Sergio Teruya

Treating Anemia in Older Adults With Heart Failure With a Preserved Ejection Fraction With Epoetin Alfa Single-blind Randomized Clinical Trial of Safety and Efficacy

Background—Anemia is a common comorbidity in older adults with heart failure and a preserved ejection fraction and is associated with worse outcomes. We hypothesized that treating anemia with subcutaneous epoetin alfa would be associated with reverse ventricular remodeling and improved exercise capacity and health status compared with placebo. Methods and Results—Prospective, randomized, single-blind, 24-week study with blinded end point assessment among anemic (average hemoglobin of 10.4±1 g/dL) older adult patients (n=56; 77±11 years; 68% women) with heart failure and a preserved ejection fraction (ejection fraction=63±15%; B-type natriuretic peptide=431±366 pg/mL) was conducted. Treatment with epoetin alfa resulted in significant increases in hemoglobin (P<0.0001). Changes in end-diastolic volume (−6±14 versus −4±16 mL; P=0.67) at 6 months did not differ between epoetin alfa and placebo, but declines in stroke volume (−5±8 versus 2±10 mL; P=0.09) without significant changes in left ventricular mass were observed. Changes in 6-minute walk distance (16±11 versus 5±12 m; P=0.52) did not differ. Although quality of life improved by the Kansas City Cardiomyopathy Questionnaire and the Minnesota Living with Heart Failure Questionnaire in both cohorts, there were no significant differences between groups. Conclusions—Administration of epoetin alfa to older adult patients with heart failure and a preserved ejection fraction compared with placebo did not change left ventricular end-diastolic volume and left ventricular mass nor did it improve submaximal exercise capacity or quality of life. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00286182.Background— Anemia is a common comorbidity in older adults with heart failure and a preserved ejection fraction and is associated with worse outcomes. We hypothesized that treating anemia with subcutaneous epoetin alfa would be associated with reverse ventricular remodeling and improved exercise capacity and health status compared with placebo. Methods and Results— Prospective, randomized, single-blind, 24-week study with blinded end point assessment among anemic (average hemoglobin of 10.4±1 g/dL) older adult patients (n=56; 77±11 years; 68% women) with heart failure and a preserved ejection fraction (ejection fraction=63±15%; B-type natriuretic peptide=431±366 pg/mL) was conducted. Treatment with epoetin alfa resulted in significant increases in hemoglobin ( P <0.0001). Changes in end-diastolic volume (−6±14 versus −4±16 mL; P =0.67) at 6 months did not differ between epoetin alfa and placebo, but declines in stroke volume (−5±8 versus 2±10 mL; P =0.09) without significant changes in left ventricular mass were observed. Changes in 6-minute walk distance (16±11 versus 5±12 m; P =0.52) did not differ. Although quality of life improved by the Kansas City Cardiomyopathy Questionnaire and the Minnesota Living with Heart Failure Questionnaire in both cohorts, there were no significant differences between groups. Conclusions— Administration of epoetin alfa to older adult patients with heart failure and a preserved ejection fraction compared with placebo did not change left ventricular end-diastolic volume and left ventricular mass nor did it improve submaximal exercise capacity or quality of life. Clinical Trial Registration— URL: . Unique identifier: [NCT00286182][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00286182&atom=%2Fcirchf%2F6%2F2%2F254.atom

The myocardial contraction fraction is superior to ejection fraction in predicting survival in patients with AL cardiac amyloidosis

