Università di Pisa
Scuola di Specializzazione in Malattie dell’Apparato Cardiovascolare
The role of natriuretic peptides and
echocardiography in the management and
follow up of patients with chronic heart failure
Tutor: Prof. Mario Marzilli Candidate: Dr. Anca Simioniuc
Tutor: Dr. Frank Lloyd Dini
2 Table of contents
Abstract ... 4
I. Introduction ... 5
I.1. Heart failure epidemiology ... 5
I.2. Congestion and diuretic use in heart failure ... 6
I.2.1.Clinical and hemodynamic congestion ... 6
I.2.2. Assessment of congestion ... 7
I.2.3. Grading of congestion ... 7
I.2.4. Loop diuretics in heart failure ... 8
I.3. Natriuretic peptides in heart failure management ... 10
I.3.1. Biology of natriuretic peptides and their role in heart failure according to current guidelines ... 10
I.3.2. Limitations of natriuretic peptides approach ... 11
I.3.4. Scientific evidence of natriuretic peptides use in chronic heart failure management ... 13
I.4. Role of echography in chronic HF management ... 17
I.5. Potential role of integrated natriuretic peptide and echocardiography in chronic heart failure management ... 19
II. Aim of the study ... 21
III. Materials and methods ... 22
III.1. Patient selection ... 22
III. 2 Echocardiography ... 22
III. 3. Clinical assessment and measurement of biological variables ... 23
II. 4 Statistical analysis ... 23
IV. Results ... 24
IV. 1. Patients characteristics ... 24
IV. 2. Mortality rate ... 25
IV. 3. Changes in biochemical parameters ... 26
IV. 4. Changes in echocardiographic parameters ... 28
IV. 4. Changes in medication ... 30
V. Discussion ... 33
VI. Study limitations and future perspectives. ... 35
VII. Conclusions ... 36
3 Abbreviations and acronyms:
ACEi = Angiotensin Converting Enzyme Inhibitor ADHF = Acute Decompensated Heart Failure ARB = Angiotensin Type 1 Receptor Blocker BB = Beta Blocker
BNP = B-type Natriuretic Peptide BV = Biological Variability EDT = E Wave Deceleration Time
eGFR = estimated Glomerular Filtration Rate HF = Heart Failure
LVDP = Left Ventricular Diastolic Pressure LVEF = Left Ventricular Ejection Fraction MDRD = Modification of Diet in Renal Disease MRA = Mineralocorticoid Receptor Antagonist
NYHA = New York Heart Association
NP = Natriuretic Peptides
NPV = Negative Predictive Value
NT-proBNP = N-Terminal pro Brain Natriuretic Peptide PPV = Positive Predictive Value
RCV = Reference Change Value RV = Right Ventricle
SOC = Standard Of Care
4
Abstract
Background. The concept of echo and natriuretic peptide (NP) guided therapy is
appealing since currently there is no objective guide to optimal dosing of therapy and loop diuretics in particular in patients with chronic heart failure (CHF).
Aim. To assess whether echo and NP guided therapy may be useful for the management
of patients with CHF due to left ventricular systolic dysfunction.
Materials and methods. We retrospectively analyzed the multicentric individual data of
414 patients with CHF with reduced ejection fraction; during ambulatory follow-up, the therapy (including loop diuretics) was titrated according to the presence of echocardiographic signs of elevated left ventricular filling pressures and NP serum levels. Mortality rate, changes in renal function, NP levels, cardiac function and medication doses were analyzed.
Results. The median follow-up duration was 1030 days. The mortality rate was 3,7% per
year. During the observation period, the dose of loop diuretics increased by 20%. An increase of ≥ 0.3 mg/dL in serum creatinine was reported in 15% of the patients. Newly diagnosed renal dysfunction (eGFR <60 ml/min/1.73m2) occurred in 10% of patients. There was a significant decrease in NP levels and an improvement in LV filling pressures and systolic function. Regarding other therapies, significantly more patients were using beta blockers at follow up and the doses were increased. Non significant changes in the percentage of patients treated and in the medication dose was noted for Angiotensin Converting Enzyme Inhibitors/ Angiotensin Type 1 Receptor Blockers (ACEi/ARB) and for Mineralocorticoid Receptor Antagonists (MRA).
Conclusion. Our study suggests that the outcome of patients with CHF might be improved
by the integrative use of clinical examination, biochemical and echocardiographic parameters. These effects are likely to be mediated by an appropriate use of loop diuretics and kidney function preservation.
5
I. Introduction
I.1. Heart failure epidemiology
Heart failure (HF) is a complex syndrome that can result from many structural or functional cardiac disorders that alter the pump function of the heart and its ability to sustain a physiological circulation.
Heart failure is a major public health problem, with a prevalence of 1–2% (in the adult population of developed countries) (1), and an incidence of 5–10 per 1000 persons per year.
The incidence and prevalence of HF significantly increase with age. In fact, the estimated prevalence is 6% to 10% in people older than 65 years of age (2), and almost 15% in those older than 85 years of age (3). This is partially explained by significant improvements in survival of people with ischaemic heart disease, more effective treatments for heart failure and consistent ageing of population in the last decades; it is reasonable therefore to prospect an even more increase of prevalence of HF in the near future. By 2030, the American Heart Association estimates an increase of 25% of HF prevalence with respect to 2013 (4).
Despite advances in the treatment of HF, morbidity and mortality remain high. Patients with HF have a poor prognosis, with worse survival rates than breast or prostate cancer (5). There is also a significant economic impact of HF, related not only to the specific pharmacologic and device therapies, but also to the high rate of hospitalizations, which amount for approximately 70% of total costs (5), (6).
