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Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. References

Anemia, a common comorbidity in older adults with heart failure and a preserved ejection fraction (HFPEF), is associated with worse outcomes. The authors quantified the effect of anemia treatment on left ventricular (LV) structure and function as measured by cardiac magnetic resonance (CMR) imaging. A prospective, randomized single-blind clinical trial (NCT NCT00286182) comparing the safety and efficacy of epoetin alfa vs placebo for 24 weeks in which a subgroup (n=22) had cardiac magnetic resonance imaging (MRI) at baseline and after 3 and 6 months to evaluate changes in cardiac structure and function. Pressure volume (PV) indices were derived from MRI measures of ventricular volume coupled with sphygmomanometer-measured pressure and Doppler estimates of filling pressure. The end-systolic and end-diastolic PV relations and the area between them as a function of end-diastolic pressure, the isovolumic PV area (PVAiso), were calculated. Patients (75±10 years, 64% women) with HFPEF (EF=63%±15%) with an average hemoglobin of 10.3±1.1 gm/dL were treated with epoetin alfa using a dose-adjusted algorithm that increased hemoglobin compared with placebo (P<.0001). As compared with baseline, there were no significant changes in end-diastolic (−7±8 mL vs −3±8 mL, P=.81) or end-systolic (−0.4±2 mL vs −0.7±5 mL, P=.96) volumes at 6-month follow-up between epoetin alfa compared with placebo. LV function as measured based on EF (−1.5%±1.6% vs −2.6%±3.3%, P=.91) and pressure volume indices (PVAiso-EDP at 30 mm Hg, −5071±4308 vs −1662±4140, P=.58) did not differ between epoetin alfa and placebo. Administration of epoetin alfa to older adult patients with HFPEF resulted in a significant increase in hemoglobin, without evident change in LV structure, function, or pressure volume relationships as measured quantitatively using CMR imaging.

Anemia is a significant comorbidity among the population with heart failure (HF) including those with a preserved ejection fraction (HFPEF).[1-6] It is well established that anemia contributes to the overall morbidity among systolic HF patients, with a prevalence ranging from 4% to 50%.[1, 3, 7] Numerous studies have shown that patients with systolic HF and anemia are at increased risk for morbidity, longer hospitalization, increased diuretic requirement, and greater mortality.[8-13] Small-scale treatment trials have been conducted in the systolic HF population with anemia and have shown that subcutaneous erythropoietin increases peak oxygen consumption and ejection fraction (EF) and reduces hospitalizations, New York Heart Association (NYHA) functional class, and diuretic requirements.[14-18] Meta-analysis suggests clinical benefits in terms of increase in hemoglobin levels, increase in exercise duration, improvement in NYHA functional class, improvement in 6-minute walk test, decrease in B-type natriuretic peptide, and improvement in peak oxygen consumption.[19] A large-scale treatment trial[20] is ongoing. The role of this therapy in patients with HFPEF is not defined.

A growing body of evidence has emerged indicating that noncardiac conditions are common in patients with HFPEF such as anemia, obesity, renal insufficiency, and diabetes.[7, 21] Adverse outcomes of anemia and HF with preserved EF occur consistently across various populations. The prevalence increases with age, advanced NYHA class, and with certain comorbidities such as renal insufficiency.[7] Evidence reveals the relationship between mortality rates, and the level of hemoglobin exhibits a J-shaped curve, noting a higher mortality in patients with hemoglobin levels <10 g\dL and >16 g\dL.[3, 5] Anemia alters cardiac structure by mechanisms of compensatory hypertrophy and dilation of left ventricular (LV) chamber size as noted on noninvasive cardiovascular imaging. This remodeling affects the left atrial volume index, LV mass, and filling pressure as measured by 2-dimensional echocardiography.[22] Additionally, anemia is associated with an augmentation in ventricular work in HFPEF as evidenced by an enhanced relationship between pressure volume area to end-diastolic pressure.[23]

Erythropoietin is a hematopoietic growth factor that stimulates red blood cell synthesis which has been used for the treatment of anemia and may have potential cardiovascular effects.[24] To date, little is known about the impact of erythropoietin on clinical parameters (ie, ventricular structure/function, functional capacity, symptoms, renal function) in the subset of HF patients with a preserved EF and anemia. In an open-label short-term (3 months) study,[25] erythropoietin administration to elderly anemic patients with HFPEF resulted in significant increases in hemoglobin and red cell volume which was associated with reverse remodeling (eg, smaller end-diastolic volume [EDV] and rightward shift in the end-diastolic pressure volume relation [EDPVR]), improved submaximal and maximal exercise tolerance, and quality of life. However, in a larger randomized controlled trial, epoetin alfa was not shown to improve functional capacity, quality of life, or 3-dimensional echocardiographic measures of LV volume or mass.[26]

