Correspondence
prothrombogenic state (eg, having metastatic cancer).3 We would like the authors1 to comment about patient and procedural characteristics for those with acute stent thrombosis. We declare no competing interests.
*Masaki Miyasaka, Yuukou Wada, Masahiro Kami [email protected] Sendaikousei Hospital, Sendai, Japan (MM); Miyagihokubu Cardiovascular Clinic, Miyagi, Japan (YW); and Tokyo University, Tokyo, Japan (MK) 1
2
3
Shahzad A, Kemp I, Mars C, et al, for the HEAT-PPCI trial investigators. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 2014; 384: 1849–58. Stone GW, Witzenbichler B, Guagliumi G, et al, for the HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218–30. Luscher TF, Steffel J, Eberli FR, et al. Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. Circulation 2007; 115: 1051–58.
Adeel Shahzad and colleagues 1 concluded that heparin, compared with bivalirudin, reduces the incidence of major adverse cardiovascular events (MACEs) in a setting of primary percutaneous coronary intervention without increasing the risk of bleeding complications. However, findings from this study1 do not accord with those from other multicentre randomised trials.2,3 In the study by Shahzad and colleagues,1 the incidence of overall MACE rates in the bivalirudin group was very high compared with other studies, but the rates reported between
the other studies were comparable (table). 4 Shahzad and colleagues 1 stated that the high MACE rates could be because of the recruitment of patients with more severe illness. If their patient population was indeed more ill, the MACE rates in the heparin group should have also been higher; however, the rate in the heparin group was comparable with those in other trials (table).4 Disease severity can be unbalanced in treatment groups, even in randomised trials. Therefore, patients in the bivalirudin group possibly could have been more severely ill than those in the heparin group, as suggested by the higher rates of previous myocardial infarction and percutaneous coronary intervention in the bivalirudin group. Another possibility is that bivalirudin was initially under-dosed and that patients given this low dose were not optimally anticoagulated, as suggested by the higher bailout use of glycoprotein (GP) IIb/IIIa inhibitors and supplemental boluses of bivalirudin4 than used in previous studies.2,3 Finally, the authors1 stated that the decrease in the bleeding rate with bivalirudin in previous trials2–4 was due to the large use of GP IIb/IIIa inhibitors in patients given heparin. However, the absence of benefits with bivalirudin in this trial1 might be because of the increased incidence of bleeding complications in the bivalirudin group, rather than the decreased incidence of bleeding complications in the heparin group (table). Therefore, this unexpected
MACE per 10 000 patient-days
Any bleeding per 10 000 patient-days
Bivalirudin group
Heparin group
Bivalirudin group
Heparin group
HEAT-PPCI1
31·1
20·5
44·5
48·1
BRIGHT2
17·0
19·0
13·6
41·3*
HORIZONS-AMI3
18·1
18·3
19·6
32·0
EUROMAX4
19·8
18·3
26·0
43·8
MACEs were defined as all-cause mortality, cerebrovascular accidents, reinfarction, or target lesion revascularisation. MACE=major adverse cardiovascular event. *Bleeding rate in the heparin plus glycoprotein IIb/IIIa inhibitor groups.
Table: Incidence of MACEs and bleeding complications in trials comparing use of bivalirudin versus heparin in primary percutaneous coronary intervention
www.thelancet.com Vol 385 May 23, 2015
and large frequency of bleeding in the bivalirudin group could have mitigated the benefits of reductions in bleeding incidence noted with bivalirudin in other trials. However, the authors1 have not addressed this issue in their article. I declare no competing interests.
Rahman Shah [email protected] Veterans Affairs Medical Center, Section of Cardiovascular Medicine, University of Tennessee, Memphis, TN 38104, USA 1
2
3
4
5
Shahzad A, Kemp I, Mars C, et al, for the HEAT-PPCI trial investigators. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 2014; 384: 1849–58. Stone GW, Witzenbichler B, Guagliumi G, et al, for the HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218–30. Steg PG, van’t Hof A, Hamm CW, et al, for the EUROMAX Trial Investigators. Bivalirudin started during emergency transport for primary PCI. N Engl J Med 2013; 369: 2207–17. Han Y, Guo J, Zheng Y, et al, for the BRIGHT Investigators. Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial. JAMA 2015; 313: 1336–46. Steyerberg EW, Bossuyt PM, Lee KL. Clinical trials in acute myocardial infarction: should we adjust for baseline characteristics? Am Heart J 2000; 139: 745–51.