Readmissions for HF are common; almost 25% of patients are readmitted within three months (7), (8). Patients also report a dramatic decrease in their quality of life, with an important social impact, as well as on their families and their caregivers (7). There is, however, considerable evidence (9) (10) that pharmacological treatments can improve the prognosis of heart failure. In fact, both pharmacological and non pharmacological treatments can improve patient quality of life, both in terms of physical functioning and subjective well-being (7).
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I.2. Congestion and diuretic use in heart failure
I.2.1.Clinical and hemodynamic congestion
Acute decompensated heart failure (ADHF) is defined as new-onset or worsening HF signs and symptoms requiring urgent therapy, most commonly in the hospital setting. Signs and symptoms usually improve during hospitalization, although mortality during admission remains high, ranging from 5 to 15% (11), (12). Studies also report high mortality rates after hospital discharge (10-15% within 3 months), while readmission rate is estimated around 30% (11), (12) (13).
The re-hospitalization for worsening HF is manly related to the symptoms and signs of congestion (dyspnoea, breathlessness, jugular venous distension, rales, and oedema), rather than low cardiac output. Although congestion is the main reason for hospitalization, many patients are discharged without losing body weight and with persistent signs of congestion (14) (15).
Clinical congestion in HF is defined as a high left ventricular diastolic pressure (LVDP) associated with signs and symptoms of HF such as dyspnoea, rales, and oedema. The term ‘haemodynamic congestion’ has been used to indicate elevation of LVDP in HF patients without overt clinical congestion (16). Often, haemodynamic congestion precedes clinical congestion by days or even weeks. (17) (18), (19).
Thus, clinical congestion may be the ‘tip of the iceberg’ of the haemodynamic derangements that precede symptoms (20). In fact, in chronic HF, even severe haemodynamic congestion rarely causes rales and/or radiographic pulmonary oedema (21), (22).
This may be related to several adaptive pathophysiological changes such as increases in alveolar capillary membrane thickness, increased lymphatic drainage, and/or pulmonary hypertension. Theoretically, haemodynamic congestion may contribute to the progression of HF by further activating neurohormones and by causing subendocardial ischaemia, resulting in myocardial necrosis/ apoptosis and/or secondary mitral insufficiency by its effects on LV geometry (changing it from an ellipsoid to a sphere).
In addition, elevated right atrial pressure may contribute to the cardio-renal syndrome through reduction of the perfusion gradient across the kidneys.
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I.2.2. Assessment of congestion
Available guidelines recommend treatment to improve symptoms and signs of congestion and that patients achieve near-optimal volume status prior to discharge; however, there is no established algorithm for the assessment of congestion. Cardiac catheterization, the gold standard for evaluating haemodynamic congestion (23), has limited applications in clinical practice, due to its invasive nature. Clinical signs and symptoms, on the other hand, are partially limited by their sensitivity and specificity, as described in Table 1.
Diagnostic value of clinical markers of congestion
Sign or symptom Sensitivity Specificity PPV NPV
Dyspnoea on exertion 66 52 45 27
Orthopnoea 66 47 61 37
Oedema 46 73 79 46
Resting jugular vein distension
70 79 85 62
Third heart sound (S3) 73 42 66 44
Table 1 Diagnostic value of clinical markers of congestion (20): PPV, Positive Predictive Value; NPV, Negative Predictive Value. All numbers are expressed as percentages
I.2.3. Grading of congestion
A systematic approach to grading congestion would be helpful in initiating and following response to therapy. Several scores for grading congestion have been proposed (20), combining clinical evaluation (dyspnoea, orthopnoea, oedema, jugular venous pressure, hepatomegaly), laboratory exams (e.g natriuretic peptides) and dynamic maneuvers (e.g. 6 minutes walking test). Based on these scores, therapy for fluid removal could be adjusted
8 with the goal of reducing the overall amount of congestion, with re-hospitalization as the measured outcome.
I.2.4. Loop diuretics in heart failure
Evaluation and optimization of volume status is an essential component of treatment in patients with systolic or diastolic heart failure (HF). Removal of excess extracellular fluid with diuretics to treat peripheral and/or pulmonary edema is fundamental for volume management. In contrast to other HF therapies such as angiotensin inhibitors, beta blockers, and aldosterone antagonists, limited outcomes data are available for diuretic therapy. According to current guidelines, diuretic therapy is recommended to restore and maintain normal volume status in patients with clinical evidence of fluid overload, generally manifested by congestive symptoms or signs of elevated filling pressures. The initial dose of diuretic may be increased as necessary to relieve congestion and restoration of normal volume status may require multiple adjustments over many days and occasionally weeks in patients with severe fluid overload. Patients requiring diuretic therapy to treat fluid retention associated with HF generally require chronic treatment, although often at lower doses than those required initially to achieve diuresis. Decreasing or even discontinuing diuretics may be considered in patients experiencing significant improvement in clinical status and cardiac function. These patients may undergo cautious weaning of diuretic dose and frequency with careful observation for recurrent fluid retention. Selected patients may be educated to adjust daily dose of diuretic in response to weight gain from fluid overload (24).
Diuretics management is crucial in patients with HF, as high diuretic doses may associate with poor outcome in patients with chronic HF (25). In the acute setting, loop diuretics are very effective in achieving euvolemia in the presence of persistent congestion; nevertheless they are often continued chronically even once congestion has resolved. In a retrospective analysis of the Studies Of Left Ventricular Dysfunction (SOLVD), the use of non– potassium-sparing diuretics (including furosemide) was associated with increased risk of hospitalization for progression of CHF, increased risk of death from progressive CHF, and increased cardiovascular and all-cause mortality when compared with no diuretic or combination therapy (i.e., combination of a potassium-sparing with a non–potassium-sparing diuretic) (26). The underlying mechanisms are likely to involve the
rennin-9 angiotensin-aldosterone system (RAAS) activation by loop diuretics, as demonstrated on animal models and patients with chronic heart failure (27).
