Author + information
- Received December 16, 1996
- Revision received March 5, 1997
- Accepted March 12, 1997
- Published online July 1, 1997.
- Jean-Michel Juliard, MDA,*,
- Dominique Himbert, MDA,
- Jean-Louis Golmard, MD, PhDB,
- Pierre Aubry, MDA,
- Gaetan J. Karrillon, MDA,
- Albert Boccara, MDA,
- Hakim Benamer, MDA and
- P.Gabriel Steg, MD, FACCA
- ↵*Dr. Jean-Michel Juliard, Service de Cardiologie A, Hôpital Bichat, 46 Rue Henri Huchard, 75018, Paris, France.
Objectives. This study sought to assess the maximal rate of acute Thrombolysis in Myocardial Infarction (TIMI) grade 3 patency that can be achieved in unselected patients.
Background. Early and complete (TIMI grade 3 flow) reperfusion is an important therapeutic goal during acute myocardial infarction. However, thrombolysis, although widely used, is often contraindicated or ineffective. The selective use of primary and rescue percutaneous transluminal coronary angioplasty (PTCA) may increase the number of patients receiving reperfusion therapy.
Methods. A cohort of 500 consecutive unselected patients with acute myocardial infarction were prospectively treated using a patency-oriented scheme: Thrombolysis-eligible patients received thrombolysis (n = 257) and underwent 90-min angiography to detect persistent occlusion for treatment with rescue PTCA. Emergency PTCA (n = 193) was attempted in patients with contraindications to thrombolysis, cardiogenic shock or uncertain diagnosis and in a subset of patients admitted under “ideal conditions.” A small group of patients (n = 38) underwent acute angiography without PTCA. Conventional medical therapy was used in 12 patients with contraindications to both thrombolysis and PTCA.
Results. Ninety-eight percent of patients received reperfusion therapy (thrombolysis, PTCA or acute angiography), and angiographically proven early TIMI grade 3 patency was achieved in 78%. Among patients with TIMI grade 3 patency, thrombolysis alone was the strategy used in 37%, emergency PTCA in 40% and rescue PTCA after failed thrombolysis in 15%; spontaneous patency occurred in 8%.
Conclusions. Reperfusion therapy can be provided to nearly every patient (98%) with acute myocardial infarction. Rescue and direct PTCA provided effective early reperfusion to patients in whom thrombolysis failed or was excluded.
(J Am Coll Cardiol 1997;30:157–64)
Early and complete patency of the infarct-related artery is an important therapeutic goal during the early hours of acute myocardial infarction ([1–7]). Intravenous thrombolysis is the most widely used reperfusion method. However, recent data indicate that despite its proven benefit with regard to mortality and morbidity ([8–11]), thrombolysis is still used in only a minority of cases because of absolute or relative contraindication, because diagnosis is uncertain or patients do not fill the electrocardiographic (ECG) criteria or because patients are in cardiogenic shock ([12–14]). In addition, even contemporary regimens of intravenous thrombolysis fail to achieve complete Thrombolysis in Myocardial Infarction (i.e., [TIMI] flow grade 3) patency in 13% to 56% of patients (). In the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) angiographic substudy, TIMI flow grade 3 patency was achieved in only 54% of patients treated with accelerated tissue-type plasminogen activator (t-PA) (). This is an important limitation of thrombolysis, given recent data indicating that only early and complete patency of the infarct-related artery provides full clinical benefit ([1, 3, 4]). The use of percutaneous transluminal coronary angioplasty (PTCA) for patients excluded from thrombolysis ([16, 17]) or with contraindications () might substantially increase the proportion of patients receiving reperfusion therapy. In addition, the use of rescue PTCA as adjunctive treatment in patients with failed thrombolysis would increase the proportion of patients achieving early TIMI flow grade 3 patency of the infarct-related artery. Therefore, a majority of patients either never receive reperfusion therapy or the therapy fails. The aim of the present prospective study was to determine whether reperfusion therapy could be applied to unselected patients with acute myocardial infarction and to determine the maximal rate of acute TIMI grade 3 patency that could be achieved using a patency-oriented management approach (Fig. 1).
