(Circulation. 1996;94:1203-1205.)
© 1996 American Heart Association, Inc.
Articles |
La Difference
Long-term Benefit of One Thrombolytic Over Another
the Bugher Foundation for Molecular Biology, Baylor College of Medicine, Houston, Tex.
Correspondence to Robert Roberts, MD, Section of Cardiology, Baylor College of Medicine, 6550 Fannin, MS SM677, Houston TX 77030.
Key Words: Editorials • myocardial infarction • thrombolysis • thrombosis • prognosis
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Introduction |
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Recanalization of coronary arteries, induced by either thrombolytic therapy or angioplasty, has revolutionized the management of acute myocardial infarction. The mean in-hospital death rate for patients who reach the hospital in time and receive thrombolytic therapy is
6% to 7%.1 This is a dramatic reduction compared with the death rate in the 1960s of 30% to 35%. Thrombolytic therapy is easy to administer and is carried out routinely in community hospitals throughout North America and many other parts of the world. In addition to the reduced death rate, there is likely to be a reduced morbidity; however, this is more difficult to prove. Clinical trials to date on thrombolytics have concentrated on mortality, in part because this is the major, if not the sole, end point required by the Food and Drug Administration to approve a new drug. In the original Global Utilization of t-PA and Streptokinase for Occluded Coronary Arteries (GUSTO-I) trial,1 the 41 021 patients who were enrolled received one of four thrombolytic agents. Patients who had ST-segment elevation and presented within 6 hours of onset were enrolled unless there was a contraindication. Enrollment had no age limit and included patients in cardiogenic shock and those with previous bypass surgery; thus, this population was highly representative of the patient population at large presenting with acute myocardial infarction.
The overall objective of GUSTO-I was to compare four thrombolytic regimens: streptokinase followed by subcutaneous heparin, streptokinase followed by intravenous heparin, tissue plasminogen activator (TPA*) 
100 mg given over 60 minutes followed by intravenous heparin, and a combination of intravenous TPA and streptokinase followed by intravenous heparin. All patients received aspirin and atenolol if there were no contraindications. The 30-day mortality rate in that trial was 6.3% for patients who received accelerated TPA, 7.2% for those receiving streptokinase and subcutaneous heparin, 7.4% for those on streptokinase and intravenous heparin, and 7% for those receiving the combination therapy. Thus, the overall benefit of TPA over streptokinase was an absolute 1% reduction in mortality and 14% reduction in relative risk.
The study reported in this issue2 provides the results of a 1-year follow-up on the GUSTO-I patients and shows that the benefit of TPA over that of streptokinase observed at 30 days of a 1% reduction in mortality was sustained (9.1% for TPA versus 10.1% for streptokinase, P<.01). The mortality rates between 30 days and 1 year were virtually identical in the four groups, averaging only 3%. The overall follow-up worldwide was 96%, with a 98% follow-up in the United States and 95% outside the United States. There was no overall follow-up of nonfatal end points except in one subgroup, which showed that the frequency of these end points was similar in the four groups.
