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Effect of Thiazolidinediones on Heart Failure Patients with Diabetes
The 9th Annual Scientific Meeting
250 Relation between Diuretic Dose and Outcome in a Heart Failure Population: Results of the ESCAPE Trial V. Hasselblad1, W. G. Stough1, M. R. Shah2, Y. Lokhnygina1, J. C. Burnett3, M. Gheorghiade4, B. K. Rayburn5, K. F. Adams, Jr.6, G. S. Francis7, R. M. Califf8; 1 Statistics Department, Duke Clinical Research Institute, Durham, NC; 2Department of Medicine, Columbia University Medical Center, New York, NY; 3Mayo Clinic, Rochester, MN; 4Division of Cardiology, Northwestern University, Chicago, IL; 5 Division of Cardiovascular Diseases, University of Alabama at Birmingham, Birmingham, AL; 6Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC; 7Department of Clinical Cardiology, The Cleveland Clinic, Cleveland, OH; 8Division of Cardiology, Department of Medicine, Duke University Medical Center, Duke Clinical Research Institute, Durham, NC Background: During therapy for fluid overload in heart failure (HF), persistent congestion leads to higher doses of diuretics, which may be associated with higher mortality. Using ESCAPE data, we examined the relation of furosemide dose to weight loss, changes in renal function, and mortality in patients with HF. Methods: ESCAPE compared PAC-guided therapy with standard care in HF patients. Of 433 patients, 366 received furosemide. Weight loss was the difference between baseline and last in-hospital weight. Mortality was assessed using a log-logistic model with nonzero background. Arrhythmia and change in creatinine level were used to evaluate the relation between furosemide dose and adverse effects. Results: Mean weight loss was 3.7 kg (22% of values ⬍0). Weight loss and diuretic dose were correlated (P ⫽ 0.0017), but the R2 was low (0.03). Only baseline weight, length of stay, and baseline BNP were significant predictors of weight loss. A strong relation between dose and mortality was seen (Figure, P ⫽ 0.0003), especially at doses ⬎300 mg/day. Dose remained a significant predictor of mortality after adjusting for age, 6-min walk, SCr, BUN, and BNP. No relation was seen between dose and SCr changes or arrhythmias. Conclusions: High-loop diuretic dose during HF is associated with mortality and a poor 6-month outcome. For patients receiving high-dose diuretics, risk vs benefit of increasing diuretic doses should be reevaluated.
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HFSA
S157
low dose furosemide in improving renal function of acute CHF patients with renal dysfunction as compared to standard dose NES.
252 Randomized, Double Blind Comparison of Acute beta-1 Blockade with 50 mg Metoprolol Versus 25 mg Carvedilol in Normal Volunteers Undergoing Cardiopulmonary Exercise Testing Rana Billeh1, David Hirsh1, Krishnan Ramanathan1, Raban Jeger1, Greg Blair1, Birgit Jorgensen1, Ulrich Jorde1; 1Cardiology, New York University Medical Center, New York, NY Background: Differential efficacy of immediate release metoprolol (Met) at 50 mg BID and carvedilol (Carv) at 25 mg BID in the treatment of congestive heart failure remains a subject of ongoing debate. The degree of beta-1 blockade achieved with these doses is at the center of this controversy and can be assessed in vivo by percent reduction of exercise heart rate. Methods: 10 male and 2 female healthy volunteers (ages 27–54) underwent symptom limited cardiopulmonary exercise testing (CPETT). Resting and peak heart rate as well as oxygen consumption at anaerobic threshold (VO2AT) and at maximal exercise (VO2Max) were determined. CPETTs were then repeated at weekly intervals and two hours after a randomized,double blind administration of 50mg Met versus 25mg Carv. Results: Baseline heart rate was reduced from 74 ⫾ 3.3 to 59 ⫾ 2.6 and 64 ⫾ 3.1 respectively with Met and Carv (P ⬍ 0.05 for all). Peak heart rate was reduced from 186 ⫾ 2.6 at baseline to 153 ⫾ 4.2 with Met and 162 ⫾ 3.9 with Carv (P ⬍ 0.05 for all). Exercise heart rate was also blunted more by Met than Carv at 70% of peak VO2 and at the anaerobic threshold (AT) (p ⬍ 0.05). Peak VO2 was reduced from 45.4 ⫾ 1.9 at baseline to 42.5 ⫾ 2.3 by Met (P ⬍ 0.03) and 43.1 ⫾ 1.8 by Carv (P 0.054). The change in VO2 was significantly correlated with the degree of beta -1 blockade as assessed by the reduction in exercise heart rate (r 0.45; P ⬍ 0.05). Conclusion: In normal volunteers, a higher degree of beta-1 blockade is achieved with 50 mg metoprolol as compared with 25 mg carvedilol. Whether this difference is sustained over a 12 hour period and/or whether these results can be extrapolated to heart failure patients is unknown.