1.1 Study Patients and Enrollment Criteria.
From June 1988 to January 1995, 500 consecutive, unselected patients with an acute myocardial infarction admitted to our institution <6 h after symptom onset were treated according to a previously described patency-oriented scheme (): patients with contraindications to thrombolysis (patients at high risk of bleeding), an uncertain diagnosis, cardiogenic shock or ideal conditions for primary PTCA (i.e., immediate availability of the catheterization laboratory during daytime) underwent emergency coronary angiography and, if the infarct-related artery was occluded (TIMI grade 0 or 1 flow), emergency angioplasty. Patients without cardiogenic shock or contraindications to thrombolysis received intravenous thrombolysis, using accepted protocols, and underwent 90-min emergency angiography to ascertain the patency of the infarct-related artery. Age alone was never a contraindication to thrombolysis. If flow in the artery was TIMI grade 2 or 3, they were treated medically. If flow was TIMI grade 0 or 1, they underwent rescue PTCA, provided that the operator considered the infarct-related artery suitable for PTCA. A subset of patients underwent acute coronary angiography because of a strong suspicion of spontaneous reperfusion and were treated medically when the latter was confirmed. Conventional medical therapy was applied to patients with poor physiologic status and contraindications to both thrombolysis and vascular access.
The diagnosis of acute myocardial infarction was based on conventional criteria: chest pain lasting >30 min and resistant to nitrates, with typical ECG changes (≥1-mV ST segment elevation in two or more limb leads or ≥2-mV ST segment elevation in two or more contiguous precordial leads on a 12-lead ECG). A small subset of patients had a typical chest pain but atypical ECG changes: minor ST segment elevation, giant T waves, left bundle branch block or accessory pathways. The diagnosis of myocardial infarction was eventually confirmed in every case by creatine kinase elevation (more than twice normal levels). Angiographic patencywas defined as TIMI grade ≥2 flow in the infarct-related vessel (). Multivessel diseasewas defined as the presence of ≥50% lumen diameter stenosis in at least two major epicardial arteries.
Medical treatment was as follows: All patients received 250 mg of intravenous aspirin acutely, followed by at least 250 mg daily until discharge. All patients undergoing emergency angioplasty received 15,000 IU heparin intravenously at the beginning of the procedure; the other patients received a 5,000-IU bolus. Subsequently, all patients received intravenous heparin for at least 48 h (starting at 1,000 IU/h), adjusted to an activated partial thromboplastin time two to three times control levels. Heparin was resumed immediately after catheterization, except for those patients who had received a non–fibrin-specific thrombolytic agent and in whom it was resumed 6 to 8 h later. All patients received beta-adrenergic blocking agents, first intravenously then orally, unless contraindicated. Before hospital discharge, patients underwent repeat coronary angiography. Elective coronary artery bypass surgery during the hospital stay was performed when severe triple-vessel disease or left main coronary artery disease was present.
1.2 Statistical Analysis.
We first performed a bivariate analysis using chi-square and Student ttests to determine the prognostic factors of in-hospital mortality. Second, multivariate analysis was performed using linear logistic regression. Variables used at this stage were those significantly linked to mortality in the bivariate analysis (p < 0.05 was considered significant). The final model was obtained using the best subsets method (), and the goodness of fit of the final model was assessed using the Hosmer-Lemeshow method () (the samples are ranked according to their calculated risk; they are divided in 10 equally sized classes; and, finally, the distribution of observed and expected number of deaths are compared using the chi-square test).
2.1 Patient Characteristics.
Baseline characteristics are given in Table 1(mean [±SD] age 59 ± 13 years; range 27 to 91; 25th, 75th percentiles 49, 68; 81.4% men). The average delay between pain and admission to the coronary care unit was 184 ± 89 min. Fifty-three percent of patients had single-vessel disease on coronary angiography. Sixty percent of patients were admitted at night or during weekends.