Authors’ reply Although the results of trials comparing heparin and bivalirudin are often portrayed as discordant and perplexing, we believe that there are some consistent messages from these and that common ground could be established to determine best practice. We agree with Philippe Steg and colleagues’ suggested mechanism for the increased risk of acute stent thrombosis reported with bivalirudin treatment. In HEAT-PPCI 1 (and in HORIZONS-AMI 2), the bivalirudin infusion was stopped at the end of the procedure, in accordance with the licensed recommendations (at the time of trial initiation). Furthermore, we agree that a continued infusion (also used in the BRIGHT trial3) has the potential to reduce or even abolish 2045
Correspondence
For more on the Diagnostic Cardiac Catheterizations and Percutaneous Coronary Interventions (CathPCI) Registry see https://www.ncdr. com/webncdr/cathpci/
2046
this threat. The optimum dose and duration of any drug infusion is still the subject of debate and further trials might be needed to establish the true safety and efficacy of this approach. Use of bivalirudin after the procedure—and possibly before, as used in EUROMAX4—could possibly increase the drug cost difference in relation to heparin from 350 times to 1500 times, which will have resulting implications for the consideration of a drug and its cost benefit. David J Schneider notes that a treatment can change over time, with new dosing or adjunctive therapy. The desire to pay even more (in drug and nursing costs) in an attempt to establish equivalent rates of ischaemic adverse events to heparin is based on the belief that the use of bivalirudin reduces bleeding. To determine the relative safety of heparin and bivalirudin in studies with differential use of glycoprotein (GP) IIb/IIIa inhibitor drugs is impossible.5 Observational data, such as from EUROMAX4 for patients treated with heparin, are interesting but cannot be regarded as definitive. An association is established between heparin dose and bleeding. A meta-analysis,6 including results from both HEAT-PPCI 1 and EUROMAX, 4 has further supported this concept by showing that heparin doses of more than 70 U/kg were associated with a significantly higher incidence of major bleeding than with bivalirudin (odds ratio 1·08, 95% CI 0·74–1·58), whereas a dose of 70 U/kg or lower was not significantly different (0·44, 0·31–0·61; pinteracton
prothrombogenic state (eg, having metastatic cancer).3 We would like the authors1 to comment about patient and procedural characteristics for those with acute stent thrombosis. We declare no competing interests.
*Masaki Miyasaka, Yuukou Wada, Masahiro Kami [email protected] Sendaikousei Hospital, Sendai, Japan (MM); Miyagihokubu Cardiovascular Clinic, Miyagi, Japan (YW); and Tokyo University, Tokyo, Japan (MK) 1
2
3
Shahzad A, Kemp I, Mars C, et al, for the HEAT-PPCI trial investigators. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 2014; 384: 1849–58. Stone GW, Witzenbichler B, Guagliumi G, et al, for the HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218–30. Luscher TF, Steffel J, Eberli FR, et al. Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. Circulation 2007; 115: 1051–58.
Adeel Shahzad and colleagues 1 concluded that heparin, compared with bivalirudin, reduces the incidence of major adverse cardiovascular events (MACEs) in a setting of primary percutaneous coronary intervention without increasing the risk of bleeding complications. However, findings from this study1 do not accord with those from other multicentre randomised trials.2,3 In the study by Shahzad and colleagues,1 the incidence of overall MACE rates in the bivalirudin group was very high compared with other studies, but the rates reported between
the other studies were comparable (table). 4 Shahzad and colleagues 1 stated that the high MACE rates could be because of the recruitment of patients with more severe illness. If their patient population was indeed more ill, the MACE rates in the heparin group should have also been higher; however, the rate in the heparin group was comparable with those in other trials (table).4 Disease severity can be unbalanced in treatment groups, even in randomised trials. Therefore, patients in the bivalirudin group possibly could have been more severely ill than those in the heparin group, as suggested by the higher rates of previous myocardial infarction and percutaneous coronary intervention in the bivalirudin group. Another possibility is that bivalirudin was initially under-dosed and that patients given this low dose were not optimally anticoagulated, as suggested by the higher bailout use of glycoprotein (GP) IIb/IIIa inhibitors and supplemental boluses of bivalirudin4 than used in previous studies.2,3 Finally, the authors1 stated that the decrease in the bleeding rate with bivalirudin in previous trials2–4 was due to the large use of GP IIb/IIIa inhibitors in patients given heparin. However, the absence of benefits with bivalirudin in this trial1 might be because of the increased incidence of bleeding complications in the bivalirudin group, rather than the decreased incidence of bleeding complications in the heparin group (table). Therefore, this unexpected
MACE per 10 000 patient-days
Any bleeding per 10 000 patient-days
Bivalirudin group
Heparin group
Bivalirudin group
Heparin group
HEAT-PPCI1
31·1
20·5
44·5
48·1
BRIGHT2
17·0
19·0
13·6
41·3*
HORIZONS-AMI3
18·1
18·3
19·6
32·0
EUROMAX4
19·8
18·3
26·0
43·8
MACEs were defined as all-cause mortality, cerebrovascular accidents, reinfarction, or target lesion revascularisation. MACE=major adverse cardiovascular event. *Bleeding rate in the heparin plus glycoprotein IIb/IIIa inhibitor groups.
