(Circulation. 1998;98:2659-2665.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
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
Presented in part at the 70th Scientific Sessions of the American Heart Association, Orlando, Fla, November 9–12, 1997, and previously published in abstract form (Circulation. 1997;96:I-718).
From the GISSI Coordinating Center (M.G.F., E.S., A.P.M., A.L., F.R., L.S., G.T.), Milano and Ospedale Niguarda Cà Granda (C.D.V.), Milano and Ospedale Cervello (E.G.), Palermo, and Ospedale L. Mandic (F.M.), Merate, and Policlinico San Matteo (L.T.), Pavia, Italy.
Correspondence to Dr Maria Grazia Franzosi, GISSI Coordinating Centre, Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche "Mario Negri," Via Eritrea 62, 20157 Milano, Italy. E-mail franzosi{at}irfmn.mnegri.it
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Abstract |
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Background—We conducted a 10-year follow-up of the 11 712 patients with acute myocardial infarction randomized in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto-1 study, the first large trial assessing thrombolytic therapy.
Methods and Results—Information on survival at 10 years was obtained for the 93% of all randomized patients through the census offices of their towns of residence. The difference in survival produced by streptokinase and sustained up to 1 year was still significant at 10 years (log-rank test, P=0.02), with the absolute benefit of 19 (95% CI 1 to 37) lives saved per 1000 patients treated. The time dependence of the extent of the benefit was confirmed, as the higher mortality rate reductions found in patients treated earlier were still present at 10 years. In the overall population, most of the benefit was obtained before hospital discharge (RR 0.81, 95% CI 0.72 to 0.90), since no difference in survival between thrombolyzed and control patients discharged alive was found at 10 years (RR 0.98, 95% CI 0.90 to 1.06). However, a slight albeit nonsignificant divergence of the survival curves of patients randomized within the first hour was observed [90 (95% CI 34 to 146) lives saved per 1000 at 10 years versus 72 (95% CI 37 to 107) lives saved at hospital discharge].
Conclusions—The benefits of a single intravenous infusion of 1.5 million units of streptokinase in prolonging survival of patients with acute myocardial infarction is sustained up to 10 years, with a still-evident trend in favor of the patients admitted earlier.
Key Words: myocardial infarction • trials • thrombolysis
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Introduction |
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The presentation of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto-1 (GISSI-1) study results in late 1985 and their publication in early 19861 have been widely recognized as the opening of the thrombolytic era.2 This large randomized trial, conducted between February 1984 and June 1985 in 11 712 patients with acute myocardial infarction (MI) to assess the efficacy of streptokinase (SK) with respect to standard therapy, showed a statistically significant 18% relative reduction of overall in-hospital mortality rate in patients treated with SK within 12 hours from the onset of symptoms. The extent of the benefit was time dependent, with relative reductions of in-hospital mortality rates of 47% and 23% in patients treated within 1 and 3 hours from the onset of symptoms, respectively. From the GISSI group came also the first report documenting that the advantage provided by the acute infusion of 1.5 million units of SK was sustained for at least 1 year.3 Thrombolytic trials, with their short- and long-term follow-up, have since become plentiful,4 5 6 7 8 9 10 11 12 with the most comprehensive review provided by the Fibrinolytic Therapy Trialists' (FTT) Collaborative Group.13 The key message of the original GISSI-1 results could not have had a better confirmation, both with respect to the time to treatment and to its implications on the time dependence of survival advantage. To assess the effect of SK on long-term survival after MI, we conducted a 10-year follow-up of the original population of the GISSI-1 study, the largest complete cohort with such an extended follow-up.
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Methods |
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Patient Eligibility
The GISSI-1 protocol has been fully described elsewhere.1 In brief, patients admitted to the 176 participant coronary care units were eligible for randomization if they had typical chest pain accompanied by ST-segment elevation or depression of
1 mm in any limb lead of the ECG
and/or 2 mm in any precordial lead and they were admitted to
a coronary care unit within 12 hours from onset of symptoms. No
age restriction was imposed, and the exclusion criteria were limited to
the presence of clinical contraindications to
thrombolytic treatment. A 24-hour telephone service was
available for central randomization. The baseline characteristics of
the groups randomized to either thrombolytic treatment
(1.5 million units of intravenous SK over 60 minutes) or
standard therapy were equally balanced.1
Follow-Up
The results of the follow-up at 1 year after admission have been
the subject of a specific publication.3 For the
present evaluation, the vital status in September 1996 or beyond
was sought for all randomized patients through the census office of
their towns of residence by means of prepaid return mail questionnaire.