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The Effects of Low Dose Nesiritide with Low Dose Furosemide on Renal Function in Patients with Acute Decompensated Heart Failure and Renal Dysfunction Henry G. Riter1, Margaret M. Redfield1, John C. Burnett1, Horng H. Chen1; 1Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, MN
Effect of Thiazolidinediones on Heart Failure Patients with Diabetes Sandra L. Chase1, Paul J. Schultz1, Prerana A. Manohar2; 1Pharmacy, Spectrum Health, Grand Rapids, MI; 2Meijer Heart Center, Spectrum Health, Grand Rapids, MI
Background: Human recombinant BNP (Nesiritide) has been approved by the FDA for the management of acute heart failure (CHF). The standard recommended dose of Nesiritide (NES) is a bolus of 2 µg/kg followed by infusion of 0.01 µg/kg/min. While preclinical studies have demonstrated the renal enhancing effects of BNP, clinical trials have been conflicting. We hypothesize that the attenuated renal actions of standard dose NES is partly due to its blood pressure (BP) lowering effects, therefore limiting renal perfusion pressure. Methods: We performed a retrospective review on consecutive patients admitted to Mayo Clinic Heart Failure Hospital Service from July 2001 to December 2004 who received NES at doses which were lower compared to the standard dose. We identified a total of 15 patients, 13 received 0.005 µg/kg/ min and 2 received 0.0025 µg/kg/min of NES without bolus. We compared this to patients (n ⫽ 13) who received standard dose NES and patients (n ⫽ 12) who did not receive NES but only standard therapy, matching groups for ejection fractional and calculated creatinine clearance (CrCl). * p ⬍ 0.05 vs Low dose. Results: Patients who received low dose NES had lower baseline systolic BP as compared to Standard dose NES and no NES (101 ⫾ 3 vs 121 ⫾ 6* vs 115 ⫾ 6* mmHg) groups. Low dose NES was well tolerated without a significant decrease in systolic BP (from 101 ⫾ 3 to 97 ⫾ 3 mmHg. P ⬎ 0.05) while systolic BP decreased in the Standard Dose NES (from 121 ⫾ 6 to 112 ⫾ 6 mmHg. P ⬍ 0.05) and no NES (from 115 ⫾ 6 to 106 ⫾ 6 mmHg, P ⬍ 0.05) groups. Most importantly, patients in the low dose NES group had improvement in renal function as measured by improvement of plasma Cr (from 2.6 ⫾ 0.3 to 2.1 ⫾ 0.2 mg/dl, P ⬍ 0.05), BUN (from 78 ⫾ 9 to 57 ⫾ 68 mg/dl, P ⬍ 0.05) and CrCl (from27 ⫾ 3 to 35 ⫾ 4 ml/min/1/73 m2, P ⬍ 0.05). Renal function did not improve in the Standard Dose NES and no NES groups. Patients in the low dose NES group required with less furosemide dose as compared to the Standard Dose NES and no NES groups (136 ⫾ 39 vs 389 ⫾ 71* vs 345 ⫾ 115*, mg of furosemide) while achieving similar diuresis and change in weight. Conclusion: This retrospective study supports the conclusion that further prospective randomized placebo controlled studies are warranted to define the efficacy of low dose NES incombination with
Introduction: Thiazolidinediones (TZD’s) are a class of medications used to increase insulin sensitivity in patients with type II diabetes mellitus. Additional effects of TZD’s on blood pressure, inflammatory markers, endothelial function, and lipid profiles suggest a benefit to patients with heart failure; however, fluid retention associated with TZD’s has prompted the creation of a contraindication for NYHA class III and IV heart failure. The additional effect of TZD’s suggest a benefit to patients with heart failure. The objective of this study was to evaluate the effect of TZD’s on the progression of heart failure in patients with the concurrent diagnoses of type 2 diabetes mellitus and heart failure. Methods: Patients who had diagnoses of both type 2 diabetes and heart failure were included if they had two measurements of LVEF by echocardiography or cardiac catheterization at least 6 months apart while enrolled in the