2.2 Intravenous Thrombolysis.
Intravenous thrombolysis was used as reperfusion therapy in 257 patients (51% of the total cohort). Standard regimens of the following agents were used: recombinant tissue-type plasminogen activator (rt-PA) (n = 140), streptokinase (n = 75), rt-PA+urokinase (n = 20), anisoylated plasmin–streptokinase activated complex (APSAC) (n = 15) and rt-PA+streptokinase (n = 7). Twenty patients were included in the Urokinase and Alteplase in Myocardial Infarction (URALMI) study (), and 23 were enrolled in the GUSTO angiographic substudy (). One hundred eighteen patients (46%) received prehospital thrombolysis in a mobile care unit. The overall time from symptom onset to thrombolysis was 173 ± 73 min; in patients receiving prehospital thrombolysis this interval was 148 ± 68 min, with admission (drug to door time) on average 57 ± 17 min later. Time to thrombolysis was 193 ± 75 min in patients receiving in-hospital thrombolysis, with a door to drug time of 25 ± 5 min. Ninety-minute angiography was performed in 244 (95%) of 257 patients receiving thrombolytic therapy. Angiographically proven patency of the infarct-related artery was TIMI grade 3 in 148 patients (57% of the 257 patients initially treated with thrombolysis and 61% of the 244 undergoing angiography), TIMI grade 2 in 21 and TIMI grade 0 or 1 in 75. Among the 75 patients with a persistently occluded infarct-related artery, rescue angioplasty was attempted in 59 and was successful (TIMI grade 3 flow and <50% residual stenosis) in 55 (93%). The time delay between admission and successful rescue PTCA was 135 ± 74 min, 31 ± 35 min after angiography and 291 ± 102 min after symptom onset. Intracoronary stents were required in three patients because of a large dissection. Angiographically proven early TIMI grade 3 patency was thus achieved in at least 203 patients (79% of those receiving intravenous thrombolysis).
2.3 Emergency PTCA.
Emergency angioplasty was performed in 193 patients (39% of the cohort). The indication for emergency angioplasty was a contraindication to thrombolysis in 103 (Table 2), cardiogenic shock (combination of systolic blood pressure <80 mm Hg despite adequate volume expansion and signs of acute cardiocirculatory failure) in 20 and uncertain diagnosis in 26. In the 26 patients, diagnostic uncertainty was related to the presence of giant T waves in 16 patients, minor ST elevation <1 mV in 7, left bundle branch block in 1 and accessory pathways in 2. Another 44 patients without contraindications to thrombolysis were admitted under “ideal conditions” for emergency PTCA. Adjunctive intraaortic balloon pumping was used in 15 patients with cardiogenic shock. An intracoronary stent was required in one patient because of a large dissection. The success rate was similar regardless of the indication for primary PTCA: 91% in patients undergoing PTCA for contraindications, 90% in those with cardiogenic shock, 88% in those with an uncertain diagnosis and 93% in those treated with emergency PTCA under “ideal conditions.” Overall, angiographically proven TIMI grade 2 or 3 patency was achieved in 176 patients (91% of the patients who underwent direct PTCA) and was TIMI grade 3 flow in 158 (82%). The average time between admission and TIMI grade 3 patency was 45 ± 12 min.
2.4 Acute Angiography without PTCA.
Angiography demonstrated spontaneous reperfusion of the infarct-related artery in 31 patients (TIMI grade 3 flow in 30 and TIMI grade 2 flow in 1) or small size of the occluded infarct-related artery (deemed unworthy of mechanical desobstruction) in 7.
2.5 Conventional Medical Therapy.
Conventional medical treatment without reperfusion therapy was applied to 12 elderly patients (81 ± 9 years old) with very poor physiologic status because of contraindications to both thrombolysis and vascular access.
Reperfusion therapy (intravenous thrombolysis, primary PTCA or acute angiography) was attempted in 488 (98%) of 500 patients and provided angiographically proven acute TIMI grade 3 patency in 391 (78%); overall, 431 (86%) of 500 patients achieved angiographically proven acute TIMI grade 2 or 3 patency (Table 3, Fig. 2). In addition to the 148 patients in whom intravenous thrombolytic therapy resulted in TIMI grade 3 patency, rescue PTCA after failed thrombolysis provided patency in 55 and emergency PTCA in an additional 158. Angiography demonstrated spontaneous reperfusion (TIMI grade 3 flow) in 30 patients. Of the 129 patients who were not eligible for thrombolysis (103 for contraindications and 26 for an uncertain diagnosis), early TIMI grade 3 patency was achieved by emergency PTCA in 109. Among patients with TIMI grade 3 patency, thrombolysis alone was the strategy used in 37%, whereas 55% achieved TIMI grade 3 patency by either emergency PTCA (40%) or rescue PTCA after failed thrombolysis (15%); 8% achieved spontaneous TIMI grade 3 patency (Fig. 3).