Information on death from any cause at the 10-year follow-up was
available for 10 889 (93%) of the 11 712 patients originally
randomized with complete data. There were no systematic differences in
follow-up between the treatment groups (SK 92.9%; control 93%). The
median follow-up in the remaining 823 patients (SK 410; control 413)
was 15 months for both treatment arms.
Statistical Analysis
Data were analyzed according to the intention-to-treat
principle. For survival analyses, the Kaplan-Meier method was
used and the P value was determined by the log-rank
test.14 The modified Mantel-Haenszel
method13 15 was used to calculate estimates of
the proportional treatment effects; estimates were described as
relative risks with their 95% confidence intervals. All P
values are 2-sided; values of 2P<0.05 were considered
conventionally significant.
To ascertain the existence of heterogeneity of the
effect of thrombolytic treatment among different
subgroups of patients, the Cox regression model including sex, age
(
65 years, 65 to 75 years, >75 years), systolic blood
pressure at entry (90 mm Hg, 90 to 150 mm Hg, >150
mm Hg), Killip class at entry (1, >1), ST-segment depression at
entry, randomized treatment (SK, control), and time from onset of
symptoms (3 hours, 3 to 6 hours, >6 to 12 hours) was used. The
improvement in terms of goodness of fit obtained comparing a model
including only the main effects and a model including also
parameters concerning interaction was measured by means of
the likelihood ratio test, which has an asymptotic
2 distribution. To make some allowance for the
effects of multiple comparisons, values of 2P<0.01 were
considered conventionally significant for this analysis.
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Results |
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Ten-Year Survival in Overall Population and by Time to Treatment
Of the 11 712 originally randomized patients in the GISSI-1 study, 5111 were dead at 10 years, with an estimated cumulative overall survival of nearly 54%. The mean age of the patients at enrollment was 61±11 (SD) years.
Figure 1
shows the cumulative survival
curves for patients allocated to SK and control groups. The difference
in survival produced by the in-hospital SK treatment was still
significant at the 10-year follow-up (log-rank test,
P=0.02). Including the hospital phase, the estimated 10-year
mortality rate was 45.0% in patients allocated to
thrombolytic therapy and 46.9% in patients given
conventional therapy, corresponding to an absolute improvement in
survival of 19 fewer deaths per 1000 patients treated (Table 1). The absolute improvement in
survival observed at hospital discharge (22 fewer deaths per 1000
patients treated) was maintained up to 10 years.
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The strong relation between mortality rate reduction and time from
symptom onset to treatment was confirmed once again at 10 years;
similar trends were noted with respect to those observed at hospital
discharge and 1-year follow-up (Table 1
and Figure 2). For the subgroups randomized within 1
hour and 3 hours, the significant reduction of total mortality rate
produced by SK treatment found at hospital discharge and confirmed at 1
year was still present at 10 years. In the subgroup of patients
treated within 1 hour of symptom onset, survival curves of patients
treated with SK diverged slightly with respect to the control group. At
10 years, the absolute benefit was increased by 18 further lives saved
per 1000 patients treated with respect to hospital discharge (90 versus
72 lives saved per 1000 patients treated). A lack of significant
benefit for the subgroup recruited after 6 hours did not change at 10
years (Table 1).
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Ten-Year Survival in Particular Subgroups of Patients
Long-term survival data are strictly symmetrical with those
observed at hospital discharge. The direction of effect is maintained
in all subgroups with ST elevation, but the size of effect remains
statistically significant only in some subpopulations. At hospital
discharge, the difference in favor of SK reached statistical
significance only in patients 65 years old, with an absolute benefit
of 20 lives saved per 1000 treated patients, which appeared slightly
increased at 10 years (27 lives saved per 1000 treated patients).
Patients older than 65 years did not benefit significantly from SK
either in-hospital or at the 1-year follow-up. No statistically
significant benefits were seen at 10 years in these patients, and, in
patients >75 years old, survival curves cross at approximately 5 years
after the acute MI (Figure 3).
Expectedly, old age is the most important prognostic factor influencing
long-term survival: Women, on average older than men at randomization,
appear to have had a reduction over time of the benefit produced by SK
treatment, since the absolute mortality reduction of 41 lives saved per
1000 treated patients recorded at hospital discharge was reduced to
21 at 10 years (log-rank test, P=0.18) (Table 1). The
absolute mortality rate reduction obtained with SK treatment was
maintained at 10 years in patients with an anterior MI site and in
patients without a previous MI (Table 1). The opposite direction of the
effect of thrombolysis (ie, increased mortality rate)
in patients with ST-segment depression at entry was confirmed
(mortality rates: SK 65.5% vs control subjects 61.1%), whereas the
statistical significance seen at 1 year (log-rank test,
P=0.18) disappeared (Table 1 and Figure 3).