clinic. Patients on TZD’s were compared to those on other oral diabetic medications or insulin with primary outcome measured as change of LVEF. Baseline LVEF was taken from the LVEF measurement closest to January 1, 2003. Endpoint LVEF was the measurement closest to 1 year after baseline. Secondary outcomes of change in weight, change in diuretic dose, number of hospital admissions, and number of days spent in the hospital were obtained from clinic notes and hospital electronic charts. Results: A total of 104 patients were reviewed, 28 on TZD’s and 76 on other diabetic medications. The LVEF improved by 5.9% (p ⫽ 0.049) in the TZD group and by 3.7% (p ⫽ 0.022)in the non-TZD group. The difference between the two groups was not statistically significant (p ⫽ 0.49). Patients in the TZD group showed a trend toward more weight gain than those in the non-TZD group, an increase of 4.4 kg versus a loss of 0.3 kg, respectively (p ⫽ 0.53). Patients on TZD’s also had an increase in diuretic dose of 23 mg from baseline to endpoint whereas patients not on TZD’s group showed an increase of 1.7 mg. The difference between the groups was significant (p ⫽ 0.02). There was no difference in number of hospitalizations or days of hospitalization. Conclusions: Thiazolidinediones increase weight but do not affect hospitalizations or days of hospitalization. Therefore, TZDs may be used in patients with heart failure without adversely effecting heart function but patients should be monitored for weight gain and diuretic doses should be adjusted if needed.
250 Relation between Diuretic Dose and Outcome in a Heart Failure Population: Results of the ESCAPE Trial V. Hasselblad1, W. G. Stough1, M. R. Shah2, Y. Lokhnygina1, J. C. Burnett3, M. Gheorghiade4, B. K. Rayburn5, K. F. Adams, Jr.6, G. S. Francis7, R. M. Califf8; 1 Statistics Department, Duke Clinical Research Institute, Durham, NC; 2Department of Medicine, Columbia University Medical Center, New York, NY; 3Mayo Clinic, Rochester, MN; 4Division of Cardiology, Northwestern University, Chicago, IL; 5 Division of Cardiovascular Diseases, University of Alabama at Birmingham, Birmingham, AL; 6Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC; 7Department of Clinical Cardiology, The Cleveland Clinic, Cleveland, OH; 8Division of Cardiology, Department of Medicine, Duke University Medical Center, Duke Clinical Research Institute, Durham, NC Background: During therapy for fluid overload in heart failure (HF), persistent congestion leads to higher doses of diuretics, which may be associated with higher mortality. Using ESCAPE data, we examined the relation of furosemide dose to weight loss, changes in renal function, and mortality in patients with HF. Methods: ESCAPE compared PAC-guided therapy with standard care in HF patients. Of 433 patients, 366 received furosemide. Weight loss was the difference between baseline and last in-hospital weight. Mortality was assessed using a log-logistic model with nonzero background. Arrhythmia and change in creatinine level were used to evaluate the relation between furosemide dose and adverse effects. Results: Mean weight loss was 3.7 kg (22% of values ⬍0). Weight loss and diuretic dose were correlated (P ⫽ 0.0017), but the R2 was low (0.03). Only baseline weight, length of stay, and baseline BNP were significant predictors of weight loss. A strong relation between dose and mortality was seen (Figure, P ⫽ 0.0003), especially at doses ⬎300 mg/day. Dose remained a significant predictor of mortality after adjusting for age, 6-min walk, SCr, BUN, and BNP. No relation was seen between dose and SCr changes or arrhythmias. Conclusions: High-loop diuretic dose during HF is associated with mortality and a poor 6-month outcome. For patients receiving high-dose diuretics, risk vs benefit of increasing diuretic doses should be reevaluated.