The in-hospital mortality rate was 9.4% (47 patients): 10 (3.9%) of 257 patients treated by intravenous thrombolysis, including 2 (3.4%) of 59 treated with rescue PTCA; 31 (16%) of 193 treated by direct PTCA; none of 37 with spontaneous reperfusion; 2 (28%) with a small infarct-related artery unsuitable for PTCA; and 4 (33%) of 12 treated by conventional medical therapy. The mortality rate was 6.6% (26 of 391) among patients with angiographically proven TIMI grade 3 flow, 17.5% (7 of 40) for TIMI grade 2 patency and 18.8% (13 of 69) for TIMI grade 0 or 1 patency or unknown status of the infarct-related artery. When patients in cardiogenic shock were excluded, the mortality rate was 6% overall and 7.25% in the emergency PTCA group.
2.8 Prognostic Factors of In-Hospital Mortality.
Using bivariate analysis, the following factors were significantly correlated with in-hospital mortality: age (p < 0.0001), female gender (p < 0.004), hypertension (p < 0.02), lack of family history of coronary artery disease (p < 0.04), lack of smoking history (p < 0.001), previous myocardial infarction (p < 0.04), multivessel disease (p < 0.001), anterior location (p < 0.02), cardiogenic shock (p < 0.001) and failed acute TIMI grade 3 patency (p < 0.001). These variables were included in the multivariate analysis, performed using linear logistic regression. Model selection was performed with the best subsets method, the results of which are displayed in Table 4. The best model with one variable is obtained with cardiogenic shock, and the best model with two variables includes cardiogenic shock and age. Because these models are embedded, they can be compared using the log-likelihood ratio test, and the two-variable model is significantly better. When three variables are included, there is no significant improvement over the two-variable model. The variables used in this model are displayed in Table 4. The fit obtained by this model is very good, as shown by the method of Hosmer and Lemeshow (): This method gives a statistic test value of 1.9597, corresponding to a chi-square variable of 8 degrees of freedom (p < 0.98) (Fig. 4).
2.9 Bleeding Complications.
Major hemorrhagic complications occurred in 37 patients (7.4%), requiring blood transfusions in 27 (5%). Four fatal cerebral hemorrhages occurred after thrombolysis, despite no patient having obvious contraindication to thrombolysis before initiation of therapy. Of the 33 remaining patients, 2 had a retroperitoneal hematoma, 17 had peri–access site bleeding (requiring surgical repair in 3), and 4 had gastrointestinal hemorrhage. Finally, 10 patients had a fall in hemoglobin >5 mg/dl, requiring transfusion, but without overt bleeding.
Repeat angiography was performed in 378 of 500 patients just before discharge. Of the 391 patients with proven early TIMI grade 3 patency, reocclusion was detected in 27 (7%) (symptomatic in 11 and silent in 16), and TIMI flow fell to grade 2 in one patient; therefore 298 patients had persistent TIMI grade 3 flow (65 patients had no angiography at discharge) (Fig. 5). In 40 patients with TIMI grade 2 flow, repeat angiography showed an improvement to TIMI grade 3 patency in 18, no change in 2 and occlusion (TIMI grade 0 or 1 flow) in 5 (15 had no repeat angiography). Finally, in 41 patients with TIMI grade 0 or 1 flow in the infarct-related artery initially, TIMI grade 3 patency was seen in 9, TIMI grade 2 patency in 2 and persistent occlusion in 8 (22 had no repeat angiography). Of the 28 patients with no angiography during the acute phase, 10 underwent predischarge angiography, which demonstrated TIMI grade 3 flow in all 10. Therefore, 335 (67%) of 500 patients had angiographically proven TIMI grade 3 patency at discharge.