There are several obvious observations from this follow-up study that are of interest for both now and the future. First, it is very rewarding to know that patients surviving acute myocardial infarction for 30 days after thrombolytic therapy, whether TPA or streptokinase, can expect a 1-year mortality rate of only 3%. We must keep in mind that this was a relatively unselected group of patients, with 37% having anterior myocardial infarction. This subsequent low 1-year mortality rate should further motivate physicians to enroll more patients into thrombolytic therapy as early as possible. Second, it is comforting to know that despite the fact that this was essentially a worldwide trial involving 15 countries, the follow-up was still 96%. Future trials of thrombolytic therapy with mortality as an end point will most likely remain broad based to obtain large numbers. This trial provides considerable optimism that it is possible to have almost excellent follow-up in a trial despite being performed on three continents. Third, the increased benefit of TPA over streptokinase 1 year later—namely 9.3% versus 10.3%, respectively—further validates the initial benefit of TPA over streptokinase. Despite the objective data indicating an absolute reduction in mortality of 1% at 30 days, which translated into a 14% relative risk reduction, there remained skepticism as to the credibility of a 1% difference in such a large number of patients with other therapies involved.3 4 5 6 7 Documentation that this absolute 1% difference was sustained 1 year later confers credibility to the original proclaimed benefit at 30 days. It does not, of course, address the issue of whether the difference in cost is justified. The authors do state that on the basis of the increased 1-year survival rate associated with TPA, 10 more lives are saved per 1000 patients treated for at least 1 year. Fourth, this study, along with several other follow-up studies after thrombolytic therapy,8 9 10 11 12 13 confirms that the short-term effect obtained from thrombolysis is sustained. The study is unique, as pointed out by the investigators, in that it is the first available long-term results on the efficacy of one thrombolytic versus another when administered concurrently. All the other long-term studies have compared one thrombolytic to a placebo or conventional therapy. Given the 30-day mortality rate of patients treated appropriately with thrombolytics of 6% to 7%, future thrombolytics will most likely show incremental improvements of only 1% or 2%; thus, it is important to know that if such a reduction is achieved at 30 days, we can expect this benefit to be maintained long-term. Last, an additional mortality of only 3% between 30 days and 1 year represents a major challenge to primary angioplasty, considering that there is a 20% to 30% restenosis rate. Whereas one study comparing primary angioplasty with TPA for acute myocardial infarction suggested that angioplasty may be up to the challenge, a large comprehensive systematic study comparing the two forms of therapy with long-term follow-up has yet to be done.14
All the follow-up studies on trials comparing thrombolytic therapy to either a placebo group or, as in the present study, another thrombolytic have consistently observed that the survival curves remain parallel rather than divergent, indicating that with time there is no further impact in the thrombolytic group.15 The GUSTO-I investigators expressed concern that the group that received TPA did not experience increasing benefit over the 1-year follow-up compared with the group that received streptokinase. The investigators looked to a possible difference in baseline risk between the two groups; however, baseline variables appear to be evenly distributed between the two groups. The other concern one might have is related to other medications such as ß-blockers or calcium channel blockers that the patients were taking. The investigators do not have data on that variable, but because other variables have been evenly distributed between the two groups, it is reasonable to assume that this will be also. The added benefit may be reflected in other clinical events such as the number of patients requiring surgery or other procedures. This seems unlikely because the investigators showed in a random subset of patients that these events were the same for both groups. It is almost self-evident that the benefit of thrombolytic therapy is maximal in the initial hours after treatment. Thrombolytic therapy limits the extent of myocardial damage if effective within the first 1 to 6 hours, and salvage of significant myocardium preserves contractile function reflected in the left ventricular ejection fraction. The latter is the single most consistent simple parameter to predict short-term and long-term mortality. There is no obvious reason why ventricular function will improve after 30 days, and subsequent events of recurrent infarction or mortality are likely to be unrelated to the thrombolytic therapy. On the other hand, if clinical events do occur, interaction with an ejection fraction of 35% may have a different outcome than that superimposed on an individual with a much greater ejection fraction (40% to 50%), but this is not relevant because there were no consistent differences in the distribution of ejection fraction between these two groups. The second factor known to affect clinical events, including long-term mortality, is coronary artery patency. In a subset of the GUSTO-I trial of >2000 patients, serial angiography was performed in the acute phase, and TPA was shown to open more vessels than streptokinase (81% verses 56%) at 90 minutes; thus, one may anticipate that at discharge patients receiving TPA would have more open vessels than those who received streptokinase. It is predicted but not proved that an open vessel would offer protection against subsequent clinical events, which could lead to less mortality at the end of 1 year than in the streptokinase group. However, coronary angiography performed in this same subset at 180 minutes showed that the patency in patients receiving TPA was now essentially the same as that in patients receiving streptokinase (76% and 73%, respectively). Similarly, at 24 hours, the patencies were virtually identical. Thus, in the GUSTO-I trial, a difference in vessel patency does not appear to be an indication for further improvement in the TPA group over that in the streptokinase groups. These findings are also relevant to future studies testing the hypothesis that an open vessel at discharge is better than a closed vessel. Studies testing this hypothesis should perhaps recognize that baseline patency for such a trial is best determined at least 24 hours after thrombolytic therapy, and perhaps that percentage of patients who have sustained occlusion should be targeted for enrollment.
