- Email: [email protected]
Angiotensin-converting enzyme inhibitor for epirubicin-induced dilated cardiomyopathy
was the most probable cause of the adverse Cyclophosphamide hypersensitivity is well documented but infrequent.4 Such a possibility was ruled out by both skin tests and in-vivo challenge in the intensive care unit. The precise mechanism of the adverse reaction to ondansetron is unclear, but negative skin-prick tests do not support an IgE-mediated mechanism, or histamine liberation by mastocytes. The risk of severe anaphylactoidlike reactions and the recent description of a possible class effect by Kataja and de Bruijnshould encourage restriction of the use of 5-HT3 antagonists such as ondansetron, granisetron, and tropisetron to highly emetogenic chemotherapy.
Ondansetron
events.
C
Frigerio,
*P A Buchwalder, F
Spertini
Divisions of Immunology and Allergy, and *Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
Murphy WK, Lester EP, et al. GR 38032F (GR-C507/75): a novel compound effective in the prevention of acute cisplatin-induced emesis. J Clin Oncol 1989; 7: 700-05. Chen M, Tanner A, Gallo-Torres H. Anaphylactoid-anaphylactic
l Hesket PJ,
2
reactions associated with ondansetron. Ann Intern Med 1993; 119: 862. Ballard HS, Bottino G, Bottino J. Ondansetron and chest pain. Lancet 1992; 340: 1107. 4 Cromar BW, Colvin M, Casale TB. Validity of skin tests to cyclophosphamide and metabolites. J Allergy Clin Immunol 1991; 88: 965-67. 5 Kataja V, de Bruijn KM. Hypersensitivity reactions associated with 5-hydroxytryptamine3-receptor antagonist: a class effect? Lancet 1996; 347: 584-85. 3
Angiotensin-converting enzyme inhibitor for epirubicin-induced dilated cardiomyopathy StR Jensen and colleagues (Feb 3, p 297)’ show that angiotensin-converting enzyme (ACE) inhibitors are useful for anthracycline-induced dilated cardiomyopathy, and it should be started soon after clinical improvement on digoxin/diuretic treatment. Their findings will be useful for clinical haematologists and oncologists who see many patients with cardiac dysfunction. Jensen and co-workers mention that ACE inhibitors should be started soon after improvement with digoxin or diuretics. In such circumstances, do we need to stop digoxin or diuretics when starting treatment with an ACE inhibitor? And if digoxin or diuretics are not being given because of contraindications or some other reason, do they still think that ACE inhibitors can be useful? Further, can ACE inhibitors prevent the development of dilated cardiomyopathy if we use them before or during treatment with anthracycline? Such questions often arise for clinical haematologists and oncologists who see many patients with anthracyclineinduced dilated cardiomyopathy.
*Kiyohiko Hatake,
Yasusada Miura
Division of Haematology, Department of Internal Medicine, Jichi Medical School, Minamikawachi, Kawachi, Tochigi, Japan 329-04
l Jensen BV, Nielsen SL, Skovsgaard T. Treatment with angiotensinconverting-enzyme inhibitor for epirubicin-induced dilated cardiomyopathy. Lancet 1996; 347: 297-99.
