- Email: [email protected]
Ibuprofen prophylaxis in preterm neonates
CORRESPONDENCE
patients in the univalent subgroup. By comparison, for the efegatran study,4 the Kaplan-Meier curves for the same endpoint suggest little or no difference at day 3 between heparin and efegatran. Furthermore, in the antithrombin-argatroban in ARGAMI-2,2 high-dose argatroban (120 g/kg bolus and 4 g kg⫺1 min⫺1 infusion) compared with heparin showed a slight decrease in ischaemic events (death, stroke, recurrent myocardial infarction, cardiogenic shock or severe congestive heart failure, or revascularisation because of ischaemia) at day 3. In the Direct Thrombin Inhibitor Trialists’ meta-analysis, hirudin was associated with excess bleeding compared with heparin, whereas bivalirudin and univalent inhibitors were associated with reduced bleeding. The absence of intracranial haemorrhage for argatroban (even in conjunction with thrombolytic therapy), efegatran, or inogatran could indicate suboptimum doses. Alternatively, this finding suggests that these univalent agents could have the best safety profile. Hence, as the trialists suggest, additional studies are needed to assess whether (and which) direct thrombin inhibitors offer improved efficacy with less bleeding. Ik-Kyung Jang Cardiology Division, Bulfinch 105, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA (e-mail: [email protected]) 1
2
3
4
Direct thrombin inhibitor trialists’ collaborative group. Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients’ data. Lancet 2002; 359: 294–302. Kaplinsky E. Direct antithrombin-argatroban in acute myocardial infarction (ARGAMI-2). J Am Coll Cardiol 1998; 32: 1–7. Thrombin inhibition in myocardial ischaemia (TRIM) study group. A low molecular weight, selective thrombin inhibitor, inogatran, vs heparin, in unstable coronary artery disease in 1209 patients: a doubleblind, randomized, dose-finding study. Eur Heart J 1997; 18: 1416–25. Klootwijk P, Lenderink T, Meij S, et al. Anticoagulant properties, clinical efficacy and safety of efegatran, a direct thrombin inhibitor, in patients with unstable angina. Eur Heart J 1999; 20: 1101–11.
Authors’ reply Sir—Our results clearly show that direct thrombin inhibitors are better than unfractionated heparin for the prevention of death or myocardial infarction in patients with acute coronary syndromes and undergoing percutaneous coronary intervention. This conclusion is based on the pooled results from all major randomised trials that met our prespecified
492
inclusion criteria, including data from the as yet unpublished ARGAMI-2 study. Subgroup analyses by agent (which were also prespecified) confirmed that hirudin and bivalirudin were better than unfractionated heparin, but showed no benefit of univalent direct thrombin inhibitors. Rather, there was an excess of death or myocardial infarction at the end of treatment that was also seen in the ARGAMI-2 study of argatroban, Klootwijk and colleagues’ study of efegatran, and the thombin inhibition in myocardial ischaemia study of inogatran, and was evident at each time point (end of treatment, day 7, and day 30) in our pooled analysis. Post-hoc exclusion of patients in the ARGAMI-2 study who may have received a suboptimum dose of argatroban does not materially affect the findings or conclusions of our meta-analysis. We conclude that there is currently no evidence that univalent direct thrombin inhibitors are better than heparin in patients with acute coronary syndromes. Whether the absence of treatment benefit with univalent thrombin inhibitors compared with heparin seen in these studies is real (perhaps due to a relative lack of efficacy of these agents or suboptimum dosing) or simply due to a lack of statistical power is unclear. John Eikelboom, *Salim Yusuf McMaster Clinic, Hamilton General Hospital, Hamilton, ON L8L 2X, Canada (e-mail: [email protected])
Ibuprofen prophylaxis in preterm neonates Sir—V Gournay and colleagues’ finding (April 27, p 1486)1 that ibuprofen prophylaxis was associated with severe hypoxaemia and pulmonary hypertension in three very preterm neonates prompted us to do ancillary analyses of our data from the Trial of Indomethacin Prophylaxis in Preterms.2 Like ibuprofen, indomethacin is a cyclo-oxygenase inhibitor and is effective for closure of patent ductus arteriosus in preterm infants.3 These two agents can potentially increase fetal and neonatal pulmonary vascular resistance through vasoconstriction of the duct or direct vasoconstriction of the pulmonary arterioles.4 Alano and co-workers5 showed a significant association between antenatal exposure to ibuprofen and persistent pulmonary hypertension of neonates.5