Abstract Cardiac amyloidosis is a cause of diastolic heart failure in which ejection fraction (EF) remains “normal” despite progression of disease. The myocardial contraction fraction (MCF) is an index of myocardial function, defined as stroke volume (SV) over myocardial volume (MV). We hypothesized that MCF would be superior to EF, the conventional measure of left ventricular function, in predicting survival among patients with cardiac amyloidosis. Sixty-six subjects (mean age = 67 ± 12 years; 20% women) with cardiac amyloidosis (34 with light-chain amyloid and 32 with transthyretin amyloid) underwent two-dimensional echocardiography to determine left ventricular structure and function. Cox proportional hazard modeling was used to determine the association of MCF and EF with survival. Over a mean follow-up of 1.86 ± 1.78 years (range 0.03–7.36 years), 37 subjects (56.1%) died. Mean EF of the study population was 51 ± 13%. There was no significant difference in EF between patients who survived the study period and those who died (54 ± 11% versus 49 ± 14%; p = 0.1196) while there was a significant difference in MCF (35 ± 19% versus 23 ± 10%, p = 0.0065). Using Cox proportional hazards modeling, MCF was associated with death (HR = 0.953, 95% CI of 0.932–0.984, p = 0.0031) while EF was not (HR = 0.991, 95% CI of 0.968–1.014, p = 0.4320). In a multivariate model, amyloid light-chain (AL) amyloid type was an independent risk predictor of death with a HR of 2.841 (95% CI of 1.214–6.648, p = 0.0161) along with a MCF < 30 with a HR of 2.567 (95% CI of 1.197–5.508, p = 0.0155), which was driven by a higher risk in AL subjects with a MCF < 30, HR of 3.39 (95% CI of 1.20–9.55, p = 0.021) than TTR subjects with a MCF < 30, HR of 1.26 (95% CI of 0.36–3.28, p = 0.87). In conclusion, MCF, a novel measure of myocardial chamber function, is superior to EF in predicting overall survival among patients with AL cardiac amyloidosis.

Peak Cardiac Power Measured Noninvasively With a Bioreactance Technique Is a Predictor of Adverse Outcomes in Patients With Advanced Heart Failure

Peak oxygen consumption (VO(2) ) during cardiopulmonary exercise testing (CPET) is a powerful predictor of survival, providing an indirect assessment of cardiac output (CO). Noninvasive indices of CO derived from bioreactance methodology would add significantly to peak VO(2) as a means of risk-stratifying patients with heart failure. In this study, 127 patients (53 ± 14 years of age, 66% male) with heart failure and an average ejection fraction of 31% ± 15% underwent symptom-limited CPET using a bicycle ergometer while measuring CO noninvasively by a bioreactance technique. Peak cardiac power was derived from the product of the peak mean arterial blood pressure and CO divided by 451. Follow-up averaged 404 ± 179 days (median, 366 days) to assess endpoints including death (n=3), heart transplant (n=10), or left ventricular assisted device implantation (n=2). Peak VO(2) and peak power had similar areas under the curve (0.77 and 0.76), which increased to 0.83 when combined. Kaplan-Meier cumulative survival curves demonstrated different outcomes in the subgroup with a VO(2) <14 mL/kg/min when stratified by a cardiac power above or below 1.5 W (92.2% vs 82.1% at 1 year and 81.6% vs 58.3% at last follow-up, P=.02 by log-rank test). Among patients with heart failure, peak cardiac power measured with bioreactance methodology and peak VO(2) had similar associations with adverse outcomes and peak power added independent prognostic information to peak VO(2) in those with advanced disease (eg, VO(2) <14 mL/kg/min).

Differences in Blood Volume Components Between Hyporesponders and Responders to Erythropoietin Alfa: The Heart Failure With Preserved Ejection Fraction (HFPEF) Anemia Trial

BACKGROUND Hyporesponders to erythropoietin-stimulating agents (ESAs) have been associated with an increased subsequent risk of death or cardiovascular events. We hypothesized that subjects who are hyporesponsive to erythropoietin alfa would have higher plasma volumes and lower red cell deficits than subjects who are responsive to therapy. METHODS As part of a prospective, single blind, randomized, placebo-controlled study comparing erythropoietin alfa with placebo in older adults (n = 56) with heart failure and a preserved ejection fraction (HFPEF), we performed blood volume analysis with the use of an indicator dilution technique with (131)iodine-labeled albumin. We evaluated differences in plasma volumes and red cell volumes in hyporesponders (eg, <1 g/dL increase in hemoglobin within the first 4 weeks of treatment with erythropoetin alfa) compared with subjects who were responders and controls. RESULTS Nine of 28 subjects (32%) assigned to ESA were hyporesponders. Hyporesponders did not differ from responders nor control subjects by any baseline demographic, clinical, or laboratory parameter, including hemoglobin. Hyporesponders had a greater total blood volume expansion (1,264.7 ± 387 vs 229 ± 206 mL; P = .02) but less of a red cell deficit (-96.2 ± 126 vs -402.5 ± 80.6 mL; P = .04) and a greater plasma volume expansion (+1,360.8 ± 264.5 vs +601.1 ± 165.5 mL; P = .01). Among responders, the increase in hemoglobin with erythropoietin alfa was associated primarily with increases in red cell volume (r = 0.91; P < .0001) as well as a decline in plasma volume (r = -0.55; P = .06). CONCLUSIONS Among older adults with HFPEF and anemia, hyporesponders to erythropoietin alfa had a hemodilutional basis of their anemia, suggesting that blood volume analysis can identify a cohort likely to respond to therapy.

