- Email: [email protected]
Nesiritide Administration in Patients With Left Ventricular Dysfunction Undergoing Coronary Artery Bypass Surgery⁎
Journal of the American College of Cardiology © 2007 by the American College of Cardiology Foundation Published by Elsevier Inc.
EDITORIAL COMMENT
Nesiritide Administration in Patients With Left Ventricular Dysfunction Undergoing Coronary Artery Bypass Surgery* Israel Belenkie, MD, FACC Calgary, Alberta, Canada
Nesiritide has the same amino acid sequence as human B-type natriuretic peptide (BNP), which is secreted by the ventricles in response to myocardial stretch. B-type natriuretic peptide relaxes vascular smooth muscle and causes arterial dilatation (1–7). Although BNP may also cause venodilation, the fact that it does not reduce right-sided pressures in precapillary pulmonary hypertension suggests that it may be only a weak venodilator (8,9). B-type natriuretic peptide promotes sodium and water excretion (1–3,10). The filtration fraction and glomerular filtration rate increase consistent with vasoconstriction of efferent arterials and vasodilation of afferent arterials. Sodium reabsorption is inhibited in both proximal and distal tubules. Associated changes include decreased stimulation of the renin angiotensin and sympathetic nervous systems and decreased plasma aldosterone and endothelin-1 levels (4,11,12). Whether these changes are related to the hemodynamic effects of BNP or are direct effects is uncertain. See page 716
As with other vasodilators, nesiritide is effective in treating acute decompensated congestive heart failure. In addition to symptomatic improvement, filling pressures and pulmonary vascular resistance are reduced and cardiac output is increased in a dose-dependent manner without an increased heart rate or plasma norepinephrine level (4). There is no apparent tachyphylaxis during infusions up to
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Department of Cardiac Sciences and the Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada. Dr. Belenkie has acted as an adviser to Ortho-Biotech, a subsidiary of Johnson & Johnson responsible for nesiritide in Canada, and has submitted a grant proposal to Ortho-Biotech to fund a study with nesiritide.
Vol. 49, No. 6, 2007 ISSN 0735-1097/07/$32.00 doi:10.1016/j.jacc.2006.11.009
48 h. Nesiritide was shown to be at least as effective as nitroglycerin in treating acute decompensated heart failure (5). However, a meta-analysis suggesting that long-term outcomes may be worse in patients treated with BNP (13) has created considerable controversy that remains to be resolved. As reported by Mentzer et al. (14) in this issue of the Journal, the NAPA (Nesiritide Administered PeriAnesthesia in Patients Undergoing Cardiac Surgery) trial was a placebo-controlled randomized study in which patients with left ventricular dysfunction (ejection fraction ⱕ40%) undergoing bypass surgery were administered nesiritide (low dose and no bolus) or placebo after induction of anesthesia for 24 to 96 h in addition to usual care. The focus was primarily on the effects of nesiritide on renal function. Patients were screened to ensure that blood pressure and filling pressures were not too low for them to safely receive an arterial dilator. The rationale was based on the association of renal dysfunction and worse outcomes after bypass surgery—improved renal protection might improve outcomes. Although serum creatinine increased in both groups, it returned to baseline within 12 h in those treated with nesiritide and remained elevated in the placebo group throughout hospitalization. There was better preservation of the glomerular filtration rate, and urine output was greater in those who received nesiritide. Renal protection was greatest in patients with preexisting renal dysfunction. Hospital length of stay was shorter, and mortality up to 180 days may have been lower in the treatment group. The effects of nesiritide on renal function were clear; however, translation of those results to clinical outcomes remains to be demonstrated. Mortality was not a prespecified end point but was added during the course of the trial and, even more importantly, data collection was incomplete. There were few deaths, so the lack of follow-up in a substantial