•
HFSA
S157
low dose furosemide in improving renal function of acute CHF patients with renal dysfunction as compared to standard dose NES.
252 Randomized, Double Blind Comparison of Acute beta-1 Blockade with 50 mg Metoprolol Versus 25 mg Carvedilol in Normal Volunteers Undergoing Cardiopulmonary Exercise Testing Rana Billeh1, David Hirsh1, Krishnan Ramanathan1, Raban Jeger1, Greg Blair1, Birgit Jorgensen1, Ulrich Jorde1; 1Cardiology, New York University Medical Center, New York, NY Background: Differential efficacy of immediate release metoprolol (Met) at 50 mg BID and carvedilol (Carv) at 25 mg BID in the treatment of congestive heart failure remains a subject of ongoing debate. The degree of beta-1 blockade achieved with these doses is at the center of this controversy and can be assessed in vivo by percent reduction of exercise heart rate. Methods: 10 male and 2 female healthy volunteers (ages 27–54) underwent symptom limited cardiopulmonary exercise testing (CPETT). Resting and peak heart rate as well as oxygen consumption at anaerobic threshold (VO2AT) and at maximal exercise (VO2Max) were determined. CPETTs were then repeated at weekly intervals and two hours after a randomized,double blind administration of 50mg Met versus 25mg Carv. Results: Baseline heart rate was reduced from 74 ⫾ 3.3 to 59 ⫾ 2.6 and 64 ⫾ 3.1 respectively with Met and Carv (P ⬍ 0.05 for all). Peak heart rate was reduced from 186 ⫾ 2.6 at baseline to 153 ⫾ 4.2 with Met and 162 ⫾ 3.9 with Carv (P ⬍ 0.05 for all). Exercise heart rate was also blunted more by Met than Carv at 70% of peak VO2 and at the anaerobic threshold (AT) (p ⬍ 0.05). Peak VO2 was reduced from 45.4 ⫾ 1.9 at baseline to 42.5 ⫾ 2.3 by Met (P ⬍ 0.03) and 43.1 ⫾ 1.8 by Carv (P 0.054). The change in VO2 was significantly correlated with the degree of beta -1 blockade as assessed by the reduction in exercise heart rate (r 0.45; P ⬍ 0.05). Conclusion: In normal volunteers, a higher degree of beta-1 blockade is achieved with 50 mg metoprolol as compared with 25 mg carvedilol. Whether this difference is sustained over a 12 hour period and/or whether these results can be extrapolated to heart failure patients is unknown.
251
253
The Effects of Low Dose Nesiritide with Low Dose Furosemide on Renal Function in Patients with Acute Decompensated Heart Failure and Renal Dysfunction Henry G. Riter1, Margaret M. Redfield1, John C. Burnett1, Horng H. Chen1; 1Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, MN
Effect of Thiazolidinediones on Heart Failure Patients with Diabetes Sandra L. Chase1, Paul J. Schultz1, Prerana A. Manohar2; 1Pharmacy, Spectrum Health, Grand Rapids, MI; 2Meijer Heart Center, Spectrum Health, Grand Rapids, MI
Background: Human recombinant BNP (Nesiritide) has been approved by the FDA for the management of acute heart failure (CHF). The standard recommended dose of Nesiritide (NES) is a bolus of 2 µg/kg followed by infusion of 0.01 µg/kg/min. While preclinical studies have demonstrated the renal enhancing effects of BNP, clinical trials have been conflicting. We hypothesize that the attenuated renal actions of standard dose NES is partly due to its blood pressure (BP) lowering effects, therefore limiting renal perfusion pressure. Methods: We performed a retrospective review on consecutive patients admitted to Mayo Clinic Heart Failure Hospital Service from July 2001 to December 2004 who received NES at doses which were lower compared to the standard dose. We identified a total of 15 patients, 13 received 0.005 µg/kg/ min and 2 received 0.0025 µg/kg/min of NES without bolus. We compared this to patients (n ⫽ 13) who received standard dose NES and patients (n ⫽ 12) who did not receive NES but only standard therapy, matching groups for ejection fractional