Cardiac magnetic resonance (CMR) imaging is among the most reproducible techniques to assess LV structure and function. Accordingly, the purpose of the current study is to assess LV structure and function at baseline and after 3 and 6 months postrandomization using CMR imaging on a subgroup of randomized patients in order to determine whether therapy with epoetin alfa was associated with changes compared with placebo.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. References

Study Design

The current analysis is a substudy prospective, randomized, single-blind 24-week study.[26] Randomization was to either epoetin alfa or placebo and was stratified based on sex and a estimated glomerular filtration rate of >40 mL/min/m2 or ≤40 mL/min/m2. The endpoints of this substudy were assessment of cardiac structure and function as quantified by CMR imaging.

Study Patients

The study population including inclusion and exclusion criteria has been described in detail previously.[26] In brief, patients were community-dwelling, older adult patients with anemia and HF with a preserved EF. Patients were recruited from outpatient clinics at an urban medical center setting and after acute hospitalization for decompensated HF (New York Presbyterian Hospital, New York City, NY). The diagnosis of HF was based on the National Health and Nutrition Examination Survey (NHANES) congestive heart failure criteria score ≥3[27] and were considered to have a preserved EF if 3-dimensional echocardiographically determined EF was >40%. Anemia was defined as hemoglobin <12 g/dL.[28] Informed consent was obtained in all patients. Columbia University Medical Center's institutional review board approved the study and the trial was registered at clinical trials.gov (NCT 00286182).

Weekly Monitoring

Patients were seen each week during which time they underwent an abbreviated physical examination including measurement of vital signs and weight with particular attention to clinical volume status. A majority of these examinations were conducted in the participant's home, given the frail nature of the study population.[29] A venous blood sample was obtained on a weekly basis and evaluated by a point-of-care system (Hemocue, Angelholm, Sweden) to determine changes in hemoglobin that were used to guide dosing of epoetin alfa.

Study Drug Administration and Dosing

Epogen (Epoetin alpha), (Janssen Biotech, Inc, Horsham, PA) was administered weekly by subcutaneous injection using a prespecified dosing algorithm.[25] The dosing algorithm was designed to make adjustments based on the rate of rise (ROR) of the hemoglobin during a 1-week period, as well as the absolute hemoglobin value. Patients initially received active treatment with 7500 units of epoetin alfa given weekly by subcutaneous injection. Patients were carefully monitored (eg, every week) when beginning therapy to avoid rapid increases in hemoglobin/hematocrit and/or increasing blood pressure control. No dose adjustments were made for the first 3 doses of erythropoietin (7500 units/wk) unless the hemoglobin rose too rapidly (>0.3 g/dL) in any given weekly interval.

Cardiac MRI

CMR images were acquired using 1.5-Tesla MRI scanners (General Electric, Waukesha, WI) with a dedicated 8-channel phased array surface coil. LV volume and function was assessed using a 2-dimensional breath-held steady-state free precession imaging sequence with short-axis images acquired throughout the LV from the level of the mitral valve annulus through the apex. Typical imaging parameters were as follows: repetition time (TR) 3.5 ms, echo time (TE) 1.6 ms, flip angle 60°, temporal resolution 35 to 40 ms, in-plane spatial resolution 1.9×1.4 mm, slice thickness 6.0 mm, and inter-slice gap 4.0 mm.

CMR quantification was performed using manual planimetry. Basal and apical image positions were defined in accordance with established criteria, with the basal LV defined by the basal-most short-axis image with at least 50% of circumferential myocardium.[30] End-diastole and end-systole were defined based on the respective frames demonstrating the largest and smallest cavity size. Quantification of end-diastolic volume (EDV) and end-systolic volume (ESV) was performed using short-axis images. Stroke volume (SV) and LVEF was calculated based on EDV and ESV (SV = EDV–ESV; EF = [(EDV–ESV)/EDV] × 100%). LV mass was quantified as the volumetric difference between end-diastolic endocardial and epicardial chamber volume, multiplied by myocardial specific gravity (1.05 g/mL). Image acquisition/analysis was performed at a high-volume CMR laboratory (Weill Cornell Medical College, New York, NY) by experienced (American College of Cardiology/American Heart Association level III–trained) readers blinded to patient clinical characteristics and treatment assignment.