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I.3. Natriuretic peptides in heart failure management
In this chapter we shall present the biology of natriuretic peptides (NP) and their role in acute HF management according to current guidelines; we shall analyze some of the NP limitations; finally, we shall resume the conclusions of the significant clinical trials comparing the standard of care (SOC) therapies for chronic HF with SOC plus NP-guided management.
I.3.1. Biology of natriuretic peptides and their role in heart failure according to current guidelines
Circulating levels of natriuretic peptides (NP) are normally very low in healthy individuals. In response to increased myocardial wall stress due to volume- or pressure-overload states (such as in HF), the BNP gene is activated in cardiomyocytes. This results in the production of an intracellular precursor propeptide (proBNP); further processing of this propeptide results in release of the biologically inert aminoterminal fragment (NT-proBNP) and the biologically active BNP (28)
In addition, a significant portion of BNP or NT-proBNP detected by current assays includes uncleaved proBNP whereas BNP concentrations also include the detection of various subfragments that arise from the degradation of the intact BNP hormone.
The biological activity of BNP includes stimulation of natriuresis and vasorelaxation; inhibition of renin, aldosterone, and sympathetic nervous activity; inhibition of fibrosis; and improvement in myocardial relaxation. Although released in a 1:1 ratio, the measured NT-proBNP level is higher than that of BNP, in part because NT-proBNP is passively cleared from the circulation more slowly (half-life of 120 versus 20 minutes). Unlike BNP, NT-proBNP is not cleared by natriuretic peptide receptors or neutral endopeptidases. Rather, NT-proBNP is cleared by various organs, including the skeletal tissue, liver, and kidneys. A common misconception is that NT-proBNP is more dependent on renal function for clearance than is BNP; both are equally cleared by the kidneys. B-type natriuretic peptide and NT-proBNP levels are increased in HF, and correlate well with ventricular wall stress and severity of HF. The Breathing Not Properly Multinational Study and the Pro-BNP Investigation of Dyspnea in the Emergency Department showed that NP levels were more accurate for diagnosis or exclusion of acute decompensated heart failure
11 (ADHF) than clinical judgment, particularly in the context of diagnostic uncertainty. When added to comprehensive clinical assessment, BNP and NT-proBNP are both incrementally useful for diagnosis of ADHF, and both are endorsed in current practice guidelines for HF evaluation (particularly when diagnostic indecision is present). Elevated BNP or NT-proBNP values are prognostically meaningful in chronic HF, and a rising pattern is predictive of impending adverse outcome, irrespective of other subjective and objective prognostic metrics. Furthermore, therapies that are favorable for chronic HF tend to lower concentrations of BNP or NT-proBNP. Thus, there is increasing interest in guiding HF therapy with BNP or NT-proBNP, with the goal of lowering concentrations of these markers (and maintaining their suppression) as part of the therapeutic approach in HF. However, recent European Society of Cardiology (ESC) and American Heart Association/ American College of Cardiology guidelines (29) (30) did not recommend biomarker-guided therapy in the management of chronic HF patients. This may be in part due to the known limitations of the NP approach; moreover, some trials comparing SOC versus SOC + NP guided management of HF give contradictory results.
I.3.2. Limitations of natriuretic peptides approach
Limitations of NP-based approach include major limitations (like biological variability, slow timecourse in response to therapy, low specificity) and minor weaknesses (such as cost and venipuncture).
Biological variability.
The term “biological variability” (BV) refers to the extent of changes of a biomarker in a stable physiological state. Biological variability has been tested for different cardiac markers. For acute decompensated heart failure diagnosis and management of therapy a within-day or day-to-day changes are relevant, while for chronic HF follow up a week-to-week testing is more appropriate (31).
For NP, the reference change value (RCV) is an important parameter and it represents the percent change that the next test result must exceed before it exceeds the biomarker’s BV. Reference change values for NT in the acute and chronic HF setting are presented in Table 2.
12 Biomarker Within-day Day-to-day Week to week
Up Down Up Down Up Down
BNP 39% -28% 109% -52% 198% -66%
NT-proBNP2 29% -22% 73% -42% 175% -61% Table 2 Reference change values for acute and chronic heart failure markers (32).
The role of BNP and NT-proBNP for monitoring heart failure disease risk can be questioned given the relatively high BVs that have been reported. In clinical practice, if the decline in the natriuretic peptides is less than the RCV, one can conclude that the biomarker cannot be used in that clinical context. Using results from published trials, the success of diuretic therapy results in a significant decrease in BNP/NT-proBNP concentrations that greatly exceed the within-day RCV. Typically, there is also a statistically significant change in the natriuretic peptide concentrations at hospitalization discharge relative to admission values. These data suggest that high biological variances do not limit the use for these tests in this context. However, when results were examined in an outpatient context, week-to-week and month-to-month changes in patients with improving or declining health were not always accompanied by a significant change in the natriuretic peptid. This may explain why routine monitoring of heart failure patients on an outpatient basis has not achieved the level of evidence warranting incorporation into international cardiology guidelines.
Time course of BNP changes in response to therapy
Ideally, a biomarker should reflect as quickly as possible improvement or worsening of patients’ conditions, either spontaneous or therapy-induced. Some studies of serial BNP measurements suggest that concentrations of NP may require a longer time (up to 2 weeks) after a therapy change to stabilize (33); obviously, this may become important when NP are planned to be used in unstable clinical scenarios.
Low specificity.
