat is an oral sGC stimulator that has been studied in patients enrolled in studies within 4 weeks of a WHF event. In the _____ study of 456 patients, vericiguat did not significantly improve log transformed NT-proBNP concentrations compared to placebo, but there was a suggestion of a dose response
SOCRATES-Reduced
218
_____ represent a new mechanistic class of agents designed to increase myocardial contractility. These agents increase the transition rate from the weakly bound to the strongly bound state necessary for initiation of a force-generating power stroke. Unlike current inotropes, they increase the systolic ejection time without altering the rate of LV pressure development, resulting in increased stroke volume and cardiac output without increases in intracellular cAMP or calcium.
Cardiac myosin activators
219
_____ is the first agent of this class (Cardiac myosin activator) to undergo testing in man. In both healthy volunteers and patients with chronic stable HFrEF, administration of this drug produced dose-dependent increases in systolic ejection time, fractional shortening, stroke volume, and ejection fraction and was well-tolerated over a broad range of plasma concentrations.
Omecamtiv mecarbil
220
In a phase IIb dose-finding study of 606 patients with AHF (_____; NCT01300013), intravenous omecamtiv mecarbil did not meet the primary endpoint of dyspnea improvement com- pared to the pooled placebo, but it was generally well-tolerated, increased systolic ejection time, and improved dyspnea in the high- dose group.
ATOMIC-AHF
221
Istaroxime, the prototype of a new class of drugs, exerts its actions on the myocyte in two ways: _____
(1) via stimulation of the membrane-bound Na-K/ATPase
(2) by enhancing the activity of the sarcoendoplas- mic reticulum Ca/ATPase type 2a (SERCA-2a)
222
The _____ study evaluated 120 patients admitted with AHF and decreased EF. The addition of istaroxime to standard therapy lowered PCWP and HR and increased SBP. The higher infusion dose increased cardiac index and reduced LVED volume. There were no changes in neurohormones, renal function, or troponin I levels during the short 6-hour infusion
HORIZON-HF
223
Therapeutics to prevent or treat acute kidney injury and maintain or improve renal function in the setting of AHF are an important unmet need. Adenosine A receptor antagonists have been developed to increase renal blood flow and enhance diuresis without activating the tubuloglomerular feedback. _____ is a highly selective adenosine A1 receptor antagonist that has been studied in patients with HF.
Rolofylline
224
Despite the positive trends seen in the PROTECT-Pilot study, the Phase III _____ trial failed to show any clinical benefit, including renal protection,139 and was associated with more seizure and stroke events when compared to placebo. Given these results, it is doubtful that these agents will undergo further evaluation in AHF.
PROTECT
