- Email: [email protected]
Nesiritide in acute heart failure
CORRESPONDENCE
although the extent of activation is not as great as we initially reported (unpublished data). We agree that the best study design should include a control group. Unfortunately, it is impossible for participants to remain unaware of a hypobaric environment, because they would notice changes in ambient air pressure immediately. We, therefore, question why Crosby and colleagues reference evidence from uncontrolled field studies in which participants were exposed to danger, cold, wind, radiation, physical and mental exhaustion, hypoglycaemia, and dehydration. *Bjørn Bendz, Per Morten Sandset Haematological Research Laboratory, Ullevål University Hospital, N-0407 Oslo, Norway (e-mail: [email protected]) 1
2
3
4
Crosby A, Talbot NP, Harrison P, Keeling D, Robbins PA. Relation between acute hypoxia and activation of coagulation in human beings. Lancet 2003; 361: 2207–08. Bendz B, Rostrup M, Sevre K, Andersen TO, Sandset PM. Association between acute hypobaric hypoxia and activation of coagulation in human beings. Lancet 2000; 356: 1657–58. Bendz B, Rostrup M, Sevre K, Andersen TO, Sandset PM. Hypobaric hypoxia. Lancet 2001; 357: 955–56. Bärtsch P, Straub PW, Haeberli A. Hypobaric hypoxia. Lancet 2001; 357: 955–56.
Nesiritide in acute heart failure Sir—James de Lemos and colleagues’ Review (July 26, p 316)1 on B-type natriuretic peptide (BNP) and its role in the diagnosis, prognosis, and treatment of cardiovascular disease is useful and timely. However, they were unduly circumspect in describing the advantages of recombinant BNP (nesiritide) over other agents, particularly dobutamine, in the treatment of heart failure. Additionally, they expressed uncertainty with respect to when to use nesiritide versus other agents, and suggested there is a lack of economic and adverse clinical outcomes data on nesiritide. There is much published work on the efficacy, safety, and economic advantages of nesiritide for treatment of heart failure emerging by contrast with publications on the evidence of negative outcomes, arrhythmias, and mortality associated with inotropes. Nesiritide has neurohormonal, diuretic, and vasoactive effects without positive inotropic or chronotropic activity. The results of the PRECEDENT study2 showed that dobutamine was associated with increased ventricular arrhythmias and heart rate, and a worsened neurohormonal profile. Nesiritide
998
decreased all measures of ventricular ectopy compared with dobutamine, reduced neurohormonal and sympathetic activation, and improved heart rate variability, suggesting that nesiritide is safer and possibly more effective than dobutamine, especially in patients with tachycardia, arrhythmias, or ventricular irritability. Findings of another trial3 showed that median treatment duration of nesiritide (26 h or 40 h, depending on dose) was shorter than that of dobutamine (65 h). Moreover, the American College of Cardiology-American Heart Association guidelines do not recommend agents with unproven value, such as inotropes, for treating advanced heart failure. The VMAC trial4 compared nesiritide and nitroglycerin in addition to standard care for decompensated congestive heart failure. Nesiritide was more effective than nitroglycerin in reducing pulmonary capillary wedge pressure and improving dyspnoea, with fewer adverse events, and without the development of tolerance or the need for titration. Nesiritide has been assessed in more than 1200 patients in more than 12 trials, which included patients with moderate and severe heart failure, systolic or diastolic dysfunction, arrhythmias, renal insufficiency, acute ischaemic syndrome, and elderly patients. Furthermore, nesiritide can be used in conjunction with other drugs, including diuretics, digoxin, angiotensin converting enzyme inhibitors, anticoagulants, oral nitrates,  blockers, class III antiarrhythmics, dobutamine, and calcium channel blockers. The primary adverse event related to nesiritide is dose-related symptomatic hypotension, manageable by dose reduction or discontinuation. The pharmacoeconomic effect of nesiritide use was assessed in several studies, including the PROACTION trial.5 The findings of this study indicated a 21% reduction in admissions for heart failure in patients treated in the emergency department with nesiritide versus placebo plus standard care, and lower rates of readmission over 30 days. Of those who were readmitted to hospital, hospital length of stay for nesiritide-treated patients was 5·5 days versus 10·2 days for placebo-treated patients.5 The efficacy, safety, and economic data suggest that nesiritide is equally or more effective in treating acutely decompensated heart failure than other agents, but is associated with fewer adverse events, fewer hospital admissions and readmissions, shorter treatment duration, and shorter length of stay in hospital. The data described here show that nesiritide is particularly
advantageous in some subgroups of patients, including severely ill patients with comorbidities. AJB receives a research fund from and is a consultant for Scios. MAS is a clinical investigator and on the speakers bureau for Scios.