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The multivariate test of interaction did not show
significant heterogeneity concerning the effects of
thrombolytic treatment in men compared with women, in
patients with previous MI compared with patients without previous MI,
in patients with different values of systolic blood pressure or
Killip class at entry, and in different time to treatment strata,
supporting the suggestion that all patients may benefit from
thrombolytic treatment (Table 2). Only for different classes of age and
for patients with ST-segment depression or elevation at entry, the
P values (0.08 and 0.07, respectively) could indicate the
presence of a trend toward some degree of
heterogeneity. Concerning patients with ST-segment
depression or elevation at entry, the lack of significant interaction
is probably attributable to the very small size of this subgroup (only
451 patients).
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Mortality From Hospital Discharge up to 10 Years
To assess whether further clinical benefit from
thrombolytic therapy after hospital discharge could be
achieved, the survival curves of patients discharged alive from the
hospital were plotted for the overall population and for the subgroup
of patients randomized within the first hour, for whom a divergence of
survival curves was suggested. As described in Table 2, in the overall
population, most of the benefit of SK treatment on mortality rate was
obtained before hospital discharge (RR 0.81, 95% CI 0.72 to 0.90). No
additive benefit was observed either from hospital discharge to 1 year
(RR 1.03, CI 95% 0.89 to 1.19) or from hospital discharge to 10 years
(RR 0.98, 95% CI 0.90 to 1.06) in surviving patients. Only the
subgroup of patients treated within the first hour shows a slight
albeit not significant divergence of the survival curves (Table 3 and
Figure 4).
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Discussion |
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Given the relative absence of criteria limiting enrollment, the GISSI-1 experimental population can be assumed to be a reliable epidemiological reference population. Accordingly, a concise reflection on the long-term survival of the population that opened the thrombolytic era appears appropriate for reviewing some of the points that have remained open to debate during the subsequent 10-year period.16 17
First, our results demonstrate that the benefits of a single intravenous infusion of 1.5 million units of SK in prolonging survival of patients with an acute MI is sustained up to 10 years after randomization. The 10-year follow-up of a relatively simple and inexpensive intervention reproduces an astonishing coherence of the original findings. Follow-up reports published so far, including the first one from GISSI-1,3 have consistently supported the maintenance of the short-term benefit, with no evidence either of convergence or divergence of survival curves.18 19 20 So far, longer-term follow-up studies have been confined to 5 years and to smaller trials,10 11 12 18 19 20 with the exception of the International Study of Infarct Survival-2, which followed up for 10 years the nearly 6200 patients originally randomized in the United Kingdom.21 The trial conducted on nearly 500 patients by the Interuniversity Cardiology Institute of the Netherlands showed that the initial survival benefit of intracoronary SK compared with conventional therapy was maintained at 5 years.18 In the APSAC Intervention Mortality Study (AIMS), which compared anistreplase with placebo, the survival benefit observed at 30 days was maintained at 1 year11 and 5 years.20 The ISIS-2 study, which compared SK with placebo, reported similar results at 10 years in a population of >6000 patients.21
Nothing is substantially new, therefore, in the GISSI-1 follow-up at 10 years, with the exception of a bigger number of patients. However, it is worth underlining how impressive the permanence of the short-term advantage over a period in which profound changes have occurred in post-MI interventions. This fact underlines the contrast between the evidence of benefit and the still unsatisfactory coverage of patients with acute MI with thrombolysis.22 23
Also, the impressive trend in favor of the patients treated within the first hour from the onset of symptoms is sustained up to 10 years, supporting the recently reassessed concept of a "first golden hour" in MI.24
The results available for subgroups confirm the expected variability of
the proportion of the benefit but should not be seen as criteria for
treating or not treating with thrombolysis one or the
other patient category. All the caveats that apply to the extrapolation
of these results to routine practice should be even more underlined
once they are obtained outside the well-defined boundaries of a trial
and over a period of time in which highly heterogeneous and
uncontrolled confounding is likely to have occurred. The clear message
of the FTT Collaboration overview,13 which showed
that there is not significant heterogeneity between the
proportional mortality reductions in different subgroups of patients,
must therefore be seen as the standard against which all our subgroup
analyses (Table 1 and Figure 3) should be read. With the
exception of patients with ST-segment depression, in which the lack of
benefit from thrombolytic treatment emphasized from the
FTT Collaboration conclusion is further confirmed by the 10-year
follow-up of the GISSI-1 study, all patients with an MI with ST-segment
elevation up to at least 12 hours from symptom onset will benefit from
thrombolytic therapy.