Blood Volume Measurements in Patients With Heart Failure and a Preserved Ejection Fraction: Implications for Diagnosing Anemia

Racial differences in the prevalence of anemia in patients with heart failure have been noted. The diagnosis of anemia in heart failure patients can be confounded by many factors. Plasma volume expansion is one of the most prominent confounders. The authors investigated the difference of anemia prevalence using two different diagnostic techniques: peripheral hemoglobin recommended by the World Health Organization criteria and blood volume (BV) analysis. Racial disparities in the prevalence of anemia using both measures were compared. Sixty patients with heart failure and preserved ejection fraction (HFPEF) underwent measurement of BV by a radio-labeled albumin technique. Anemia was defined by both WHO criteria and by measured red blood cell volume (RBCV) >10% below ideal. Anemia was found in 67% of patients by the peripheral hemoglobin technique with no racial disparity. Only 35% of the patients had anemia by the BV analysis, with a 2-fold higher prevalence among Hispanics compared with whites and blacks. In patients with HFPEF, the diagnosis of anemia based on hemoglobin is confounded by plasma volume derangements resulting in significant overdiagnosis in this cohort. Racial differences in the rate of anemia were found. Such data could have important implications for the diagnosis and management of anemia in ethnic minorities with HFPEF.

Cardiovascular effects of hemoglobin response in patients receiving epoetin alfa and oral iron in heart failure with a preserved ejection fraction

Background Previous data from a recently conducted prospective, single blind randomized clinical trial among community dwelling older patients with heart failure with a preserved ejection fraction (HFPEF) and anemia randomized to treatment with epoetin alfa (erythropoiesis-stimulating agents, ESA) vs. placebo did not demonstrate significant benefits of therapy regarding left ventricular (LV) structure, functional capacity, or quality of life (QOL). However, several patients randomized to the treatment arm were non-responders with a suboptimal increase in hemoglobin. All patients in the trial also received oral ferrous gluconate, which could have contributed to increases in hemoglobin observed in those receiving placebo. Accordingly, we performed an analysis separating patients into responders vs. non-responders in order to determine if measured improvement in anemia would have any effect on clinical endpoints. Methods A total of 56 patients (age 77 ± 11 years, 68% female) were recruited who had anemia defined as a hemoglobin of ≤ 12 g/dL (average, 10.4 ± 1 g/dL) with HFPEF defined as having NHANES-CHF (National Health And Nutrition Examination Survey: Congestive Heart Failure) criteria score of ≥ 3 and an ejection fraction of > 40% (average EF = 63% ± 15%). Patients were randomly allocated to receive either ESA and ferrous gluconate or ferrous gluconate only. In this analysis, a responder was defined as a patient with an increase of 1 g/dL in the first 4 weeks of the trial. Results Nineteen subjects were classified as responders compared to 33 non-responders. While the average hemoglobin increased significantly at the end of 6 months for responders (1.8 ± 0.3 vs. 0.8 ± 0.2 g/dL, P = 0.004), 50% of the subjects assigned to ESA were non-responders. Left ventricular function including ejection fraction (P = 0.32) and end diastolic volume (P = 0.59) was unchanged in responders compared to non-responders. Responders also showed no significant improvements in New York Heart Association (NYHA) class, Six Minute Walk Test (6 MWT) and peak VO2. Though QOL improved significantly within each group, there was no difference between the two. Conclusions A significant hemoglobin response to anemia treatment with ESA and oral iron does not lead to differences in LV remodeling, functional status, or QOL. Additionally, a significant percent of older adults with HFPEF and anemia do not respond to ESA therapy. Given the results of this small trial, it appears as though using objective improvements in anemia as a marker in older adult subjects with HFPEF does not have significant clinical utility.