proportion of the patients precludes acceptance of the mortality difference with confidence despite the statistical significance of the results. Concomitant drug use would be of great interest. If nesiritide administration can reduce dependence on inotropic agents and diuretics to achieve similar or better hemodynamics in addition to renal protection, this would support considering its use. The mechanism of renal protection was unclear in the NAPA trial— hemodynamic results were similar in both groups. A direct renal protective effect is a viable but unproven hypothesis. Perhaps inotropes and vasoconstrictors may provide seemingly good acute responses but with negative downstream effects, as has been suggested in acute decompensated heart failure (15,16), but incomplete documentation of their use is a missed opportunity to test that hypothesis. Vasoactive agents, diuretics, and inotropes were listed, but the details, including doses, were such that no conclusion can be offered regarding the effects of nesiritide on concomitant drug use. It is also important to note that 303 patients were randomized in 54 participating centers
728
Belenkie Editorial Comment
over 15 months; therefore, the general applicability of the results in consecutive study-eligible patients is uncertain. As stated by the authors, the NAPA trial should be considered exploratory. The results in patients with left ventricular dysfunction undergoing bypass surgery support the need for further study of nesiritide in this patient population, as well as in others with congestive heart failure. At this time, it remains unclear just where nesiritide best fits among agents available for parenteral treatment of heart failure. It is also important to assess the venodilating effects of nesiritide. If it is only effective as an arterial dilator, combined use with nitroglycerin may be appropriate in some patients, particularly in those with relatively low blood pressure in whom hypotension should be avoided (17–19). Optimal dosing, including whether a bolus should be used, needs clarification. Low doses may improve renal function when blood pressure is maintained, whereas higher doses may cause hypotension and decrease renal perfusion, exaggerated by concomitant diuretic use (20). Experience with other parenteral vasodilators would suggest that doses should be titrated to desired effects rather than using arbitrary doses. Although recent meta-analyses cause concern regarding outcomes, including worsening renal function with nesiritide in acute decompensated heart failure (13,21), results from ongoing clinical trials will soon address these issues. However, there is still much to learn regarding how best to use this promising agent. The NAPA trial provides encouraging results in one subgroup of patients who might benefit from the use of nesiritide, but more comprehensive data are required before promoting routine use in this population. Reprint requests and correspondence: Dr. Israel Belenkie, Health Sciences Centre, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. E-mail: [email protected]. REFERENCES
1. Burger AJ. A review of the renal and neurohormonal effects of B-type natriuretic peptide. Congest Heart Fail 2005;11:30 – 8. 2. Adams KF Jr., Mathur VS, Gheorghiade M. B-Type natriuretic peptide: from bench to bedside. Am Heart J 2003;145:S34 – 46. 3. de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet 2003;362:316 –22. 4. Colucci WS, Elkayam U, Horton DP; Nesiritide Study Group. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med 2000;343:246–53.
JACC Vol. 49, No. 6, 2007 February 13, 2007:727–8 5. Publication Committee for the VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure. JAMA 2002;287:1531– 40. 6. Mills RM, Horton DP, LeJemtel TH. Sustained hemodynamic effects of an infusion of nesiritide (human B-type natriuretic peptide) in heart failure: a randomized, double-blind, placebo-controlled clinical trial. J Am Coll Cardiol 1999;34:155– 62. 7. Marcus LS, Hart D, Packer M. Hemodynamic and renal excretory effects of human brain natriuretic peptide infusion in patients with congestive heart failure. Circulation 1996;94:3184 –9. 8. Michaels AD, Chatterjee K, de Marco T. Effects of intravenous nesiritide on pulmonary vascular hemodynamics in pulmonary hypertension. J Card Fail 2005;11:425–31. 