Although NP directly reflect variations in parietal stress, the specificity of this finding is not absolute. In fact, BNP and NT-proBNP levels change not only in case of volume overload/volume reduction, but also in response to arrhythmias, myocardial ischemia,
13 valvular heart disease, only to mention cardiac factors. Also non-cardiac factors, including age, sex, body mass index and genetic factors may act as confounders, as also pulmonary hypertension, pulmonary embolism and chronic kidney disease (34).
Cost
NP measurements, though not very expensive add to the overall cost of HF therapy. The additional cost for each BNP measurement varies largely from hospital to hospital, and averages 30 €. NTproBNP measurement is generally more expensive. Given the need for serial measurements and the number of the HF populations, it is easy to estimate how much a systematic NP based approach would impact on health cost. Therefore, before entering the routine clinical practice measurement costs of NP should be balanced versus the potential benefits of this approach (e.g. reduced costs of hospitalization, socio-economic impact of quality of life improvement etc).
Need for venipuncture
This may appear as a minor nuisance for doctor and patients, but sometimes the blood sampling may be a challenging task in elderly, fragile or obese patients.
I.3.4. Scientific evidence of natriuretic peptides use in chronic heart failure management
Several clinical trials have been published since NP have been proposed for guiding HF therapy. Most of them where relatively small, and results were contradictory; some were clearly sustaining the NP guided therapy (e.g. PROTECT (35), STARS-BNP (36)), some suggested that this strategy might have advantages (e.g.TIME-CHF (37), BATTELSCARRED (38)) and some concluded that there is no benefit from such approach (e.g. PRIMA (39), STARBRITE (40)).
Considering the relative small number of patients enrolled in each of these studies, several meta-analysis were published while attending larger randomized clinical trials. Most of them used aggregate data with limitations relating to potential heterogeneity of patient characteristics and outcome definitions. Nevertheless, a 20 to 30% reduction in all cause mortality due to NP guided therapy was suggested.
14 As recent as March 2014, Troughton and al. (41) published a meta-analysis of 11 studies, including 9 studies providing individual patient data and 2 studies providing aggregate data; this methodology allowed for a more rigorous testing and offered the opportunity to consider important patient characteristics that could influence outcomes or moderate the effects of treatment interventions on outcomes. The peptide target, primary end-point and the follow up schedule of these 11 studies are presented in Tables 3a and 3b.
Studies providing individual patient data
Peptide target Primary endpoint Follow-up
Christchurch Pilot (42) NT-proBNP <1700 pg/mL Mortality + CV hospitalization + out-patient HF
2-weekly until target met, then 3-monthly TIME-CHF (37) NT-proBNP <400; NT-proBNP <800 Survival free of hospitalization 1, 3, 6, 12, 18 months Vienna (43) NT-proBNP <2200 pg/mL Survival without HF hospitalization
2-weekly to meet target, 1, 3, 6, and 12 months
PRIMA (39)
Individual: lowest NT-proBNP at discharge or at 2-week follow-up
Days alive and out of hospital
2 and 4 weeks, then 3 monthly
SIGNAL-HF (44) NT-proBNP reduction >50% from baseline
Composite of days alive, days out of hospital and symptom score 1, 3, 6, and 9 months BATTLESCARRED (38) NT-proBNP <1300 pg/mL All-cause mortality
2-weekly until target met, then 3-monthly
STARBRITE (40) Individual BNP at discharge
Days alive and out of hospital
10, 30, 60, 90, 120 days and additional visits as required
UPSTEP (45) BNP <150 ng/L; BNP <300 ng/L Composite of all-cause mortality, hospitalization, or HF worsening Weeks 2, 6, 10, 16, 24, 36, 48, then 6-monthly PROTECT (35) NT-proBNP <1000 pg/mL Total cardiovascular events
As required to achieve target then 3-monthly
Table 3a. Modified from (41): Peptide target, primary endpoint and follow up in studies providing individual patient data.
15 Studies providing aggregate data
Peptide target Primary endpoint Follow-up
STARS-BNP (36) BNP < 100 pg/mL HF mortality + HF hospitalization
Months 1, 2, 3 and then 3-monthly
Anguita et al. (46) BNP < 100 pg/mL Survival free of HF
hospitalization 1, 2, 3, 6, 12, and 18 months Table 4b. Modified from (41): Peptide target, primary endpoint and follow up in studies providing aggregate data.
Interestingly, the majority of studies used a single target BNP or NT-proBNP level for the NP-guided group. In one study, a target of ≥50% reduction in NT-proBNP was used (44) and in a further two studies an individualized BNP or NT-proBNP target was utilized based on levels at discharge from hospital (39), (40).
The largest study included in the meta-analysis was the TIME-CHF (251 patients in the NP-guided group vs 248 patient in the clinically guided group). The 9 studies providing individual patient data amounted for 1081 vs1070 patients in the BNP- vs clinically guided groups.
The mean age of patients was 72 years old, two thirds were male, the mean baseline left ventricular ejection fraction (LVEF) was 31 %; most patients had a baseline LVEF ≤ 45%, but 4 out of 8 studies also enrolled a small number of patients with a LVEF ≥45%. Overall, 91% of patients had a LVEF ≤ 45%. The baseline mean creatinine levels were 120 micromol/L (equivalent to 1,36 mg/dL). Seven studies used NT-proBNP as biomarker (with a mean baseline value of 2697 pg/mL); four studies used BNP (with a mean baseline level of 446 pg/mL).
The percentage of patients receiving medications recommended by heart failure guidelines was very high and similar to percentages reported in large randomized controlled trials performed during the same time period. Among NP-guided patients, ACEi/ARB, BB, and MRA were prescribed in 91, 78, and 29%, respectively, compared with 89, 73, and 29% in clinically guided patients. Medications at baseline and at follow up are described in Table 4 and Table 5, respectively.