Impact of Epoetin Alfa on Left Ventricular Structure, Function, and Pressure Volume Relations as Assessed by Cardiac Magnetic Resonance: The Heart Failure Preserved Ejection Fraction (HFPEF) Anemia Trial

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.

Hip and knee arthroplasty are common among patients with transthyretin cardiac amyloidosis, occurring years before cardiac amyloid diagnosis: can we identify affected patients earlier?

Abstract Transthyretin cardiac amyloidosis (ATTR-CA) causes a restrictive cardiomyopathy in older adults, often diagnosed at advanced stages when emerging therapies in late phase clinical trials may not have clinical benefit. This investigation aimed to detect clinical entities that may provide more advanced warning of ATTR-CA. Since ATTR preferentially deposits in ligaments, tendons, and articular cartilage, we hypothesized that ATTR-CA patients have a greater prevalence of total hip (THA) and knee (TKA) arthroplasties compared with the general population, and that arthroplasty occurs significantly before ATTR-CA diagnosis. Three-hundred and thirteen patients with cardiac amyloidosis (172 with ATTR-CA, 141 with light-chain) from our institutional database were analyzed and compared to published data in over 300 million patients. Overall, 23.3% of patients with ATTR-CA and 9.2% of patients with light-chain cardiac amyloidosis (AL-CA) underwent lower extremity arthroplasty. Compared to the general population, both THA and TKA were significantly more common among patients with ATTR-CA (THA: RR 5.61, 95% CI 2.25–4.64; TKA: RR 3.32, 95% CI 2.25–4.64) but not those with AL-CA (THA: RR 1.87, 95% CI 0.85–4.08; TKA: RR 1.42, 95% CI 0.73–2.84). On an average, arthroplasty occurred 7.2 years before ATTR-CA diagnosis.

Treating Anemia in Older Adults With Heart Failure With a Preserved Ejection Fraction With Epoetin AlfaClinical Perspective

Background—Anemia is a common comorbidity in older adults with heart failure and a preserved ejection fraction and is associated with worse outcomes. We hypothesized that treating anemia with subcutaneous epoetin alfa would be associated with reverse ventricular remodeling and improved exercise capacity and health status compared with placebo. Methods and Results—Prospective, randomized, single-blind, 24-week study with blinded end point assessment among anemic (average hemoglobin of 10.4±1 g/dL) older adult patients (n=56; 77±11 years; 68% women) with heart failure and a preserved ejection fraction (ejection fraction=63±15%; B-type natriuretic peptide=431±366 pg/mL) was conducted. Treatment with epoetin alfa resulted in significant increases in hemoglobin (P<0.0001). Changes in end-diastolic volume (−6±14 versus −4±16 mL; P=0.67) at 6 months did not differ between epoetin alfa and placebo, but declines in stroke volume (−5±8 versus 2±10 mL; P=0.09) without significant changes in left ventricular mass were observed. Changes in 6-minute walk distance (16±11 versus 5±12 m; P=0.52) did not differ. Although quality of life improved by the Kansas City Cardiomyopathy Questionnaire and the Minnesota Living with Heart Failure Questionnaire in both cohorts, there were no significant differences between groups. Conclusions—Administration of epoetin alfa to older adult patients with heart failure and a preserved ejection fraction compared with placebo did not change left ventricular end-diastolic volume and left ventricular mass nor did it improve submaximal exercise capacity or quality of life. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00286182.Background— Anemia is a common comorbidity in older adults with heart failure and a preserved ejection fraction and is associated with worse outcomes. We hypothesized that treating anemia with subcutaneous epoetin alfa would be associated with reverse ventricular remodeling and improved exercise capacity and health status compared with placebo. Methods and Results— Prospective, randomized, single-blind, 24-week study with blinded end point assessment among anemic (average hemoglobin of 10.4±1 g/dL) older adult patients (n=56; 77±11 years; 68% women) with heart failure and a preserved ejection fraction (ejection fraction=63±15%; B-type natriuretic peptide=431±366 pg/mL) was conducted. Treatment with epoetin alfa resulted in significant increases in hemoglobin ( P <0.0001). Changes in end-diastolic volume (−6±14 versus −4±16 mL; P =0.67) at 6 months did not differ between epoetin alfa and placebo, but declines in stroke volume (−5±8 versus 2±10 mL; P =0.09) without significant changes in left ventricular mass were observed. Changes in 6-minute walk distance (16±11 versus 5±12 m; P =0.52) did not differ. Although quality of life improved by the Kansas City Cardiomyopathy Questionnaire and the Minnesota Living with Heart Failure Questionnaire in both cohorts, there were no significant differences between groups. Conclusions— Administration of epoetin alfa to older adult patients with heart failure and a preserved ejection fraction compared with placebo did not change left ventricular end-diastolic volume and left ventricular mass nor did it improve submaximal exercise capacity or quality of life. Clinical Trial Registration— URL: . Unique identifier: [NCT00286182][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00286182&atom=%2Fcirchf%2F6%2F2%2F254.atom