9. Protter AA, Wallace AM, Ferraris VA, Weishaar RE. Relaxant effect of human brain natriuretic peptide on human artery and vein tissue. Am J Hypertens 1996;9:432– 6. 10. Jensen KT, Eiskjaer H, Carstens J, Pedersen EB. Renal effects of brain natriuretic peptide in patients with congestive heart failure. Clin Sci (Lond) 1999;96:5–15. 11. Abraham WT, Lowes BD, Ferguson DA, et al. Systemic hemodynamic, neurohormonal, and renal effects of a steady-state infusion of human brain natriuretic peptide in patients with hemodynamically decompensated heart failure. J Card Fail 1998;4:37– 44. 12. Aronson D, Burger AJ. Intravenous nesiritide (human B-type natriuretic peptide) reduces plasma endothelin-1 levels in patients with decompensated congestive heart failure. Am J Cardiol 2002;90:435– 8. 13. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA 2005;293:1900 –5. 14. Mentzer RM Jr., Oz MC, Sladen RN, et al., on behalf of the NAPA Investigators. Effects of perioperative nesiritide in patients with left ventricular dysfunction undergoing cardiac surgery: the NAPA trial. J Am Coll Cardiol 2007;49:716 –26. 15. Abraham WT, Adams KF, Fonarow GC, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol 2005;46:57– 64. 16. Silver MA, Horton DP, Ghali JK, Elkayam U. Effect of nesiritide versus dobutamine on short-term outcomes in the treatment of patients with acutely decompensated heart failure. J Am Coll Cardiol 2002;39:798– 803. 17. Abraham W. Serum creatinine elevations in patients receiving nesiritide are related to starting dose (abstr). J Card Fail 2005;11:S156. 18. Chen HH, Grantham JA, Schirger JA, Jougasaki M, Redfield MM, Burnett JC Jr. Subcutaneous administration of brain natriuretic peptide in experimental heart failure. J Am Coll Cardiol 2000;36:1706 –12. 19. Riter HG, Redfield MM, Burnett JC, Chen HH. Nonhypotensive low-dose nesiritide has differential renal effects compared with standard-dose nesiritide in patients with acute decompensated heart failure and renal dysfunction. J Am Coll Cardiol 2006;47:2334 –5. 20. Heywood JT. Combining nesiritide with high-dose diuretics may increase the risk of increased serum creatinine (abstr). J Card Fail 2005;11:S154. 21. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005;111:1487–91.
EDITORIAL COMMENT
Nesiritide Administration in Patients With Left Ventricular Dysfunction Undergoing Coronary Artery Bypass Surgery* Israel Belenkie, MD, FACC Calgary, Alberta, Canada
Nesiritide has the same amino acid sequence as human B-type natriuretic peptide (BNP), which is secreted by the ventricles in response to myocardial stretch. B-type natriuretic peptide relaxes vascular smooth muscle and causes arterial dilatation (1–7). Although BNP may also cause venodilation, the fact that it does not reduce right-sided pressures in precapillary pulmonary hypertension suggests that it may be only a weak venodilator (8,9). B-type natriuretic peptide promotes sodium and water excretion (1–3,10). The filtration fraction and glomerular filtration rate increase consistent with vasoconstriction of efferent arterials and vasodilation of afferent arterials. Sodium reabsorption is inhibited in both proximal and distal tubules. Associated changes include decreased stimulation of the renin angiotensin and sympathetic nervous systems and decreased plasma aldosterone and endothelin-1 levels (4,11,12). Whether these changes are related to the hemodynamic effects of BNP or are direct effects is uncertain. See page 716
As with other vasodilators, nesiritide is effective in treating acute decompensated congestive heart failure. In addition to symptomatic improvement, filling pressures and pulmonary vascular resistance are reduced and cardiac output is increased in a dose-dependent manner without an increased heart rate or plasma norepinephrine level (4). There is no apparent tachyphylaxis during infusions up to
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Department of Cardiac Sciences and the Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada. Dr. Belenkie has acted as an adviser to Ortho-Biotech, a subsidiary of Johnson & Johnson responsible for nesiritide in Canada, and has submitted a grant proposal to Ortho-Biotech to fund a study with nesiritide.
