Correspondence
Coronary Angioplasty versus Fibrinolytic Therapy in Acute Myocardial Infarction
N Engl J Med 2003; 349:2167-2169November 27, 2003
- Article
To the Editor:
Trials have shown that thrombolysis, as compared with placebo, reduces mortality even though it is associated with increases in the rates of reinfarction and stroke.1,2 The Danish Multicenter Randomized Study on Fibrinolytic Therapy versus Acute Myocardial Infarction (DANAMI-2) investigators (Aug. 21 issue)3 compared primary angioplasty with thrombolysis and used a combined end point of death, reinfarction, and stroke with the knowledge that the rates of the latter two would be higher after thrombolysis than they would be after angioplasty. Use of this combined outcome biased the results against thrombolysis. Moreover, long-term follow-up data on thrombolysis show that its effect is confined to reducing in-hospital case fatality rates; after discharge, the survival curves for those treated with thrombolysis and those treated with placebo are superimposable.4 This means that nonfatal reinfarction before discharge has no effect on subsequent survival. In addition, the DANAMI-2 trial included only 37 percent of the population with myocardial infarction and ST-segment elevation and specifically excluded patients with a higher intervention-related mortality rate, such as those with diabetes. The enrolled population had a mortality rate of less than 8 percent, which is about half that expected in an average population undergoing thrombolysis.5
It is incorrect to state that primary angioplasty is superior to thrombolysis. The two have an equivalent effect on 30-day mortality.
5 ReferencesKevin S. Channer, M.D.
Royal Hallamshire Hospital, Sheffield S10 2JF, United Kingdom
kevin.channer@sth. nhs. uk 1
ISIS-2 (Second International Study of Infarct Survival) Collaborative Group
Web of Science | Medline2
Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardio (GISSI)
Web of Science | Medline3
Andersen HR ,Nielsen TT ,Rasmussen K , et al. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003;349:733-742
Full Text | Web of Science | Medline4
Franzosi MG ,Santoro E ,De Vita C , et al. Ten-year follow-up of the first megatrial testing thrombolytic therapy in patients with acute myocardial infarction: results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto-1 study. Circulation 1998;98:2659-2665
Web of Science | Medline5
Malacrida R ,Genoni M ,Maggioni AP , et al. A comparison of the early outcome of acute myocardial infarction in women and men. N Engl J Med 1998;338:8-14
Full Text | Web of Science | Medline
To the Editor:
We commend the DANAMI-2 investigators for evaluating reperfusion strategies in patients who had myocardial infarction with ST-segment elevation. Several of their findings deserve comment.
First, the patients represent 37 percent of those screened; those deemed to be at “high risk” during ambulance transport were excluded.1 Second, the antithrombotic regimen, consisting of a 5000-U bolus of unfractionated heparin and a non–weight-adjusted infusion targeting an activated partial-thromboplastin time of 70 to 90 seconds, substantially exceeds both American College of Cardiology–American Heart Association guidelines and regimens used in recent clinical trials.2
Third, whereas patients with standard contraindications to fibrinolysis were excluded, it is noteworthy that those with a previous stroke were included. This point is especially germane since the patients assigned to fibrinolysis had an overall excess of previous stroke (4.0 percent vs. 2.7 percent among the patients assigned to invasive treatment; one-sided P=0.06). This, coupled with the protocol-recommended repeated fibrinolysis for reinfarction or recurrent ischemia in 26 patients within 12 hours after randomization, probably contributed to the high incidence (2.0 percent) of stroke in the fibrinolysis group.
Fourth, since there was no significant difference between the groups in the rate of death and because some strokes were potentially avoidable, the rates of reinfarction are paramount. Had the reinfarctions associated with invasive procedures been included, the difference would have been narrowed.
2 ReferencesPaul W. Armstrong, M.D.
University of Alberta, Edmonton, AB T6G 2H7, Canada
paul.armstrong@ualberta. ca Elliott M. Antman, M.D.
Brigham and Women's Hospital, Boston, MA 021151
Andersen HR ,Nielsen TT ,Vesterlund T , et al. Danish multicenter randomized study on fibrinolytic therapy versus acute coronary angioplasty in acute myocardial infarction: rationale and design of the DANish trial in Acute Myocardial Infarction-2 (DANAMI-2). Am Heart J 2003;146:234-241
CrossRef | Web of Science | Medline2
Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators
CrossRef | Web of Science | Medline
To the Editor:
Andersen et al. report a reduction in cardiac events in patients treated with primary angioplasty as compared with those treated with fibrinolysis after acute myocardial infarction with ST-segment elevation. The better outcome with angioplasty was driven by a reduction in the rate of reinfarction. The authors conclude that primary angioplasty is superior to fibrinolytic therapy. That is one explanation. However, the authors ignore another possible explanation: the patients were not matched according to whether they received antiplatelet therapy after reperfusion therapy. Therefore, not only was the study comparing two different reperfusion strategies, it also looked at two different postreperfusion strategies.