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Baseline
Dose (mean ± SEM) Percent of patients at target (%)
Clinical NP Clinical NP
ACEi/ARBa 61 ± 2 64 ± 2 32% 36%
Beta-blockera 32 ± 1 38 ± 1 11% 14% Spironolactone (mg) 9.1 ± 0.6 9.5 ± 0.6 26% 26% Loop diuretic (mg) 72 ± 3 66 ± 3 – –
Table 5 . Medication at baseline.a ACEi/ARB and beta-blocker doses are expressed as percent of target values as defined by guidelines and reported as mean ± standard error of the mean for all subjects within each treatment group; percent at target, percentage of patients within each treatment group who were at 100% of target dose as defined by guidelines.
Study end
Dose (mean ± SEM) Percent of patients at target (%)
Clinical NP Clinical NP
ACEi/ARBa 60 ± 2 70 ± 3 34% 41%
Beta-blockera 39 ± 2 42 ± 2 19% 19% Spironolactone (mg) 9.8 ± 0.6 11.1 ± 0.7 26% 28% Loop diuretic (mg) 66 ± 5 67 ± 5 – –
Table 6. Medication at study end.aACEi/ARB and beta-blocker doses are expressed as percent of target values as defined by guidelines and reported as mean ± standard error of the mean for all subjects within each treatment group; percent at target, percentage of patients within each treatment group who were at 100% of target dose as defined by guidelines.
Of note, mean doses of all medications were much lower than those recommended by guidelines, and very few patients were at target dose (less than half for ACEi/ARB and less than one fifth for beta-blockers).
17 At a mean 2 years follow up, the primary end point (overall mortality) was lower for the NT-guided group; this was mainly due to an improved survival in younger patients. In patients older than 75 years , the NT approach showed no benefit.
For the secondary end point, NT-guided treatment was superior to clinically-guided group for heart failure hospitalizations, but not for all cause hospitalizations, irrespective of age. The NP levels equally decreased in both treatment groups, and the fall was significantly grater for patients younger than 75 years.
At follow up, doses of ACEi/ARB were significantly increased in the NP-group, and unchanged clinical-group. When discriminated by age, ACEi/ARB doses increased in the NP-group independently of age, while in the clinical-group the doses were increased for patient under 75 years, but tend to fall for older patients. Beta blockers increased in both treatment groups, more significantly in younger patients with respect to older patients. Inclusion of change in ACEi/ARB dose, change in BB dose, and change in MRA dose demonstrated that increasing doses of each of these medications was significantly associated with reduced all-cause mortality, irrespective of the treatment group..
Loop diuretic doses increased for both strategy groups in patients younger than 75 years, but not in older patients.
The meta-analysis concludes that for patients younger than 75 years NP-guided treatment reduced all-cause mortality compared with clinically guided therapy, while hospitalizations for heart failure are reduced by the NP strategy irrespective of age.
I.4. Role of echography in chronic HF management
Echography in patients with HF shows several prerequisites for being useful, not only in the acute clinical setting, but also in the long term follow up. According to the recent ESC guidelines on heart failure, echocardiography is the imaging method of choice for reasons of accuracy, availability (including portability), safety and cost. The more frequently used echo parameters are reported in Table 6.
18 MEASUREMENT ABNORMALITY
CLINICAL IMPLICATIONS Parameters related to systolic function
LV ejection fraction Reduced (< 50%)
LV global systolic dysfunction
RV TAPSE Reduced (< 16 mm)
RV global systolic dysfunction Parameters related to diastolic function
E/e' ratio Increased (> 15) High LV filling pressure Parameters related to pulmonary congestion
B-lines > 5 in anterior chest scan Extravascular lung water Parameters related to valvular function
Mitral valve dysfunction Severe mitral regurgitation Cause/consequences of HF Parameters related to contractile reserve
Global LV function during
stress No contractile reserve Unresponsive scar tissue Table 7. Common echocardiographic and lung sonography abnormalities in patients with heart failure. LV, left ventricle; RV, right ventricle; TAPSE, tricuspid annular plane systolic excursion.
They are certainly simple to measure, even with pocket-size instruments, and reasonably reproducible in expert hands. They are associated with strong prognostic power, and several have shown independent and incremental prognostic value over standard clinical and bio-humoral predictors. They explore different and complementary aspects of HF pathophysiology including: left ventricular function (usually with ejection fraction with biplane Simpson method, or - even better - with Real Time 3D); right ventricular function (with tricuspid annular plane systolic excursion); diastolic function (with left atrial volume index, E/e’ ratio, E wave deceleration time); extravascular lung water (exploring pulmonary congestion with lung B-lines); mitral-insufficiency; pulmonary hypertension (with pulmonary artery systolic pressure). Another extremely attractive field is the assessment of the behavior of these markers during exercise. Stress echo applications beyond coronary artery disease are emerging as an attractive field, and there is no question
19 that a moderate mitral insufficiency becoming severe during stress and accompanied by B-lines and pulmonary hypertension can make a mitral valve repair an attractive therapeutic option.
I.5. Potential role of integrated natriuretic peptide and echocardiography in chronic heart failure management
Echocardiography and NPs both provide powerful assessments of cardiac structure and function and clinical status across the spectrum of cardiac disease.
As previously shown, echocardiographic indices and NP levels yield important prognostic information in patients with acute and chronic stable HF independent of other clinical variables, and both of them are helpful in the management of patients with HF.
Therefore, it is reasonable to hypothesize the NPs may provide additive predictive power to echocardiography in patients with HF, and vice versa.