Vol. 49, No. 6, 2007 ISSN 0735-1097/07/$32.00 doi:10.1016/j.jacc.2006.11.009
48 h. Nesiritide was shown to be at least as effective as nitroglycerin in treating acute decompensated heart failure (5). However, a meta-analysis suggesting that long-term outcomes may be worse in patients treated with BNP (13) has created considerable controversy that remains to be resolved. As reported by Mentzer et al. (14) in this issue of the Journal, the NAPA (Nesiritide Administered PeriAnesthesia in Patients Undergoing Cardiac Surgery) trial was a placebo-controlled randomized study in which patients with left ventricular dysfunction (ejection fraction ⱕ40%) undergoing bypass surgery were administered nesiritide (low dose and no bolus) or placebo after induction of anesthesia for 24 to 96 h in addition to usual care. The focus was primarily on the effects of nesiritide on renal function. Patients were screened to ensure that blood pressure and filling pressures were not too low for them to safely receive an arterial dilator. The rationale was based on the association of renal dysfunction and worse outcomes after bypass surgery—improved renal protection might improve outcomes. Although serum creatinine increased in both groups, it returned to baseline within 12 h in those treated with nesiritide and remained elevated in the placebo group throughout hospitalization. There was better preservation of the glomerular filtration rate, and urine output was greater in those who received nesiritide. Renal protection was greatest in patients with preexisting renal dysfunction. Hospital length of stay was shorter, and mortality up to 180 days may have been lower in the treatment group. The effects of nesiritide on renal function were clear; however, translation of those results to clinical outcomes remains to be demonstrated. Mortality was not a prespecified end point but was added during the course of the trial and, even more importantly, data collection was incomplete. There were few deaths, so the lack of follow-up in a substantial proportion of the patients precludes acceptance of the mortality difference with confidence despite the statistical significance of the results. Concomitant drug use would be of great interest. If nesiritide administration can reduce dependence on inotropic agents and diuretics to achieve similar or better hemodynamics in addition to renal protection, this would support considering its use. The mechanism of renal protection was unclear in the NAPA trial— hemodynamic results were similar in both groups. A direct renal protective effect is a viable but unproven hypothesis. Perhaps inotropes and vasoconstrictors may provide seemingly good acute responses but with negative downstream effects, as has been suggested in acute decompensated heart failure (15,16), but incomplete documentation of their use is a missed opportunity to test that hypothesis. Vasoactive agents, diuretics, and inotropes were listed, but the details, including doses, were such that no conclusion can be offered regarding the effects of nesiritide on concomitant drug use. It is also important to note that 303 patients were randomized in 54 participating centers
728
Belenkie Editorial Comment
over 15 months; therefore, the general applicability of the results in consecutive study-eligible patients is uncertain. As stated by the authors, the NAPA trial should be considered exploratory. The results in patients with left ventricular dysfunction undergoing bypass surgery support the need for further study of nesiritide in this patient population, as well as in others with congestive heart failure. At this time, it remains unclear just where nesiritide best fits among agents available for parenteral treatment of heart failure. It is also important to assess the venodilating effects of nesiritide. If it is only effective as an arterial dilator, combined use with nitroglycerin may be appropriate in some patients, particularly in those with relatively low blood pressure in whom hypotension should be avoided (17–19). Optimal dosing, including whether a bolus should be used, needs clarification. Low doses may improve renal function when blood pressure is maintained, whereas higher doses may cause hypotension and decrease renal perfusion, exaggerated by concomitant diuretic use (20). Experience with other parenteral vasodilators would suggest that doses should be titrated to desired effects rather than using arbitrary doses. Although recent meta-analyses cause concern regarding outcomes, including worsening renal function with nesiritide in acute decompensated heart failure (13,21), results from ongoing clinical trials will soon address these issues. However, there is still much to learn regarding how best to use this promising agent. The NAPA trial provides encouraging results in one subgroup of patients who might benefit from the use of nesiritide, but more comprehensive data are required before promoting routine use in this population. Reprint requests and correspondence: Dr. Israel Belenkie, Health Sciences Centre, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. E-mail: [email protected]. REFERENCES
1. Burger AJ. A review of the renal and neurohormonal effects of B-type natriuretic peptide. Congest Heart Fail 2005;11:30 – 8. 2. Adams KF Jr., Mathur VS, Gheorghiade M. B-Type natriuretic peptide: from bench to bedside. Am Heart J 2003;145:S34 – 46. 3. de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet 2003;362:316 –22. 4. Colucci WS, Elkayam U, Horton DP; Nesiritide Study Group. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med 2000;343:246–53.