Andrew J Burger, *Marc A Silver Department of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA (AJB); *Heart Failure Institute, Advocate Christ Medical Center, Oak Lawn, IL 60453, USA (MAS) (e-mail: [email protected]) 1
2
3
4
5
de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet 2003; 362: 316–22. Burger AJ, Horton DP, LeJemtel T, et al. Effect of nesiritide (B-type natriuretic peptide) and dobutamine on ventricular arrhythmias in the treatment of patients with acutely decompensated congestive heart failure: the PRECEDENT study. Am Heart J 2002; 144: 1102–08. 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. Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 2002; 287: 1531–40. Peacock WF, Emerman CL, on behalf of the PROACTION study group. Safety and efficacy of nesiritide in the treatment of decompensated heart failure in observation patients. J Am Coll Cardiol 2003; 41: (suppl A): 336A.
Authors’ reply Sir—We appreciate the interest of Andrew Burger and Marc Silver in our Review and concur that the issue they raise is an important one. They disagree with our contention that “when [nesiritide] should be used instead of other parenteral agents such as dobutamine, milrinone, sodium nitroprusside, or nitroglycerin remains unclear”. In support of their viewpoint, they cite the PRECEDENT and VMAC studies and a retrospective outcome analysis of the earlier open label study in which mortality was significantly improved with a lower but not higher dose of nesiritide versus a fixed dose of dobutamine. They also cite economic data from the PROACTION study, which has been reported only in abstract form. Although Burger and Silver think that this aggregate experience is adequate to support the routine use of nesiritide in patients with decompensated heart failure, we do not. The fundamental concern we have with the studies of nesiritide to date is that they have been largely based on surrogate endpoints. For example, Silver and Burger cite the VMAC
THE LANCET • Vol 362 • September 20, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet publishing Group.
although the extent of activation is not as great as we initially reported (unpublished data). We agree that the best study design should include a control group. Unfortunately, it is impossible for participants to remain unaware of a hypobaric environment, because they would notice changes in ambient air pressure immediately. We, therefore, question why Crosby and colleagues reference evidence from uncontrolled field studies in which participants were exposed to danger, cold, wind, radiation, physical and mental exhaustion, hypoglycaemia, and dehydration. *Bjørn Bendz, Per Morten Sandset Haematological Research Laboratory, Ullevål University Hospital, N-0407 Oslo, Norway (e-mail: [email protected]) 1
2
3
4
Crosby A, Talbot NP, Harrison P, Keeling D, Robbins PA. Relation between acute hypoxia and activation of coagulation in human beings. Lancet 2003; 361: 2207–08. Bendz B, Rostrup M, Sevre K, Andersen TO, Sandset PM. Association between acute hypobaric hypoxia and activation of coagulation in human beings. Lancet 2000; 356: 1657–58. Bendz B, Rostrup M, Sevre K, Andersen TO, Sandset PM. Hypobaric hypoxia. Lancet 2001; 357: 955–56. Bärtsch P, Straub PW, Haeberli A. Hypobaric hypoxia. Lancet 2001; 357: 955–56.