Estimates of Ventricular Chamber Properties by Noninvasive Pressure Volume Indices

End-systolic pressure volume relation (ESPVR) and end-diastolic pressure-volume relationship (EDPVR) were estimated in the following manner. The ESPVR, an index of chamber contractility, is traditionally measured invasively and defined by a slope, the end-systolic elastance (Ees), and a volume axis intercept, Vo. We indexed ventricular contractility by the end-systolic pressure volume ratio (Res ≡ Pes/ESV)[31] where the end-systolic pressure Pes ≈ systolic blood pressure × 0.9.[32] Res as a single contractile index assumes that V0 = 0 mL and simplifies statistical assessment of contractility. Effective arterial elastance (Ea), an index of arterial properties, representable on the pressure volume plane, is defined as E ≡ Pes/Sv.[32]

To characterize the EDPVR (where EDP = αEDVβ), α is a scaling constant and β is a diastolic stiffness constant), a validated single-beat approach was used.[33, 34] This approach relies on the empiric observation that volume-normalized EDPVRs share a common shape, thereby allowing estimation of α and β to define the entire EDPVR from a single measured pressure volume point. Measured EDP (estimated from Doppler echocardiography by previously validated formulas[35]) and EDV (measured from CMR imaging) were used to derive α and ß in each patients. To account for covariance in α and β,[36] both of which impact the shape and position of the EDPVR, the values of these parameters derived from each patient were used to predict the EDV at a common EDP of 30 mm Hg to yield a pressure-independent index of heart size or ventricular capacitance (EDV30).

The area between the EDPVR and Res measured as a function of EDP was used to index overall pump function.[40, 41] This specific area is called the isovolumic pressure volume area (PVAiso) and is independent of afterload and can be calculated analytically as a function of LV following curve fitting of the EDPVR and the Res: inline image , where Pes(V) and Ped(V) are the end-systolic and end-diastolic pressures, respectively, as a function of volume.

Statistical Analyses

Results are expressed as mean±standard error unless otherwise noted. Changes in principle measures were compared from baseline to both 3 and 6 months values by a Student t test for paired comparisons. The primary endpoint of this substudy was change in LVEDV after 6 months of study. Preliminary data indicate that the standard deviation of the LVEDV by MRI was approximately 55 mL and 45 mL and the correlation coefficient of repeated measures was high (r=0.95), such that with a calculated standard deviation of the difference of 19 mL, with 8 patients in each group accounting for dropouts, we would have an 80% power at an alpha of 0.05 to detect a 22-mL difference in LV volumes. Given that the mean LVEDV is approximately 120 mL in this population, then we had sufficient power to detect an approximate 20% change over the course of the study. SAS for Windows (version 8.0, SAS Institute Inc, Cary, NC) was used for all analyses.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. References

The study population was older adults (approximately 77 years of age), predominately women of Hispanic ethnicity, with concomitant hypertension and several other comorbid conditions, similar to large demographic series of patients with HFPEF. Almost all patients were taking diuretics and on average 2 other cardioactive medications including angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, β-blockers, and calcium channel blockers. Laboratory testing revealed anemia (as required by the protocol), chronic kidney disease, and elevated B-type natriuretic peptides (Table 1). None of the demographic and clinical characteristics differed significantly in patients randomized to active drug (epoetin alfa) compared with placebo except for use of β-blockers. The patients in this substudy did not meaningfully differ from patients in the full trial.[26]

Table 1. Demographic and Clinical Characteristics of Study Patients
ParameterOverall (n=22)Epoetin alfa (n=11)Placebo (n=11)P Value
  1. Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BNP, B-type natriuretic peptide; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate. Values are mean±standard error. P values were calculated using chi-square, Fisher exact, or Student t tests as appropriate.