In summary, optimism should prevail in view of the findings by Califf et al2 in the follow-up of 41 021 patients after thrombolytic therapy. It is to be commended that therapy today for acute myocardial infarction can reduce the acute mortality to 6% or 7% and that the subsequent mortality over the next year is only 3%. It is also suggested that a further reduction in acute mortality (2% to 4%) would be expected to be sustained. The cardiologist needs to be reminded that despite a 6% to 7% in-hospital mortality rate for acute myocardial infarction in patients receiving thrombolytic therapy, there are still 300 000 to 400 000 patients who die of acute myocardial infarction before reaching the hospital. There is every reason to believe that prehospital thrombolytic therapy would translate into significant salvage. Only after we have conquered prehospital thrombolysis can we reap the full benefit of this therapeutic revolution for the treatment of acute myocardial infarction.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
*AHA uses the acronym TPA because t-PA is a trademarked name.
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References |
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TopIntroductionReferences |
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1. GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329:673-682.
2.
Califf RM, White HD, Van de Werf F, Sadowski Z, Armstrong PW, Vahanian A, Simoons ML, Simes RJ, Lee KL, Topol EJ, for the GUSTO-I Investigators. One-year results from the Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries (GUSTO-I) trial. Circulation. 1996;94:1233-1238.
3.
Lee KL, Califf RM, Simes J, Van de Werf F, Topol EJ, for the GUSTO Investigators. Holding GUSTO up to the light. Ann Intern Med. 1994;120:876-881.
4.
Ridker PM, O'Donnel CJ, Marde VJ, Hennekens CH. A response to `Holding GUSTO up to the light.' Ann Intern Med. 1994;120:882-885.
5.
GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med. 1993;329:1615-1622.
6.
Farkouh ME, Lang JD, Sackett DL. Thrombolytic agents: the science of the art of choosing the better treatment. Ann Intern Med. 1994;120:886-888.
7.
Huth EJ. `In the balance': weighing the evidence. Ann Intern Med. 1994;120:889.
8. Wilcox RG, Von der Lipp G, Olsson CG, Jensen G, Skene AM, Hampton JR. Effects of alteplase in acute myocardial infarction: 6-month results from the ASSET study-Anglo-Scandinavian Study of Early Thrombolysis. Lancet. 1990;335:1175-1178.[Medline] [Order article via Infotrieve]
9. AIMS Trial Study Group. Long-term effects of intravenous anistreplase in acute myocardial infarction. Lancet. 1990;335:427-431.[Medline] [Order article via Infotrieve]
10. Simoons ML, Vos J, Tijssen JG, Vermeer F, Verheugt FW, Krauss XH, Cats VM. Long-term benefit of early thrombolytic therapy in patients wtih acute myocardial infarction: 5-year follow-up of a trial conducted by the Interuniversity Cardiology Institute of the Netherlands. J Am Coll Cardiol. 1989;14:1609-1615.[Abstract]
11. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico. Long-term effects of intravenous thrombolysis in acute myocardial infarction: final report of the GISSI study. Lancet. 1987;2:871-874.[Medline] [Order article via Infotrieve]
12.
Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico. Six-month survival in 20,891 patients with acute myocardial infarction randomised between alteplase and streptokinase with or without heparin: GISSI-2 and International Study Group. Eur Heart J. 1992;13:1692-1697.
13. Baigent C, Collins R, for the ISIS Collaborative Group. ISIS-2: 4-year mortality follow-up of 17,187 patients after fibrinolytic and antiplatelet therapy in suspected acute myocardial infarction. Circulation. 1993;88(suppl I):I-291. Abstract.
14.
Grines CL, Browne KF, Marco J, Rothbaum D, Stone GW, O'Keefe J, Overlie P, Donohue B, Chelliah N, Timmis GC, Vliestra RE, Strzelecki M, Puchrowicz-Ochocki S, O'Neill WW, for the Primary Angioplasty in Myocardial Infarction Study Group. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction: the Primary Angioplasty in Myocardial Infarction Study. N Engl J Med. 1993;328:673-679.
15.
Van de Werf F. Thrombolysis for acute myocardial infarction: why is there no extra benefit after hospital discharge? Circulation. 1995;91:2862-2864.
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