No strong conclusions could be drawn about the risks of antenatal indomethacin because few infants in this study had been exposed to this particular non-steroidal anti-inflammatory drug. In our trial, we randomly assigned 1202 extremely-low-birthweight neonates, within 6 h of birth, indomethacin or placebo once daily for 3 days.2 We have reviewed all adverse events reported to the coordinating centre on days 1–4 of life. 165 adverse events were documented. Hypoxaemia was noted in only two neonates, and was described as continuous hypoxaemia and persistent pulmonary hypertension, respectively; they had received placebo. The proportion of neonates who required at least 70% supplemental oxygen on each of the first 4 days did not differ significantly between the two treatment groups. Daily records of the respiratory status did, however, suggest that prophylactic indomethacin adversely affected gas exchange in week 1 of life. We are doing further analyses to find out whether these negative drug effects can explain why indomethacin prophylaxis does not reduce the risk of bronchopulmonary dysplasia, despite reduction of the frequency of patent ductus arteriosus.2 *Barbara Schmidt, Linda L Wright, Peter Davis, Alfonso Solimano, Robin S Roberts, for the Trial of Indomethacin Prophylaxis in Preterms Investigators *Departments of Pediatrics and Clinical Epidemiology, McMaster University, Hamilton, ON L8N 3Z5, Canada; Neonatal Research Network, National Institute of Child Health and Human Development, Bethesda, MD, USA; Royal Women’s Hospital, Melbourne, Australia; Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada (e-mail: [email protected])
1
2
3
4
5
Gournay V, Savagner C, Thiriez G, Kuster A, Roze J-C. Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants. Lancet 2002: 359: 1486–88. Schmidt B, Davis P, Moddemann D, et al, for the Trial of Indomethacin Prophylaxis in Preterms Investigators. Long-term effects of indomethacin prophylaxis in extremelylow-birth-weight infants. N Engl J Med 2001: 344: 1966–72. Van Overmeire B, Smets K, Lecoutere D, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med 2000; 343: 674–81. Turner GR, Levin DL. Prostaglandin synthesis inhibition in persistent pulmonary hypertension of the newborn. Clin Perinatol 1984: 11: 581–89. Alano MA, Ngougmna E, Ostrea EM, Konduri GG. Analysis of nonsteroidal antiinflammatory drugs in meconium and its relation to persistent pulmonary hypertension of the newborn. Pediatrics 2001: 107: 519–23.
THE LANCET • Vol 360 • August 10, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
patients in the univalent subgroup. By comparison, for the efegatran study,4 the Kaplan-Meier curves for the same endpoint suggest little or no difference at day 3 between heparin and efegatran. Furthermore, in the antithrombin-argatroban in ARGAMI-2,2 high-dose argatroban (120 g/kg bolus and 4 g kg⫺1 min⫺1 infusion) compared with heparin showed a slight decrease in ischaemic events (death, stroke, recurrent myocardial infarction, cardiogenic shock or severe congestive heart failure, or revascularisation because of ischaemia) at day 3. In the Direct Thrombin Inhibitor Trialists’ meta-analysis, hirudin was associated with excess bleeding compared with heparin, whereas bivalirudin and univalent inhibitors were associated with reduced bleeding. The absence of intracranial haemorrhage for argatroban (even in conjunction with thrombolytic therapy), efegatran, or inogatran could indicate suboptimum doses. Alternatively, this finding suggests that these univalent agents could have the best safety profile. Hence, as the trialists suggest, additional studies are needed to assess whether (and which) direct thrombin inhibitors offer improved efficacy with less bleeding. Ik-Kyung Jang Cardiology Division, Bulfinch 105, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA (e-mail: [email protected]) 1
2
3
4
Direct thrombin inhibitor trialists’ collaborative group. Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients’ data. Lancet 2002; 359: 294–302. Kaplinsky E. Direct antithrombin-argatroban in acute myocardial infarction (ARGAMI-2). J Am Coll Cardiol 1998; 32: 1–7. Thrombin inhibition in myocardial ischaemia (TRIM) study group. A low molecular weight, selective thrombin inhibitor, inogatran, vs heparin, in unstable coronary artery disease in 1209 patients: a doubleblind, randomized, dose-finding study. Eur Heart J 1997; 18: 1416–25. Klootwijk P, Lenderink T, Meij S, et al. Anticoagulant properties, clinical efficacy and safety of efegatran, a direct thrombin inhibitor, in patients with unstable angina. Eur Heart J 1999; 20: 1101–11.