Age, y75±277±372±4.26
Women, No. (%)14 (64)8 (72)6 (55).65
Race, white/black/other13/9/07/4/06/5/0.81
Hispanic, No. (%)14 (64)7 (64)7 (64).67
Body surface area, m21.89±0.041.84±0.071.94±0.06.29
Body mass index32±632±733±6.93
Medications, No. (%)
Diuretics20 (91)10 (91)10 (91%).99
β-Blockers16 (73)5 (45)11 (100).006
ACE inhibitors/ARBs15 (68)9 (82)6 (55).19
Ca channel blockers11 (50)6 (55)5 (45).69
Aldosterone antagonists5 (23)3 (27)2 (18).63
Systolic blood pressure, mm Hg147±4150±6144±6.49
Diastolic blood pressure, mm Hg66±264±368±4.36
Comorbid conditions, No. (%)
Hypertension22 (100)11 (100)11 (100)
Diabetes16 (72)9 (82)7 (64).63
Coronary artery disease12 (55)6 (55)6 (55).99
Obesity15 (68)7 (64)8 (73).99
COPD3 (14)2 (18)1 (9).99
Laboratory results
BNP, pg/mL402±71406±78398±122.96
Hemoglobin, g/dL10.3±0.210.4±0.410.3±0.2.81
Creatinine, mg/dL1.7±0.21.8±0.21.7±0.3.83
eGFR, mL/min44±441±647±5.49

During the course of the trial, hemoglobin increased in the group assigned to active therapy in compared with placebo (Figure 1). Hemoglobin increases were seen within the first weeks of starting therapy and reached a plateau by 7 to 8 weeks after starting therapy. During the course of the trial, patients taking active therapy had an approximate 1.5-g/dL increase in hemoglobin while those taking placebo had an approximate 0.7-g/dL increase in hemoglobin, resulting in an average difference between groups of approximately 0.8 g/dL (P<.0001). The average dose of epoetin alfa in the active therapy group was 4655 units/wk.

image

Figure 1. Weekly changes in hemoglobin from baseline during study period in subjects randomized to ESA (red) or placebo (blue). Data represent mean ± standard error.

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As shown in Table 2, there were minimal changes in LV volumes and mass as well as EF over the course of the 6-month trial. Changes in LV volumes, mass, and EF did not differ between patients randomized to active therapy as compared with placebo (Figure 2). Additionally, PV analysis (Figure 3) did demonstrate a reduction in chamber capacitance after 6 months in patients receiving epoetin alfa with concomitant declines in SV, but these changes were not statistically significant compared with baseline values nor did they differ from controls. There was no difference in the change in pressure volume area to EDP relationship in the placebo group compared with the epoetin alfa group (P=.58, nonpaired t test). Additionally, the 6-month pressure volume area at an EDP of 30 mm Hg was not different from baseline in the placebo group (P=.7, paired t test) or in the epoetin alfa group (P=.3, paired t test).

Table 2. LV Volumes, Mass, and Pressure Volume Indices With Treatment of Epoetin Alfa vs Placebo
ParameterBaseline3 Months6 Months
Placebo (n=11)Epoetin Alfa (n=11)Placebo (n=10)Epoetin Alfa (n=9)Placebo (n=8)Epoetin Alfa (n=7)
  1. Abbreviations: LV, left ventricular; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; MRI, magnetic resonance imaging. Values are expressed as mean±standard error.

Cardiac MRI
LVEDV, mL/m279±673±877±667±577±666±4
LVESV, mL/m230±427±627±323±429±323±4
LV stroke volume, mL/m249±346±450±445±445±443±2
LV mass, g/m277±666±571±665±473±667±5
LV ejection fraction, %64±366±465±370±361±471±3
Pressure volume indices
V120, mm Hg/mL50±1035±1352±1137±1352±722±10
V30, mL158±12145±20153±13124±15146±10114±12
image

Figure 2. Left ventricular end diastolic volume index (EDVI), ejection fraction (LVEF), stroke volume index (SVI) and cardiac output cardiac magnetic resonance imaging in subjects randomized to ESA (red) or placebo (blue). Data represent mean ± standard error.

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image

Figure 3. Pressure-volume relation and iso-volumetric pressure-volume area (PVA) at baseline and at 6 months is the ESA group (left panel) and the placebo group (right panel).

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Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. References

The primary results of the CMR substudy of this prospective, randomized trial with blinded endpoint assessment is that correction of anemia in patients with HFPEF with epoetin alfa did not result in significant changes in LV structure (volume and mass) or function as assessed by EF and indices of pressure volume analysis including sophisticated measures of chamber function. Minimal changes in stroke volume, LV end-diastolic volume, and EF were observed during the course of this 6-month trial, which were of smaller magnitude than observed in previous studies of epoetin therapy. These differences are likely attributable to several factors including differences in the: (1) population under investigation; (2) degree of anemia and associated chronic renal disease; and (3) erythropoietin dosing regimens used, targets achieved, and treatment duration.