congestive heart failure (CHF) we gradually reduced the use of digoxin and diuretics. We were not systematically aiming at monotherapy, but eventually achieved this in three patients after 6 months to 2 years when they were stable on triple therapy. They remained stable as evaluated clinically and by left ventricular ejection faction (LVEF). When we tried to discontinue ACE-inhibitor therapy they had a decline in LVEF and we resumed ACE-inhibitor monotherapy (see figure in our original report). Three patients died from cancer before they could be given monotherapy. A further ten patients with CHF after various anthracycline regimens who were not reported in our paper were treated with an ACE-inhibitor, yielding a total of 18 patients. Six did well on triple therapy and three on ACE-inhibitor monotherapy. We believe that one should aim at ACE-inhibitor monotherapy, and it is our experience that this treatment can maintain clinical stability. In the whole group of 18 we had only two treatment failures: a male patient who was not initially given digoxin and an HIV-positive female after combined doxorubicin/paclitaxel therapy. Our long-term survivors with chronic cardiotoxicity after anthracycline therapy started ACE-inhibitor therapy 0-5-6 months after diagnosis of CHF. Another patient from the series had decline in LVEF from 59% to 37% 4 months after 920 mg/m2 of epirubicin. She developed CHF after our report was accepted for publication and she had a gradual decline in LVEF from 37% to 31% in 21 months, after which she fulfilled the diagnostic criteria for CHF that we used (NYHA class IV). She required admission for treatment of congestion but digitalo-diuretic therapy did not improve her condition. When an ACE-inhibitor was introduced she had rapid relief in symptoms with weight loss of 21 kg. 4 months after ACE-inhibitor therapy she only had a minor increase in LVEF (43%, NYHA II), but after another 4 months of therapy LVEF increased to normal values (52%, NYHA I). Another patient developed CHF after 925 mg/m2 of epirubicin; 2 years later LVEF was still suppressed (36%, NYHA 11-111) and increased (to 46%, NYHA I) after 1 year of ACE inhibition. These cases invite investigation of therapy in the growing number of long-term survivors with chronic cardiotoxicity after anthracycline therapy that has caused considerable concern. They indicate that spontaneous reversibility is unlikely to occur and that ACE-inhibitor therapy of progressive, longstanding suppression of cardiac function after anthracycline therapy can be successful but requires a much longer treatment period. We only treated postmenopausal women. Another group of immense importance is the growing number of children and young adults with chronic cardiotoxicity. ACE-inhibitors might prevent dilated cardiomyopathy if used immediately after ending anthracycline therapy since clinical overt heart failure usually appears 2-3 months later. As proposed by The Lancet in the talking point on our we are now conducting a double-blind, prospective study, randomising patients who have ended epirubicin 900-1000 mg/m2 for metastatic breast cancer to receive an ACE inhibitor or placebo for 6 months. Whether it is safe to administer an ACE inhibitor concomitant with anthracycline therapy remains to be investigated, but an interaction should
report,
be considered.
Authors’ reply
questioned about the meaning of "blinding the treating doctors for data on LVEF". This referred to doctors giving chemotherapy until development of clinical symptoms of CHF, after which
SIR-In response to Hatake and colleagues’ questions, we will address the difficulties of ACE-inhibitor monotherapy,
echocardiography and LVEF was used diagnosis of left ventricular dysfunction.
Finally,
our
treatment of chronic
cardiotoxicity, preventive therapy, and
protective therapy. When
treating patients
with
anthracycline-induced
dilated
we
have been
statement
to
confirm the
*Benny Vittrup Jensen, Steen Levin Nielsen, Torben Skovsgaard Department of Oncology, Herlev Hospital, University of Copenhagen, DK-2730 Herlev, Denmark
1485
Ondansetron
events.
C
Frigerio,
*P A Buchwalder, F
Spertini
Divisions of Immunology and Allergy, and *Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
Murphy WK, Lester EP, et al. GR 38032F (GR-C507/75): a novel compound effective in the prevention of acute cisplatin-induced emesis. J Clin Oncol 1989; 7: 700-05. Chen M, Tanner A, Gallo-Torres H. Anaphylactoid-anaphylactic
l Hesket PJ,
2
reactions associated with ondansetron. Ann Intern Med 1993; 119: 862. Ballard HS, Bottino G, Bottino J. Ondansetron and chest pain. Lancet 1992; 340: 1107. 4 Cromar BW, Colvin M, Casale TB. Validity of skin tests to cyclophosphamide and metabolites. J Allergy Clin Immunol 1991; 88: 965-67. 5 Kataja V, de Bruijn KM. Hypersensitivity reactions associated with 5-hydroxytryptamine3-receptor antagonist: a class effect? Lancet 1996; 347: 584-85. 3
Angiotensin-converting enzyme inhibitor for epirubicin-induced dilated cardiomyopathy StR Jensen and colleagues (Feb 3, p 297)’ show that angiotensin-converting enzyme (ACE) inhibitors are useful for anthracycline-induced dilated cardiomyopathy, and it should be started soon after clinical improvement on digoxin/diuretic treatment. Their findings will be useful for clinical haematologists and oncologists who see many patients with cardiac dysfunction. Jensen and co-workers mention that ACE inhibitors should be started soon after improvement with digoxin or diuretics. In such circumstances, do we need to stop digoxin or diuretics when starting treatment with an ACE inhibitor? And if digoxin or diuretics are not being given because of contraindications or some other reason, do they still think that ACE inhibitors can be useful? Further, can ACE inhibitors prevent the development of dilated cardiomyopathy if we use them before or during treatment with anthracycline? Such questions often arise for clinical haematologists and oncologists who see many patients with anthracyclineinduced dilated cardiomyopathy.