Treating Anemia in Older Adults With Heart Failure With a Preserved Ejection Fraction With Epoetin AlfaClinical Perspective: Single-blind Randomized Clinical Trial of Safety and Efficacy

Background—Anemia is a common comorbidity in older adults with heart failure and a preserved ejection fraction and is associated with worse outcomes. We hypothesized that treating anemia with subcutaneous epoetin alfa would be associated with reverse ventricular remodeling and improved exercise capacity and health status compared with placebo. Methods and Results—Prospective, randomized, single-blind, 24-week study with blinded end point assessment among anemic (average hemoglobin of 10.4±1 g/dL) older adult patients (n=56; 77±11 years; 68% women) with heart failure and a preserved ejection fraction (ejection fraction=63±15%; B-type natriuretic peptide=431±366 pg/mL) was conducted. Treatment with epoetin alfa resulted in significant increases in hemoglobin (P<0.0001). Changes in end-diastolic volume (−6±14 versus −4±16 mL; P=0.67) at 6 months did not differ between epoetin alfa and placebo, but declines in stroke volume (−5±8 versus 2±10 mL; P=0.09) without significant changes in left ventricular mass were observed. Changes in 6-minute walk distance (16±11 versus 5±12 m; P=0.52) did not differ. Although quality of life improved by the Kansas City Cardiomyopathy Questionnaire and the Minnesota Living with Heart Failure Questionnaire in both cohorts, there were no significant differences between groups. Conclusions—Administration of epoetin alfa to older adult patients with heart failure and a preserved ejection fraction compared with placebo did not change left ventricular end-diastolic volume and left ventricular mass nor did it improve submaximal exercise capacity or quality of life. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00286182.Background— Anemia is a common comorbidity in older adults with heart failure and a preserved ejection fraction and is associated with worse outcomes. We hypothesized that treating anemia with subcutaneous epoetin alfa would be associated with reverse ventricular remodeling and improved exercise capacity and health status compared with placebo. Methods and Results— Prospective, randomized, single-blind, 24-week study with blinded end point assessment among anemic (average hemoglobin of 10.4±1 g/dL) older adult patients (n=56; 77±11 years; 68% women) with heart failure and a preserved ejection fraction (ejection fraction=63±15%; B-type natriuretic peptide=431±366 pg/mL) was conducted. Treatment with epoetin alfa resulted in significant increases in hemoglobin ( P <0.0001). Changes in end-diastolic volume (−6±14 versus −4±16 mL; P =0.67) at 6 months did not differ between epoetin alfa and placebo, but declines in stroke volume (−5±8 versus 2±10 mL; P =0.09) without significant changes in left ventricular mass were observed. Changes in 6-minute walk distance (16±11 versus 5±12 m; P =0.52) did not differ. Although quality of life improved by the Kansas City Cardiomyopathy Questionnaire and the Minnesota Living with Heart Failure Questionnaire in both cohorts, there were no significant differences between groups. Conclusions— Administration of epoetin alfa to older adult patients with heart failure and a preserved ejection fraction compared with placebo did not change left ventricular end-diastolic volume and left ventricular mass nor did it improve submaximal exercise capacity or quality of life. Clinical Trial Registration— URL: . Unique identifier: [NCT00286182][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00286182&atom=%2Fcirchf%2F6%2F2%2F254.atom