Nesiritide in acute heart failure Sir—James de Lemos and colleagues’ Review (July 26, p 316)1 on B-type natriuretic peptide (BNP) and its role in the diagnosis, prognosis, and treatment of cardiovascular disease is useful and timely. However, they were unduly circumspect in describing the advantages of recombinant BNP (nesiritide) over other agents, particularly dobutamine, in the treatment of heart failure. Additionally, they expressed uncertainty with respect to when to use nesiritide versus other agents, and suggested there is a lack of economic and adverse clinical outcomes data on nesiritide. There is much published work on the efficacy, safety, and economic advantages of nesiritide for treatment of heart failure emerging by contrast with publications on the evidence of negative outcomes, arrhythmias, and mortality associated with inotropes. Nesiritide has neurohormonal, diuretic, and vasoactive effects without positive inotropic or chronotropic activity. The results of the PRECEDENT study2 showed that dobutamine was associated with increased ventricular arrhythmias and heart rate, and a worsened neurohormonal profile. Nesiritide
998
decreased all measures of ventricular ectopy compared with dobutamine, reduced neurohormonal and sympathetic activation, and improved heart rate variability, suggesting that nesiritide is safer and possibly more effective than dobutamine, especially in patients with tachycardia, arrhythmias, or ventricular irritability. Findings of another trial3 showed that median treatment duration of nesiritide (26 h or 40 h, depending on dose) was shorter than that of dobutamine (65 h). Moreover, the American College of Cardiology-American Heart Association guidelines do not recommend agents with unproven value, such as inotropes, for treating advanced heart failure. The VMAC trial4 compared nesiritide and nitroglycerin in addition to standard care for decompensated congestive heart failure. Nesiritide was more effective than nitroglycerin in reducing pulmonary capillary wedge pressure and improving dyspnoea, with fewer adverse events, and without the development of tolerance or the need for titration. Nesiritide has been assessed in more than 1200 patients in more than 12 trials, which included patients with moderate and severe heart failure, systolic or diastolic dysfunction, arrhythmias, renal insufficiency, acute ischaemic syndrome, and elderly patients. Furthermore, nesiritide can be used in conjunction with other drugs, including diuretics, digoxin, angiotensin converting enzyme inhibitors, anticoagulants, oral nitrates,  blockers, class III antiarrhythmics, dobutamine, and calcium channel blockers. The primary adverse event related to nesiritide is dose-related symptomatic hypotension, manageable by dose reduction or discontinuation. The pharmacoeconomic effect of nesiritide use was assessed in several studies, including the PROACTION trial.5 The findings of this study indicated a 21% reduction in admissions for heart failure in patients treated in the emergency department with nesiritide versus placebo plus standard care, and lower rates of readmission over 30 days. Of those who were readmitted to hospital, hospital length of stay for nesiritide-treated patients was 5·5 days versus 10·2 days for placebo-treated patients.5 The efficacy, safety, and economic data suggest that nesiritide is equally or more effective in treating acutely decompensated heart failure than other agents, but is associated with fewer adverse events, fewer hospital admissions and readmissions, shorter treatment duration, and shorter length of stay in hospital. The data described here show that nesiritide is particularly
advantageous in some subgroups of patients, including severely ill patients with comorbidities. AJB receives a research fund from and is a consultant for Scios. MAS is a clinical investigator and on the speakers bureau for Scios.
Andrew J Burger, *Marc A Silver Department of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA (AJB); *Heart Failure Institute, Advocate Christ Medical Center, Oak Lawn, IL 60453, USA (MAS) (e-mail: [email protected]) 1
2
3
4
5
de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet 2003; 362: 316–22. Burger AJ, Horton DP, LeJemtel T, et al. Effect of nesiritide (B-type natriuretic peptide) and dobutamine on ventricular arrhythmias in the treatment of patients with acutely decompensated congestive heart failure: the PRECEDENT study. Am Heart J 2002; 144: 1102–08. 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. Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 2002; 287: 1531–40. Peacock WF, Emerman CL, on behalf of the PROACTION study group. Safety and efficacy of nesiritide in the treatment of decompensated heart failure in observation patients. J Am Coll Cardiol 2003; 41: (suppl A): 336A.
Authors’ reply Sir—We appreciate the interest of Andrew Burger and Marc Silver in our Review and concur that the issue they raise is an important one. They disagree with our contention that “when [nesiritide] should be used instead of other parenteral agents such as dobutamine, milrinone, sodium nitroprusside, or nitroglycerin remains unclear”. In support of their viewpoint, they cite the PRECEDENT and VMAC studies and a retrospective outcome analysis of the earlier open label study in which mortality was significantly improved with a lower but not higher dose of nesiritide versus a fixed dose of dobutamine. They also cite economic data from the PROACTION study, which has been reported only in abstract form. Although Burger and Silver think that this aggregate experience is adequate to support the routine use of nesiritide in patients with decompensated heart failure, we do not. The fundamental concern we have with the studies of nesiritide to date is that they have been largely based on surrogate endpoints. For example, Silver and Burger cite the VMAC
THE LANCET • Vol 362 • September 20, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet publishing Group.