and calculated creatinine clearance (CrCl). * p ⬍ 0.05 vs Low dose. Results: Patients who received low dose NES had lower baseline systolic BP as compared to Standard dose NES and no NES (101 ⫾ 3 vs 121 ⫾ 6* vs 115 ⫾ 6* mmHg) groups. Low dose NES was well tolerated without a significant decrease in systolic BP (from 101 ⫾ 3 to 97 ⫾ 3 mmHg. P ⬎ 0.05) while systolic BP decreased in the Standard Dose NES (from 121 ⫾ 6 to 112 ⫾ 6 mmHg. P ⬍ 0.05) and no NES (from 115 ⫾ 6 to 106 ⫾ 6 mmHg, P ⬍ 0.05) groups. Most importantly, patients in the low dose NES group had improvement in renal function as measured by improvement of plasma Cr (from 2.6 ⫾ 0.3 to 2.1 ⫾ 0.2 mg/dl, P ⬍ 0.05), BUN (from 78 ⫾ 9 to 57 ⫾ 68 mg/dl, P ⬍ 0.05) and CrCl (from27 ⫾ 3 to 35 ⫾ 4 ml/min/1/73 m2, P ⬍ 0.05). Renal function did not improve in the Standard Dose NES and no NES groups. Patients in the low dose NES group required with less furosemide dose as compared to the Standard Dose NES and no NES groups (136 ⫾ 39 vs 389 ⫾ 71* vs 345 ⫾ 115*, mg of furosemide) while achieving similar diuresis and change in weight. Conclusion: This retrospective study supports the conclusion that further prospective randomized placebo controlled studies are warranted to define the efficacy of low dose NES incombination with
Introduction: Thiazolidinediones (TZD’s) are a class of medications used to increase insulin sensitivity in patients with type II diabetes mellitus. Additional effects of TZD’s on blood pressure, inflammatory markers, endothelial function, and lipid profiles suggest a benefit to patients with heart failure; however, fluid retention associated with TZD’s has prompted the creation of a contraindication for NYHA class III and IV heart failure. The additional effect of TZD’s suggest a benefit to patients with heart failure. The objective of this study was to evaluate the effect of TZD’s on the progression of heart failure in patients with the concurrent diagnoses of type 2 diabetes mellitus and heart failure. Methods: Patients who had diagnoses of both type 2 diabetes and heart failure were included if they had two measurements of LVEF by echocardiography or cardiac catheterization at least 6 months apart while enrolled in the clinic. Patients on TZD’s were compared to those on other oral diabetic medications or insulin with primary outcome measured as change of LVEF. Baseline LVEF was taken from the LVEF measurement closest to January 1, 2003. Endpoint LVEF was the measurement closest to 1 year after baseline. Secondary outcomes of change in weight, change in diuretic dose, number of hospital admissions, and number of days spent in the hospital were obtained from clinic notes and hospital electronic charts. Results: A total of 104 patients were reviewed, 28 on TZD’s and 76 on other diabetic medications. The LVEF improved by 5.9% (p ⫽ 0.049) in the TZD group and by 3.7% (p ⫽ 0.022)in the non-TZD group. The difference between the two groups was not statistically significant (p ⫽ 0.49). Patients in the TZD group showed a trend toward more weight gain than those in the non-TZD group, an increase of 4.4 kg versus a loss of 0.3 kg, respectively (p ⫽ 0.53). Patients on TZD’s also had an increase in diuretic dose of 23 mg from baseline to endpoint whereas patients not on TZD’s group showed an increase of 1.7 mg. The difference between the groups was significant (p ⫽ 0.02). There was no difference in number of hospitalizations or days of hospitalization. Conclusions: Thiazolidinediones increase weight but do not affect hospitalizations or days of hospitalization. Therefore, TZDs may be used in patients with heart failure without adversely effecting heart function but patients should be monitored for weight gain and diuretic doses should be adjusted if needed.