Table: Incidence of MACEs and bleeding complications in trials comparing use of bivalirudin versus heparin in primary percutaneous coronary intervention
www.thelancet.com Vol 385 May 23, 2015
and large frequency of bleeding in the bivalirudin group could have mitigated the benefits of reductions in bleeding incidence noted with bivalirudin in other trials. However, the authors1 have not addressed this issue in their article. I declare no competing interests.
Rahman Shah [email protected] Veterans Affairs Medical Center, Section of Cardiovascular Medicine, University of Tennessee, Memphis, TN 38104, USA 1
2
3
4
5
Shahzad A, Kemp I, Mars C, et al, for the HEAT-PPCI trial investigators. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 2014; 384: 1849–58. Stone GW, Witzenbichler B, Guagliumi G, et al, for the HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218–30. Steg PG, van’t Hof A, Hamm CW, et al, for the EUROMAX Trial Investigators. Bivalirudin started during emergency transport for primary PCI. N Engl J Med 2013; 369: 2207–17. Han Y, Guo J, Zheng Y, et al, for the BRIGHT Investigators. Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial. JAMA 2015; 313: 1336–46. Steyerberg EW, Bossuyt PM, Lee KL. Clinical trials in acute myocardial infarction: should we adjust for baseline characteristics? Am Heart J 2000; 139: 745–51.
Authors’ reply Although the results of trials comparing heparin and bivalirudin are often portrayed as discordant and perplexing, we believe that there are some consistent messages from these and that common ground could be established to determine best practice. We agree with Philippe Steg and colleagues’ suggested mechanism for the increased risk of acute stent thrombosis reported with bivalirudin treatment. In HEAT-PPCI 1 (and in HORIZONS-AMI 2), the bivalirudin infusion was stopped at the end of the procedure, in accordance with the licensed recommendations (at the time of trial initiation). Furthermore, we agree that a continued infusion (also used in the BRIGHT trial3) has the potential to reduce or even abolish 2045
Correspondence
For more on the Diagnostic Cardiac Catheterizations and Percutaneous Coronary Interventions (CathPCI) Registry see https://www.ncdr. com/webncdr/cathpci/
2046
this threat. The optimum dose and duration of any drug infusion is still the subject of debate and further trials might be needed to establish the true safety and efficacy of this approach. Use of bivalirudin after the procedure—and possibly before, as used in EUROMAX4—could possibly increase the drug cost difference in relation to heparin from 350 times to 1500 times, which will have resulting implications for the consideration of a drug and its cost benefit. David J Schneider notes that a treatment can change over time, with new dosing or adjunctive therapy. The desire to pay even more (in drug and nursing costs) in an attempt to establish equivalent rates of ischaemic adverse events to heparin is based on the belief that the use of bivalirudin reduces bleeding. To determine the relative safety of heparin and bivalirudin in studies with differential use of glycoprotein (GP) IIb/IIIa inhibitor drugs is impossible.5 Observational data, such as from EUROMAX4 for patients treated with heparin, are interesting but cannot be regarded as definitive. An association is established between heparin dose and bleeding. A meta-analysis,6 including results from both HEAT-PPCI 1 and EUROMAX, 4 has further supported this concept by showing that heparin doses of more than 70 U/kg were associated with a significantly higher incidence of major bleeding than with bivalirudin (odds ratio 1·08, 95% CI 0·74–1·58), whereas a dose of 70 U/kg or lower was not significantly different (0·44, 0·31–0·61; pinteracton