In a review published in 2012, Yin et al (47) describe the potential complementary role of echocardiography and NP for the management of patients with HF. First of all, the echocardiographic estimation of mitral E/e’ ratio, as well as the NP correlate well with LV filling pressures. The correlation in stronger for the E/e’ ratio, but the measurements of NP may be useful when the echocardiographic estimation is less precise (“gray zone” of the E/e’ ratio, patients with non sinus rhythm or mitral valve disease etc.).
Second, NPs are proteins released by the ventricles in the presence of myocytic stretch, and the NP levels reflect a compilation of systolic and diastolic as well as RV and valvular functions. Therefore, NPs may provide additive clinical information independently to other cardiac morphological abnormalities and may predict long-term mortality and readmission for HF independent of echocardiographic parameters.
Third, as already shown in a previous chapter, NPs are significantly affected by age, sex, renal function and obesity and they may yield intraindividual variations over time. NPs are characterized with high sensitivity, but low specificity for the detection of elevated LV filling pressures whereas echocardiography may improve the accuracy of HF diagnosis and prognostication in the setting of intermediate BNP or NT-proBNP levels.
Fourth, the treatment for patients with HF can cause changes of mitral E/e’ and NP levels. While LV filling pressures were being manipulated, the relationships between mitral E/e’ and PCWP may became variable. Hence, both NP levels and mitral E/e’ may not be
20
interchangeable, but rather complementary in monitoring the response to treatment of patients with HF.
Finally, in patients with chronic systolic HF stabilized by medical treatment, the combination of echocardiographic indices and NPs has been noted to supply independent and incremental contributions to prognostic stratification . In New York Heart Association (NYHA) class I and II patients, NT-proBNP and mitral E/Ea ratio are also incremental for risk stratification. Moreover, NT-proBNP or BNP may guide more effective use of echocardiography in screening and risk stratification for stage A/B HF patients. In addition, the integration of both tests may identify patients with valvular disease at the greatest risk for progression and guide decision making timely to an intervention.
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II. Aim of the study
Natriuretic peptides and echocardiography are both useful tools in management of patients with HF. Their role is fundamental especially in the acute setting of HF, as confirmed by current guidelines.
In chronic heart failure management, NP have been tested in several small trials. More than one meta-analysis suggested beneficial outcomes of the NP –guided strategy, but convincing, strong scientific evidence is still lacking. This is confirmed by the fact that larger clinical trials are still ongoing, while current guidelines do not advise at the moment such approach for the chronic HF management.
We believe that NP and echocardiopraphy may add a significant benefit to the outcome of patients with chronic HF, when utilized in an integrative and personalized manner. The complementarity of methodologies can overweight their intrinsic limitations, with crucial benefits for the patient.
The purpose of our study is to investigate the additional role of echocardiography and NP assessment for the management of patients with chronic HF.
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III. Materials and methods
III.1. Patient selection
The population of our study included patients hospitalized for acute decompensated HF (enrolled at the time of hospital discharge) as well as patients referred to our ambulatories with an occasional finding of asymptomatic LV systolic dysfunction. All patients had a LVEF ≤45%, assessed by transthoracic echocardiography at baseline. Natriuretic peptides at baseline did not represent a selection criteria.
Exclusion criteria were hypertrophic cardiomyopathy, secondary forms of cardiomyopathy such as restrictive cardiomyopathy or infiltrative cardiomyopathy, congenital heart diseases, and any life-threatening conditions with adverse prognosis other than cardiovascular disease. The study was performed by the University Cardiology of Pisa in collaboration with the Cardiology of Perugia and Cardiology of Pavia. Data were analyzed in a retrospective manner.
During the follow-up period, the frequency of clinical assessments was decided by the clinician, on individual basis. Echocardiography and NP measurements were available at each visit and decisions were taken based on guidelines standard of care, NP values and echocardiographic parameters.
III. 2 Echocardiography
Transthoracic 2-dimensional and Doppler echocardiographic examination was performed at each visit. LV volumes and EF were calculated from apical 2- and 4-chamber views using the modified Simpson’s rule. LV volume indices and LV mass index were calculated. Maximal left atrial (LA) end-systolic volume was measured from the apical 4-chamber view. Right ventricular systolic function was evaluated by M-mode echocardiography using the tricuspid annular plane systolic excursion (TAPSE). Pulsed wave Doppler mitral flow was analyzed for peak E and peak A velocities, E⁄A ratio, and E wave deceleration time (EDT). Tissue Doppler-derived e’ septal and lateral mitral annulus velocities were measured. The ratio of mitral E peak velocity and averaged e’ velocity (E ⁄ e’) was calculated. Mitral regurgitation severity was graded according to the vena contracta method. The estimated pulmonary artery systolic pressure was obtained by the sum of the
23 Doppler-derived transtricuspid gradient and the estimated right atrial pressure, as assessed by the inspiratory collapse of the inferior vena cava.
III. 3. Clinical assessment and measurement of biological variables
A complete clinical assessment was performed at each visit, including physical examination, hart rate and blood pressure measurements. An ECG was also recorded. B-type natriuretic peptide (BNP), as well as hemoglobin and creatinine levels were registered. Glomerular filtration rate (eGFR) was estimated according to the MDRD formula.
II. 4 Statistical analysis
Continuous variables are expressed as mean ±standard error of the mean, except variables with a non-Gaussian distribution, which are reported as medians and interquartile (IQ) ranges. Differences were assessed by analysis of variance, Mann–Whitney test, or contingency tables for categorical variables. A P value <.05 was considered statistically significant. Data were analyzed using the GraphPad Prisma 5 Software.