Authors’ reply Sir—Our results clearly show that direct thrombin inhibitors are better than unfractionated heparin for the prevention of death or myocardial infarction in patients with acute coronary syndromes and undergoing percutaneous coronary intervention. This conclusion is based on the pooled results from all major randomised trials that met our prespecified
492
inclusion criteria, including data from the as yet unpublished ARGAMI-2 study. Subgroup analyses by agent (which were also prespecified) confirmed that hirudin and bivalirudin were better than unfractionated heparin, but showed no benefit of univalent direct thrombin inhibitors. Rather, there was an excess of death or myocardial infarction at the end of treatment that was also seen in the ARGAMI-2 study of argatroban, Klootwijk and colleagues’ study of efegatran, and the thombin inhibition in myocardial ischaemia study of inogatran, and was evident at each time point (end of treatment, day 7, and day 30) in our pooled analysis. Post-hoc exclusion of patients in the ARGAMI-2 study who may have received a suboptimum dose of argatroban does not materially affect the findings or conclusions of our meta-analysis. We conclude that there is currently no evidence that univalent direct thrombin inhibitors are better than heparin in patients with acute coronary syndromes. Whether the absence of treatment benefit with univalent thrombin inhibitors compared with heparin seen in these studies is real (perhaps due to a relative lack of efficacy of these agents or suboptimum dosing) or simply due to a lack of statistical power is unclear. John Eikelboom, *Salim Yusuf McMaster Clinic, Hamilton General Hospital, Hamilton, ON L8L 2X, Canada (e-mail: [email protected])
Ibuprofen prophylaxis in preterm neonates Sir—V Gournay and colleagues’ finding (April 27, p 1486)1 that ibuprofen prophylaxis was associated with severe hypoxaemia and pulmonary hypertension in three very preterm neonates prompted us to do ancillary analyses of our data from the Trial of Indomethacin Prophylaxis in Preterms.2 Like ibuprofen, indomethacin is a cyclo-oxygenase inhibitor and is effective for closure of patent ductus arteriosus in preterm infants.3 These two agents can potentially increase fetal and neonatal pulmonary vascular resistance through vasoconstriction of the duct or direct vasoconstriction of the pulmonary arterioles.4 Alano and co-workers5 showed a significant association between antenatal exposure to ibuprofen and persistent pulmonary hypertension of neonates.5
No strong conclusions could be drawn about the risks of antenatal indomethacin because few infants in this study had been exposed to this particular non-steroidal anti-inflammatory drug. In our trial, we randomly assigned 1202 extremely-low-birthweight neonates, within 6 h of birth, indomethacin or placebo once daily for 3 days.2 We have reviewed all adverse events reported to the coordinating centre on days 1–4 of life. 165 adverse events were documented. Hypoxaemia was noted in only two neonates, and was described as continuous hypoxaemia and persistent pulmonary hypertension, respectively; they had received placebo. The proportion of neonates who required at least 70% supplemental oxygen on each of the first 4 days did not differ significantly between the two treatment groups. Daily records of the respiratory status did, however, suggest that prophylactic indomethacin adversely affected gas exchange in week 1 of life. We are doing further analyses to find out whether these negative drug effects can explain why indomethacin prophylaxis does not reduce the risk of bronchopulmonary dysplasia, despite reduction of the frequency of patent ductus arteriosus.2 *Barbara Schmidt, Linda L Wright, Peter Davis, Alfonso Solimano, Robin S Roberts, for the Trial of Indomethacin Prophylaxis in Preterms Investigators *Departments of Pediatrics and Clinical Epidemiology, McMaster University, Hamilton, ON L8N 3Z5, Canada; Neonatal Research Network, National Institute of Child Health and Human Development, Bethesda, MD, USA; Royal Women’s Hospital, Melbourne, Australia; Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada (e-mail: [email protected])
1
2
3
4
5
Gournay V, Savagner C, Thiriez G, Kuster A, Roze J-C. Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants. Lancet 2002: 359: 1486–88. Schmidt B, Davis P, Moddemann D, et al, for the Trial of Indomethacin Prophylaxis in Preterms Investigators. Long-term effects of indomethacin prophylaxis in extremelylow-birth-weight infants. N Engl J Med 2001: 344: 1966–72. Van Overmeire B, Smets K, Lecoutere D, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med 2000; 343: 674–81. Turner GR, Levin DL. Prostaglandin synthesis inhibition in persistent pulmonary hypertension of the newborn. Clin Perinatol 1984: 11: 581–89. Alano MA, Ngougmna E, Ostrea EM, Konduri GG. Analysis of nonsteroidal antiinflammatory drugs in meconium and its relation to persistent pulmonary hypertension of the newborn. Pediatrics 2001: 107: 519–23.
THE LANCET • Vol 360 • August 10, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.