Our cohort consists solely of symptomatic HFPEF patients, the majority of whom were women older than 75 years. Previous cross-sectional data of the European Survey of Anemia Management indicate that women achieve approximately 0.25 g/dL lower hemoglobin than men with erythropoietin-stimulating agents (ESAs) and are more likely to be classified as poor responders to epoetin.[37] Additionally, studies of ESAs in chronic kidney disease populations have identified older age, higher body mass index, angiotensin-converting enzyme inhibitor or angiotensin receptor antagonist use, and diabetes as being associated with increased epoetin requirements when normalizing hemoglobin.[38, 39] Thus, the population characteristics of patients with HFPEF include many factors that make them particularly susceptible to hyporesponsiveness with ESAs. However, despite these characteristics, we were able to achieve a significant difference in the hemoglobin levels between patients randomized to epoetin alfa compared with placebo using relatively low doses of epoetin alfa (4655 units\wk).

Previous studies of ESA have shown statistical reductions in LV mass and volumes and improvements in EF both in patient with chronic kidney disease not on dialysis[40-44] and in those on dialysis.[45, 46] Similar results have been shown in patients with systolic HF.[14, 15, 47] However, not all trials have demonstrated a clinical effect.[48] Collectively, these trials suggest that the more severe the anemia, greater the LV mass, lower the EF, and worse the renal function, the greater the benefit from correction of anemia with ESA therapy. Most of these studies enrolled patients with more severe anemia than the population studied in this trial with more significant decrements in renal function and higher LV mass. The decrements in LV mass in these previous studies ranged from 6 g\m2 to 31 g\m2, typically within 6 months of therapy. Additionally, all of the previous trials used echocardiography rather than CMR imaging, which is considered a noninvasive reference standard for assessment of LV structure and function.[49, 50] Most previous investigations did not have imaging performed by investigators blinded to the patients' treatment assignment. These differences may explain the discrepant results in this trial compared with previous investigations.

Regarding regression of LV hypertrophy, a previous study has shown that the normalization of hematocrit was more effective than a partial correction of anemia during therapy with ESAs. These investigators observed more than a doubling of the LV mass reduction observed during a 12-month period in the normalized hematocrit vs partial correction cohort.[44] Additionally, other trials that demonstrated benefit in terms of remodeling used higher doses of ESA[41] and demonstrated no difference between epoetin alfa and darbepoetin alfa in their efficacy in this regard.[40] However, in patients with CKD in whom anemia was prevented by use of epoetin alfa, maintenance of the hemoglobin >12.0 g/dL, compared with patients allowed to develop anemia in the range of 9.0 g/dL to 10.0 g/dL, did not differ in terms of the effects on LV mass index and did not affect the development or progression of LV hypertrophy.[48] Similarly, in our study, patients had relatively mild degrees of anemia (average hemoglobin of 10.3 g/dL) and achieved final hemoglobins of approximately 12.0 g/dL, using a dosing algorithm that was conservative and designed to address concerns about the risks of ESAs to achieve higher targets.[51, 52] While more aggressive dosing protocols could have resulted in greater differences between cohorts studied, this may be associated with adverse outcomes as noted in previous investigations.[51, 52]

The duration of treatment in this trial was similar to a majority of previous studies that demonstrated an effect. However, some previous studies only demonstrated effects after 12 months of therapy and the duration of anemia correction has been shown to be a factor influencing the rate of LV regression; hence, improving LV performance and structure. Such data raise the possibility that structural remodeling may be noted after a longer period of time. Indeed, the duration of this trial was intermediate in length, compared with trials performed in this arena (eg, 6 months) and hemoglobin targets were not achieved until 6 to 8 weeks after starting therapy, limiting the time in which the effect of reversing anemia could be observed to affect measured cardiac structural and functional parameters. Whether the lack of an effect of treatment on measured outcomes could be a result of the 24-week duration of this study is unknown.

The reported data are based on a relatively small cohort of a larger clinical trial. However, despite the modest sample size, we had adequate power to detect a 20-mL change in EDV. Whether a smaller change, which could be observed with a larger cohort of patients receiving CMR, would be detected and have clinical significance is unknown. While we did observe statistically significant changes in hemoglobin in patients randomized to active therapy vs placebo, the observed increase in hemoglobin in the placebo group negated the absolute differences between cohorts.

Conclusions

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. References

The administration of subcutaneous erythropoietin in older adult patients with HFPEF and anemia did not demonstrate significant effect on LV structure or function as measured by CMR imaging.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. References
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