The stratification by age in the GISSI-1 follow-up produces groups that
are obviously numerically underpowered to provide reliable information.
Indeed, the apparently worrying crossing of the curves only after 5
years of follow-up for patients 75 years old is the
more-than-expected expression of the fact that life expectancy of an
already old (and mainly male) population cannot be specifically
prolonged for patients who have had an MI. The descriptive interest of
the data from Table 1 and Figure 3 should not, therefore, be seen as a
reason for decreasing the indication for a thrombolytic
treatment for populations which, in the framework of both the
short-term overview and the longer ISIS-2 follow-up, are numerically
stable enough to produce reliable therapeutic guidelines.
The consistency of our findings on subgroups with those of the FTT Collaboration is supported by the results of the multivariate test of interaction, which did not show any statistically significant heterogeneity of the effect of SK among different subgroups of patients.
The observation that no additional benefit arises after hospital discharge has been noted at 1-year follow-up of the GISSI-1 study3 and other long-term follow-up studies20 21 and is now confirmed at 10 years. No difference could be found between thrombolyzed and control groups with respect to the outcome of patients discharged alive. This disappointing result is in part surprising. A late (after 1 year) extra benefit could be expected as a result of the salvage of ischemic myocardium produced by thrombolytic treatment. The plausibility and reasons for a lack of an extra late benefit has long been debated.16 17 Better survival rates after hospital discharge in patients successfully treated with thrombolytic therapy could be related to a restoration of an early and sustained coronary patency with infarct size reduction and subsequent attenuation of ventricular dilation, whereas worse survival rates may be related to an excess of rethrombosis and reinfarction. The net result of survival rates could also have a different direction in different categories of patients. In the GISSI-1 study, the early reperfusion in the subgroup treated within the first hour leads to a measurable trend of increased survival at 10 years; the advantage disappears, however, once the events related to the small subgroup (one ninth of the whole population) are merged with the majority of "late comers," for whom the permanence of advantage in the long run is already a great achievement.
Our findings suggesting a correlation between early reperfusion and additional separation of survival rates over time are in agreement with the recent report of the GUSTO-1 (Global Utilization of Streptokinase and TPA for Occluded arteries) Angiographic Investigators, which showed that successful reperfusion and myocardial salvage produce significant mortality benefits that are amplified beyond the initial 30 days.25 The analysis of survival at 2-years of the 1072 patients assigned to the angiographic evaluation at 90 minutes after thrombolytic treatment indicates that patients achieving early complete reperfusion (Thrombolysis In Myocardial Infarction [TIMI]-3 flow) had a 30-day mortality rate significantly lower with respect to those with lesser flow grades, corresponding to an approximate advantage of 3 lives saved per 100 patients. Recalculated curves, beginning with survivors at 30 days, showed a further divergence with an approximate gain of 5 lives per 100 in the TIMI-3 group of patients. These observations further underscore, besides the need to develop more effective reperfusion strategies, the message that a multidimensional strategy decreasing the delay to presentation and treatment is needed if meaningful improvements in survival after MI are to be achieved.26 27 28
The overlapping of in-hospital and 10-year survival curves underlines another key message of a pragmatic trial like GISSI in that the clinical results of a population-based trial are translated directly and lastingly into epidemiological effects.
It is finally worth underlining that the many life-years saved are the product of an experiment in which the cost of the treatment and the financial support for coordination have been very low.29
In conclusion, the 2 major strengths of the results presented above can be seen in the completeness and length of follow-up. Our data show that the benefit of a single intravenous infusion of 1.5 million units of SK in prolonging survival of patients with acute MI is sustained up to 10 years after randomization, with an evident trend in favor of the patients admitted earlier. The impressive advantage of the group treated within the first hour from symptom onset is maintained throughout the 10-year follow-up. Even if no additional benefit arises from hospital discharge to 10 years in the overall population, the slight divergence observed in the survival curves of patients randomized within the first hour and discharged alive supports the hypothesis that early reperfusion correlates with a survival benefit that may increase in the long run.