24
IV. Results
IV. 1. Patients characteristics
Baseline patients characteristics are presented in Table 7.
Age (years) 66±11.9 Male (%) 75 Heart Rate (bpm) 73±14 Atrial Fibrillation (%) 18 Ischemic Ethiology (%) 47 Hypertension (%) 52 Diabetes (%) 26 Anemia (%) 31 Echocardiographic Parameters EF (%) 31.6±0.42 EDVi (ml/m2) 111±2.1 ESVi (ml/m2) 91±2.5 EDT (ms) 178±4.7 TAPSE (mm) 19.1±0.24 Biochemical Parameters eGFR (ml/min/1.73m2) 69±1.2 BNP (pg/mL) 366 ( 209 - 635 ) Medication Furosemide (%) 83
Furosemide Dose (mg/week) 336±0.24
ACEi/ARB (%) 88
Beta Blockers (%) 58
MRA (%) 48
Digoxin (%) 34
Table 8. Baseline characteristics. Data are presented as Mean ± SD or as Median (IQR). Abbreviations: EF, ejection fraction; EDVi, end-diastolic volume index; EF, ejection fraction; ESVi, end-systolic volume index; EDT, E wave deceleration time; TAPSE, tricuspid annular plane systolic excursion; eGFR, estimated glomerular filtration rate; BNP, B-type natriuretic peptide; ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin type 1 receptor blocker; MRA, mineralocorticoid receptor antagonist
Mean age of our patients was 66±11.9 years. Half patients had an ischemic etiology of their LV dysfunction, half had systemic hypertension and a quarter were diabetics.
25 Baseline LVEF was 31.6±0.42%, similar to other randomized trials (41). Estimated GFR was 66±11.13 ml/min/1.73m2, baseline BNP value was 366 pg/mL (IQR: 209 - 635 pg/mL)
Compared to randomized studies (41), in our registry more patients were receiving MRA at baseline (48% vs 29%) and less patients were receiving beta-blockers (58% vs 75%). One third of patients were receiving digoxin and 83% were using loop diuretics. The baseline furosemide dose was 336±0.24 mg/week (equivalent to 48 mg/day).
IV. 2. Mortality rate
The median follow-up duration was 1030 days (IQR 405-1680 days). The survival rate was 97% at one year, 92% at 2 years, 89% at 3 years, 87% at 4 years and 82% at 5 years (Figure 1). Randomized trials (41) report higher mortality rates when patients receive standard of care treatment, as well as when they receive standard of care plus natriuretic peptide guided therapy (up to 19% and 16% at 2 years follow up, respectively).
26
IV. 3. Changes in biochemical parameters
There was a significant fall in the BNP values at follow up with respect to baseline, from 366 pg/mL (IQR: 209 - 635 pg/mL) to 288 pg/mL (IQR: 116 - 861 pg/mL) (Figure 2)
Figure 2. BNP fall at follow-up with respect to baseline
At follow-up, BNP values were reduced in 25% of patients, increased in 13% of patients and stable in 62% of patients (Figure 3).
27 Figure 3. BNP variations at follow up with respect to baseline
There were no significant variations in the renal function at follow-up with respect to baseline (Figure 4).
Figure 4. Estimated glomerular filtration rate at follow-up with respect to baseline
An increase of ≥ 0.3 mg/dL in serum creatinine was reported in 15% of the patients. Newly diagnosed renal dysfunction (eGFR <60 ml/min/1.73m2) occurred in 10% of patients.
68.78 66.01 0 50 100
Baseline
Follow-up
eGFR (ml/min/1.73m2)
p = 0.0728
IV. 4. Changes in echocardiographic parameters
Both LV systolic function and filling pressure were improved (Figure 5-6). Indexed end-diastolic and end-systolic LV volumes were slightly, but significantly reduced (Figure 7-8). Right ventricular systolic function, as assessed by TAPSE, did not change significantly Table 8 resumes echocardiographic parameters changes.
Figure 5. Left ventricular EF improvement at follow-up with respect to baseline
Figure 6. E wave deceleration time improvement at follow up with respect to baseline
31.6 35.7 0 25 50
Baseline
Follow-up
EF (%)
p < 0.0001 178 196 0 100 200 300Baseline
Follow-up
EDT (ms)
p = 0.00729 Figure 7. Indexed EDV reduction at follow-up with respect to baseline
Figure 8. Indexed ESV reduction at follow-up with respect to baseline
111.4 98.73 0 50 100 150
Baseline
Follow-up
EDVi (ml/m2)
p < 0.0001 91.4 84.5 0 50 100 150Baseline
Follow-up
ESVi (ml/m2)
p = 0.00830 Baseline Follow-up P EF (%) 31.6±0.42 35.7±0.57 <0.0001 EDT (ms) 178±4.7 196±4.7 0.007 EDVi (ml) 111.4±2.1 98.73±2.3 <0.0001 ESVi (ml) 91.4±2.5 84.5±2.7 0.008 TAPSE (mm) 19.1±0.24 19.7±0.24 0.06
Table 9. Variation of echocardiographic parameters. Data are presented as mean ± SEM. Abbreviations: EF, ejection fraction; EDVi, end-diastolic volume index; EF, ejection fraction; ESVi, end-systolic volume index; EDT, E wave deceleration time; TAPSE, tricuspid annular plane systolic excursion.