JACC Vol. 49, No. 6, 2007 February 13, 2007:727–8 5. Publication Committee for the VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure. JAMA 2002;287:1531– 40. 6. Mills RM, Horton DP, LeJemtel TH. Sustained hemodynamic effects of an infusion of nesiritide (human B-type natriuretic peptide) in heart failure: a randomized, double-blind, placebo-controlled clinical trial. J Am Coll Cardiol 1999;34:155– 62. 7. Marcus LS, Hart D, Packer M. Hemodynamic and renal excretory effects of human brain natriuretic peptide infusion in patients with congestive heart failure. Circulation 1996;94:3184 –9. 8. Michaels AD, Chatterjee K, de Marco T. Effects of intravenous nesiritide on pulmonary vascular hemodynamics in pulmonary hypertension. J Card Fail 2005;11:425–31. 9. Protter AA, Wallace AM, Ferraris VA, Weishaar RE. Relaxant effect of human brain natriuretic peptide on human artery and vein tissue. Am J Hypertens 1996;9:432– 6. 10. Jensen KT, Eiskjaer H, Carstens J, Pedersen EB. Renal effects of brain natriuretic peptide in patients with congestive heart failure. Clin Sci (Lond) 1999;96:5–15. 11. Abraham WT, Lowes BD, Ferguson DA, et al. Systemic hemodynamic, neurohormonal, and renal effects of a steady-state infusion of human brain natriuretic peptide in patients with hemodynamically decompensated heart failure. J Card Fail 1998;4:37– 44. 12. Aronson D, Burger AJ. Intravenous nesiritide (human B-type natriuretic peptide) reduces plasma endothelin-1 levels in patients with decompensated congestive heart failure. Am J Cardiol 2002;90:435– 8. 13. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA 2005;293:1900 –5. 14. Mentzer RM Jr., Oz MC, Sladen RN, et al., on behalf of the NAPA Investigators. Effects of perioperative nesiritide in patients with left ventricular dysfunction undergoing cardiac surgery: the NAPA trial. J Am Coll Cardiol 2007;49:716 –26. 15. Abraham WT, Adams KF, Fonarow GC, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol 2005;46:57– 64. 16. Silver MA, Horton DP, Ghali JK, Elkayam U. Effect of nesiritide versus dobutamine on short-term outcomes in the treatment of patients with acutely decompensated heart failure. J Am Coll Cardiol 2002;39:798– 803. 17. Abraham W. Serum creatinine elevations in patients receiving nesiritide are related to starting dose (abstr). J Card Fail 2005;11:S156. 18. Chen HH, Grantham JA, Schirger JA, Jougasaki M, Redfield MM, Burnett JC Jr. Subcutaneous administration of brain natriuretic peptide in experimental heart failure. J Am Coll Cardiol 2000;36:1706 –12. 19. Riter HG, Redfield MM, Burnett JC, Chen HH. Nonhypotensive low-dose nesiritide has differential renal effects compared with standard-dose nesiritide in patients with acute decompensated heart failure and renal dysfunction. J Am Coll Cardiol 2006;47:2334 –5. 20. Heywood JT. Combining nesiritide with high-dose diuretics may increase the risk of increased serum creatinine (abstr). J Card Fail 2005;11:S154. 21. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005;111:1487–91.