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Acknowledgments |
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The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto (GISSI) is endorsed by the ANMCO (Associazione Nazionale Medici Cardiologi Ospedalieri) and by the Istituto di Ricerche Farmacologiche "Mario Negri."
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Footnotes |
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1 A complete list of GISSI-1 study committees, collaborators, and participating centers was published in The Lancet (1986;1:397–402).
Received May 12, 1998; revision received August 18, 1998; accepted August 31, 1998.
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References |
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Part 8: Stabilization of the Patient With Acute Coronary Syndromes Circulation, December 13, 2005; 112(24_suppl): IV-89 - IV-110. [Full Text] [PDF]
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C. Carpeggiani, M. Emdin, F. Bonaguidi, P. Landi, C. Michelassi, M. G. Trivella, A. Macerata, and A. L'Abbate Personality traits and heart rate variability predict long-term cardiac mortality after myocardial infarction Eur. Heart J., August 2, 2005; 26(16): 1612 - 1617. [Abstract] [Full Text] [PDF]
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R. T. van Domburg, K. Sonnenschein, R. Nieuwlaat, O. Kamp, C. J. Storm, J. J. Bax, and M. L. Simoons Sustained Benefit 20 Years After Reperfusion Therapy in Acute Myocardial Infarction J. Am. Coll. Cardiol., July 5, 2005; 46(1): 15 - 20. [Abstract] [Full Text] [PDF]
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G. Ndrepepa, A. Kastrati, F.-J. Neumann, C. Schmitt, J. Mehilli, and A. Schomig Five-year outcome of patients with acute myocardial infarction enrolled in a randomised trial assessing the value of abciximab during coronary artery stenting Eur. Heart J., September 2, 2004; 25(18): 1635 - 1640. [Abstract] [Full Text] [PDF]
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V. Menon, R. A. Harrington, J. S. Hochman, C. P. Cannon, S. D. Goodman, R. G. Wilcox, H. J. Schunemann, and E. M. Ohman Thrombolysis and Adjunctive Therapy in Acute Myocardial Infarction: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 549S - 575S. [Abstract] [Full Text] [PDF]
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S. Lee, Y. Otsuji, S. Minagoe, S. Hamasaki, K. Toyonaga, M. Negishi, M. Tsurugida, H. Toda, and C. Tei Noninvasive Evaluation of Coronary Reperfusion by Transthoracic Doppler Echocardiography in Patients With Anterior Acute Myocardial Infarction Before Coronary Intervention Circulation, December 2, 2003; 108(22): 2763 - 2768. [Abstract] [Full Text] [PDF]
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 K. S. Channer, P. W. Armstrong, E. M. Antman, A. G. Zaman, H. R. Andersen, and T. T. Nielsen Coronary Angioplasty versus Fibrinolytic Therapy in Acute Myocardial Infarction N. Engl. J. Med., November 27, 2003; 349(22): 2167 - 2169. [Full Text] [PDF]
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S. Savonitto, P.W. Armstrong, A.M. Lincoff, G. Jia, C.A. Sila, J. Booth, P. Terrosu, C. Cavallini, H.D. White, D. Ardissino, et al. Risk of intracranial haemorrhage with combined fibrinolytic and glycoprotein IIb/IIIa inhibitor therapy in acute myocardial infarction: Dichotomous response as a function of age in the GUSTO V trial Eur. Heart J., October 2, 2003; 24(20): 1807 - 1814. [Abstract] [Full Text] [PDF]
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A A Awad-Elkarim, J P Bagger, C J Albers, J S Skinner, P C Adams, and R J C Hall A prospective study of long term prognosis in young myocardial infarction survivors: the prognostic value of angiography and exercise testing Heart, August 1, 2003; 89(8): 843 - 847. [Abstract] [Full Text] [PDF]
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K. O. Akosah, A. Schaper, C. Cogbill, and P. Schoenfeld Preventing myocardial infarction in the young adult in the first place: how do the national cholesterol education panel iii guidelines perform? J. Am. Coll. Cardiol., May 7, 2003; 41(9): 1475 - 1479. [Abstract] [Full Text] [PDF]
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F. Ribichini and W. Wijns ACUTE MYOCARDIAL INFARCTION: REPERFUSION TREATMENT Heart, September 1, 2002; 88(3): 298 - 305. [Full Text] [PDF]