The pathophysiological mechanism for reinfarction is platelet-driven. In the study by Andersen et al., patients assigned to fibrinolytic therapy received aspirin, whereas those assigned to primary angioplasty received aspirin along with a thienopyridine for “one month.” The study period was 30 days. Although it involved a different patient population, the PCI-CURE (Percutaneous Coronary Intervention–Clopidogrel in Unstable Angina to Prevent Recurrent Events) study1 showed the benefit of clopidogrel (plus aspirin), which reduced (by 31 percent) myocardial infarction or death due to cardiovascular events. Could the mechanism for the discrepancy reported by Andersen et al. be a result of thienopyridine treatment, rather than the reperfusion strategy? Investigators conducting comparative studies in the future should take note.
1 ReferencesAzfar G. Zaman, M.D.
Freeman Hospital, Newcastle NE7 7DN, United Kingdom
azfar.zaman@nuth. northy. nhs. uk 1
Mehta SR ,Yusuf S ,Peters RJG , et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527-533
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Zaman asks whether the better outcome in patients treated with primary angioplasty as compared with fibrinolysis may be explained by the difference between the groups in the use of postreperfusion antiplatelet therapy. In accordance with our daily routine, patients treated with angioplasty received a thienopyridine (ticlopidine or clopidogrel) for one month, whereas patients treated with fibrinolysis did not. Although it cannot be ruled out that the thienopyridine may have contributed to the reduction in the rate of reinfarction after primary angioplasty, we do not consider this a likely possibility. In the PRAGUE (Primary Angioplasty in Patients Transferred from General Community Hospitals to Specialized PTCA Units with or without Emergency Thrombolysis) study,1 which also showed the superiority of angioplasty, ticlopidine was given to both reperfusion groups.
We do not agree with Dr. Channer that our combined end point “biased the results against thrombolysis.” Even if the only effect of primary angioplasty is to reduce the increase in the rates of reinfarction and stroke after thrombolysis, such an effect is of benefit to patients. Our combined end point did not include “nonfatal reinfarction,” a widely used but vaguely defined event that we agree probably has only a minor influence on long-term survival. We chose to count “clinical reinfarction” (defined in detail elsewhere2) and to omit recurrent ischemic episodes and reinfarction related to invasive procedures. Even during the short (30-day) follow-up, patients with clinical reinfarction were found to have a risk of death that was four times higher than the risk among patients without reinfarction. In our opinion, 37 percent of the total screened population of patients with myocardial infarction and ST-segment elevation represents a high inclusion fraction for a trial that necessitated the transportation of patients over long distances. The extent to which the results can be generalized cannot be evaluated from this figure. Twenty percent of the screened population refused to participate or had contraindications to fibrinolysis or angioplasty. Severe hemodynamic deterioration prevented ambulance transportation in less than 5 percent of the patients admitted to referral hospitals. We did not exclude patients with diabetes. Because of concerns about kidney failure due to radiographic contrast medium (which later proved to be unfounded), metformin-treated diabetic patients were excluded, as required by the National Ethics Committee.
We appreciate the comments by Drs. Armstrong and Antman and agree that our use of a rather high dose of unfractionated heparin and the imbalance between the angioplasty and fibrinolysis groups in the rates of previous stroke may have influenced the results. We do not, however, consider the incidence of stroke (2.0 percent) in the fibrinolysis group to be substantially different from that in previous trials.
2 ReferencesHenning R. Andersen, M.D.
Torsten T. Nielsen, M.D.
Skejby Hospital, DK-8200 Aarhus N, Denmark
henning.rud. andersen@iekf. au. dk 1
Widimsky P ,Groch L ,Zelizko M ,Aschermann M ,Bednar F ,Suryapranata H . Multicentre randomized trial comparing transport to primary angioplasty vs immediate thrombolysis vs combined strategy for patients with acute myocardial infarction presenting to a community hospital without a catheterization laboratory: the PRAGUE study. Eur Heart J 2000;21:823-831
CrossRef | Web of Science | Medline2
Andersen HR ,Nielsen TT ,Vesterlund T , et al. Danish multicenter randomized study on fibrinolytic therapy versus acute coronary angioplasty in acute myocardial infarction: rationale and design of the DANish trial in Acute Myocardial Infarction-2 (DANAMI-2). Am Heart J 2003;146:234-241
CrossRef | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
Tamer A Elbayoumi, Vladimir P Torchilin. (2008) Liposomes for targeted delivery of antithrombotic drugs. Expert Opinion on Drug Delivery 5:11, 1185-1198
CrossRef2
Marino Labinaz, Terri Swabey, Randal Watson, Madhu Natarajan, Wendy Fucile, Bruce Lubelsky, Bruce Sawadsky, Eric Cohen, Kevin Glasgow. (2006) Delivery of primary percutaneous coronary intervention for the management of acute ST segment elevation myocardial infarction: Summary of the Cardiac Care Network of Ontario Consensus Report. Canadian Journal of Cardiology 22:3, 243-250
CrossRef