*Kiyohiko Hatake,
Yasusada Miura
Division of Haematology, Department of Internal Medicine, Jichi Medical School, Minamikawachi, Kawachi, Tochigi, Japan 329-04
l Jensen BV, Nielsen SL, Skovsgaard T. Treatment with angiotensinconverting-enzyme inhibitor for epirubicin-induced dilated cardiomyopathy. Lancet 1996; 347: 297-99.
congestive heart failure (CHF) we gradually reduced the use of digoxin and diuretics. We were not systematically aiming at monotherapy, but eventually achieved this in three patients after 6 months to 2 years when they were stable on triple therapy. They remained stable as evaluated clinically and by left ventricular ejection faction (LVEF). When we tried to discontinue ACE-inhibitor therapy they had a decline in LVEF and we resumed ACE-inhibitor monotherapy (see figure in our original report). Three patients died from cancer before they could be given monotherapy. A further ten patients with CHF after various anthracycline regimens who were not reported in our paper were treated with an ACE-inhibitor, yielding a total of 18 patients. Six did well on triple therapy and three on ACE-inhibitor monotherapy. We believe that one should aim at ACE-inhibitor monotherapy, and it is our experience that this treatment can maintain clinical stability. In the whole group of 18 we had only two treatment failures: a male patient who was not initially given digoxin and an HIV-positive female after combined doxorubicin/paclitaxel therapy. Our long-term survivors with chronic cardiotoxicity after anthracycline therapy started ACE-inhibitor therapy 0-5-6 months after diagnosis of CHF. Another patient from the series had decline in LVEF from 59% to 37% 4 months after 920 mg/m2 of epirubicin. She developed CHF after our report was accepted for publication and she had a gradual decline in LVEF from 37% to 31% in 21 months, after which she fulfilled the diagnostic criteria for CHF that we used (NYHA class IV). She required admission for treatment of congestion but digitalo-diuretic therapy did not improve her condition. When an ACE-inhibitor was introduced she had rapid relief in symptoms with weight loss of 21 kg. 4 months after ACE-inhibitor therapy she only had a minor increase in LVEF (43%, NYHA II), but after another 4 months of therapy LVEF increased to normal values (52%, NYHA I). Another patient developed CHF after 925 mg/m2 of epirubicin; 2 years later LVEF was still suppressed (36%, NYHA 11-111) and increased (to 46%, NYHA I) after 1 year of ACE inhibition. These cases invite investigation of therapy in the growing number of long-term survivors with chronic cardiotoxicity after anthracycline therapy that has caused considerable concern. They indicate that spontaneous reversibility is unlikely to occur and that ACE-inhibitor therapy of progressive, longstanding suppression of cardiac function after anthracycline therapy can be successful but requires a much longer treatment period. We only treated postmenopausal women. Another group of immense importance is the growing number of children and young adults with chronic cardiotoxicity. ACE-inhibitors might prevent dilated cardiomyopathy if used immediately after ending anthracycline therapy since clinical overt heart failure usually appears 2-3 months later. As proposed by The Lancet in the talking point on our we are now conducting a double-blind, prospective study, randomising patients who have ended epirubicin 900-1000 mg/m2 for metastatic breast cancer to receive an ACE inhibitor or placebo for 6 months. Whether it is safe to administer an ACE inhibitor concomitant with anthracycline therapy remains to be investigated, but an interaction should
report,
be considered.
Authors’ reply
questioned about the meaning of "blinding the treating doctors for data on LVEF". This referred to doctors giving chemotherapy until development of clinical symptoms of CHF, after which
SIR-In response to Hatake and colleagues’ questions, we will address the difficulties of ACE-inhibitor monotherapy,
echocardiography and LVEF was used diagnosis of left ventricular dysfunction.
Finally,
our
treatment of chronic
cardiotoxicity, preventive therapy, and
protective therapy. When
treating patients
with
anthracycline-induced
dilated
we
have been
statement
to
confirm the
*Benny Vittrup Jensen, Steen Levin Nielsen, Torben Skovsgaard Department of Oncology, Herlev Hospital, University of Copenhagen, DK-2730 Herlev, Denmark
1485