IV. 4. Changes in medication
Furosemide weekly dose increased from 336 ± 17.9 mg/week to 402 ± 29.3 mg/week, but the increase was not statistically significant (p = 0.054) (Figure 9)
Figure 9. Furosemide dose increase at follow up with respect to baseline
The percentage of patients taking beta blockers significantly increased from baseline to follow-up, while the patients taking digoxin were less. Almost 90% of patients were taking ACEi/ARB, almost 90% of patients were using diuretics, and half of the patients were
336 402 0 250 500
Baseline
Follow-up
Furosemide dose (mg/week)
31 taking MRA, without significant changes from baseline to follow-up. Detailed data are presented in Table 9. Baseline Follow-up p ACEi/ARB (%) 88 87 0.71 Beta blockers (%) 58 69 0.018 MRA (%) 48 49 0.87 Furosemide (%) 83 85 0.44 Digoxin (%) 35 25 0.013
Table 10. Percentage of patients taking the main classes of drugs at baseline and at follow-up.
For a sub-set of 160 patients, the doses of the main classes of drugs at baseline and follow-up were also available; percentage of target doses and percentage of patients at target were calculated.
Tables 10 shows the percentage of patients at target dose, according to current guidelines (29), at baseline and follow-up. Table 10 presents the mean percentage of target dose taken by patients for each category of drugs, at baseline and follow-up.
Compared to randomized trials (41), very few patients were at guidelines recommended target doses in our registry. The doses of drugs increased significantly from baseline to last follow-up only for beta-blockers, and remained unchanged for ACEi/ARB and MRB.
Baseline Follow-up p
ACEi/ARB (%) 11 15 0.41
Beta blockers (%) 2 9 0.09
MRA (%) 27 22 0.43
32
Baseline Follow-up p
ACEi/ARB (%) 36.7±2.5 38.8±2.5 0.56
Beta blockers (%) 28.7±3 43.2±4.1 0.017
MRA (%) 43.2±4.1 43.1±3.5 0,97
Table 12. Percentage of the guidelines target doses taken by patients at baseline and follow-up. Doses are expressed as percent of target values as defined by guidelines and reported as mean ± standard error of the mean
33
V. Discussion
We retrospectively analyzed the multicentric individual data of 414 patients with CHF with reduced ejection fraction. The baseline evaluation was performed at the time of hospital discharge or at the first contact during an ambulatory visit.
During follow up visits, medical decisions were taken on patient individual basis, with an integrative approach, including clinical examination, biochemical parameters (in particular BNP and renal function) and echocardiographic parameters. Current guidelines do not recommend the use of NP and echocardiography in the routine follow up of patients with CHF.
We did not provide a comparison group of patients treated according to current guidelines. Nevertheless, several randomized trials (41) already addressed the issue of the potential benefit of NP guided therapy with respect to standard of care therapy.
There are several significant discrepancies between our results and the data already published in literature, the most evident and significant one being the mortality rate, which seems improved in our study. We shall further try to systemize and find explanations for these differences.
1. Inclusion and exclusion criteria. We selected patients with a LVEF inferior to 45%, while in previous studies 10% of patients had an LVEF >45%; mixing different pathologic entities, in our opinion, may add difficulty in interpreting the results of those studies. However, we also suspect a selection bias in our study, that may explain the lower mortality rate; most of our patients were previously admitted or evaluated in a Cardiology Department, which might correlate with less comorbidities. Multiorgan compromised patients are often directed to Internal Medicine or Emergency Medicine Departments and further bypass our ambulatories. It is reasonable to believe that mortality rates are much higher in that category on CHF patients.
2. Single target versus multi-target approach. Studies published by now focus exclusively on NP levels. Therapy titration is based on target values, which are arbitrarily defined, generating ulterior dishomogeneity. Some studies use individual targets, while most of them choose a fixed cut-off for all patients. If NPs express parietal wall-stress, it is difficult to expect homogeneous NPs levels in a heterogeneous population of patients.
34 Unsurprisingly, a significant percentage of patients do not reach predefined NPs targets despite aggressive therapy, while collateral effects of such strategy are difficult to evaluate. Moreover, when a single biochemical parameter is targeted, all its intrinsic limitations (like biological variability, low specificity etc) may impact on clinical decisions. It is surprising to notice that in previous randomized studies important parameters, like renal function, for example, were not evaluated in about one third of patients.
In our study, we chose an integrated and individualized approach focused on the patient. Clinical evaluation was correlated with BNP levels and echocardiographic parameters in order to promptly identify and correct fluid overload and to avoid HF decompensation. Due to the heart-kidney interdependency in fluid management, kidney function evaluation was an imperative. In fact, the most relevant observation of our study is the preservation of renal function, which is most likely related to an appropriate use of loop diuretics.
The key points of our strategy were the early identification of fluid overload (using BNP and echocardiography for unmasking subclinical congestion) and the appropriate use of diuretics, increasing them when necessary, and cautiously reducing them to the minimal doses which allow fluid equilibrium.
While previous studies mainly focused on titration of other therapies (ACEi/ARB, beta blockers, ARB), little attention was given to diuretics and heart-kidney interaction and this may explain the different results of the two approaches.
3. Follow up schedule. In previous studies follow up schedules were predefined for all patients. In our study the intensity of follow up visits was different from patient to patient; based on integrated clinical judgment, individual profile risk was identified and the frequency of follow-up visits was dynamically modulated.
35
VI. Study limitations and future perspectives.
The main limitation of our study is the lack of a randomized control group treated according to standard of care therapy alone. Our data is descriptive and may lack of statistical power. Nevertheless, comparison to the available literature is possible and reasonable within certain limits. A randomized clinical study however, could reinforce our results.
36
VII. Conclusions
Our study suggests that the outcome of patients with CHF might be improved by the integrative use of clinical examination, biochemical and echocardiographic parameters. These effects are likely to be mediated by an appropriate use of loop diuretics and kidney function preservation.
Nevertheless, our results need to be consolidated by further large scale randomized trials, before entering the routine clinical practice.
.
37
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