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F. Mauri, M. G. Franzosi, A. P. Maggioni, E. Santoro, and L. Santoro Clinical value of 12-lead electrocardiography to predict the long-term prognosis of gissi-1 patients J. Am. Coll. Cardiol., May 15, 2002; 39(10): 1594 - 1600. [Abstract] [Full Text] [PDF]
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E.P. McFadden Fibrinolysis and stenting in acute myocardial infarction: newlyweds destined for a 'menage a trois'? Eur. Heart J., July 1, 2001; 22(13): 1067 - 1069. [PDF]
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C Loubeyre, T Lefevre, Y Louvard, P Dumas, J.-F Piechaud, J.-J Lanore, J.-F Angellier, J.-Y Le Tarnec, G Karrillon, A Margenet, et al. Outcome after combined reperfusion therapy for acute myocardial infarction, combining pre-hospital thrombolysis with immediate percutaneous coronary intervention and stent Eur. Heart J., July 1, 2001; 22(13): 1128 - 1135. [Abstract] [PDF]
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K S Channer and P J Pugh Interfering with healing: the benefits of intervention during acute myocardial infarction Heart, June 1, 2001; 85(6): 620 - 622. [Full Text]
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J. S. Hochman, L. A. Sleeper, H. D. White, V. Dzavik, S. C. Wong, V. Menon, J. G. Webb, R. Steingart, M. H. Picard, M. A. Menegus, et al. One-Year Survival Following Early Revascularization for Cardiogenic Shock JAMA, January 10, 2001; 285(2): 190 - 192. [Abstract] [Full Text] [PDF]
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E. J. Topol, E. M. Ohman, P. W. Armstrong, R. Wilcox, A. M. Skene, P. Aylward, J. Simes, A. Dalby, A. Betriu, C. Bode, et al. Survival Outcomes 1 Year After Reperfusion Therapy With Either Alteplase or Reteplase for Acute Myocardial Infarction : Results From the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) III Trial Circulation, October 10, 2000; 102(15): 1761 - 1765. [Abstract] [Full Text] [PDF]
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E. Braunwald, E. M. Antman, J. W. Beasley, R. M. Califf, M. D. Cheitlin, J. S. Hochman, R. H. Jones, D. Kereiakes, J. Kupersmith, T. N. Levin, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-st-segment elevation myocardial infarction: A report of the american college of cardiology/ american heart association task force on practice guidelines (committee on the management of patients with unstable angina) J. Am. Coll. Cardiol., September 1, 2000; 36(3): 970 - 1062. [Full Text] [PDF]
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A. K. Berger, M. J. Radford, Y. Wang, and H. M. Krumholz Thrombolytic therapy in older patients J. Am. Coll. Cardiol., August 1, 2000; 36(2): 366 - 374. [Abstract] [Full Text] [PDF]
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D. R. Thiemann, J. Coresh, S. P. Schulman, G. Gerstenblith, W. J. Oetgen, and N. R. Powe Lack of Benefit for Intravenous Thrombolysis in Patients With Myocardial Infarction Who Are Older Than 75 Years Circulation, May 16, 2000; 101(19): 2239 - 2246. [Abstract] [Full Text] [PDF]
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J. W. Kennedy Thrombolytic therapy in acute myocardial infarction J. Am. Coll. Cardiol., April 1, 2000; 35(5_Suppl_B): 25B - 28B. [PDF]
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E BOERSMA Acute myocardial infarction: bring the treatment to the patient Heart, October 1, 1999; 82(4): 404 - 404. [Full Text] [PDF]
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J. K. French, T. A. Hyde, H. Patel, D. J. Amos, S. C. McLaughlin, B. J. Webber, and H. D. White Survival 12 years after randomization to streptokinase: the influence of thrombolysis in myocardial infarction flow at three to four weeks J. Am. Coll. Cardiol., July 1, 1999; 34(1): 62 - 69. [Abstract] [Full Text] [PDF]
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S. Gottlieb, V. Boyko, D. Harpaz, H. Hod, M. Cohen, L. Mandelzweig, Z. Khoury, S. Stern, S. Behar, and for the Israeli Thrombolytic Survey Group Long-term (three-year) prognosis of patients treated with reperfusion or conservatively after acute myocardial infarction J. Am. Coll. Cardiol., July 1, 1999; 34(1): 70 - 82. [Abstract] [Full Text] [PDF]
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 GISSI-1 Success is Durable at 10 Years! Journal Watch Emergency Medicine, February 1, 1999; 1999(201): 7 - 7. [Full Text]
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R. M. Califf Ten Years of Benefit From a One-Hour Intervention Circulation, December 15, 1998; 98(24): 2649 - 2651. [Full Text] [PDF]
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