Data from several countries indicate that only a minority of patients with acute myocardial infarction are eligible for thrombolysis ([13, 14, 16, 17, 24, 25]). Recently, classical restrictions to the use of thrombolytic therapy have been challenged ([26–30]) in an attempt to strictly limit contraindications, widen the time interval for inclusion ([31, 32]) and to ensure that no eligible patient is unduly excluded. However, recent data from the large National Registry of Myocardial Infarction (NRMI) () still indicate that only a minority of patients (31%) receive thrombolysis. In addition, even marginal widening of the indications for thrombolysis may markedly increase the risk of hemorrhagic stroke ().
The main finding of this study is that by using a therapeutic strategy that does not rely solely on intravenous thrombolysis to achieve reperfusion, the proportion of patients with an acute myocardial infarction undergoing reperfusion therapy can be substantially increased. Indeed, nearly all the patients from the present cohort underwent reperfusion therapy. A subset of patients in whom early angiography demonstrated “spontaneous” early TIMI grade 3 patency of the infarct-related artery did not require emergency PTCA but were treated medically, without incurring the hemorrhagic risks of unnecessary thrombolysis. In addition, the adjunctive use of rescue angioplasty in case of failed thrombolysis allowed the achievement of an angiographically proven early TIMI grade 3 patency rate of 78% (which was probably underestimated because 25 patients did not undergo emergency angiography).
The overall mortality rate was 9.4%. Although this rate may appear somewhat high, the patients were consecutive and unselected, particularly with respect to contraindications to thrombolysis or age (). Whereas the effectiveness of intravenous thrombolysis is considered to be poor in patients with cardiogenic shock ([8, 9]), improved survival has been reported after primary PTCA ([34, 35]). The high mortality rate (71%) observed in patients with cardiogenic shock, despite the high reperfusion rate and the liberal use of intraaortic balloon pumping, together with data from other studies ([36, 37]), suggest that this approach may not be sufficient for patients with early cardiogenic shock. The apparent high mortality rate among patients treated by emergency angioplasty can be ascribed, at least in part, to the patients admitted with cardiogenic shock, as well as to a tendency to bias elderly patients toward primary PTCA (patients receiving thrombolysis were on average 5 years younger than those treated with primary PTCA for contraindications to thrombolysis or under ideal conditions).
3.3 Noninvasive Detection of Reperfusion.
Simple clinical and ECG data are poor indicators of infarct-related vessel patency (). New noninvasive methods remain to be validated prospectively ([39, 40]) or achieve suboptimal results ([40–42]). Routine emergency angiography had several advantages: It provided early information on coronary anatomy and allowed the identification of patients with spontaneous reperfusion. Furthermore, angiography alone has been reported to improve the patency rate by 5% to 8% ([15, 43]).
3.4 Rescue Angioplasty.
The benefit of rescue angioplasty is controversial ([44, 45]). The Randomized Evaluation of Salvage Angioplasty With Combined Utilization of Endpoints (RESCUE) trial () demonstrated benefit after failed thrombolysis for anterior acute myocardial infarction. Whether this is applicable to patients with inferior infarction or with TIMI grade 2 flow in the infarct-related vessel remains to be determined, although there is abundant evidence that achieving TIMI grade 2 flow is not associated with the same clinical benefit as TIMI grade 3 flow ([2, 4, 47, 48]).
3.5 Study Limitations.
This was a single-center cohort, and there may have been a recruitment bias in favor of patients with mild myocardial infarction or young age. However, 19% of the patients were >70 years old, a proportion similar to that in the NRMI registry (). The rate of stenting during primary or rescue PTCA was low. The results of emergency PTCA may be improved by the routine use of stenting ().
By adding emergency and rescue PTCA to intravenous thrombolysis in the therapeutic armamentarium used during acute myocardial infarction, it is possible to provide reperfusion therapy to nearly all patients with myocardial infarction. In unselected patients, this strategy achieved a high rate of angiographically proven early TIMI grade 3 patency (78%). The number of patients with early patency was more than twice that provided by intravenous thrombolysis alone.
We are indebted to the catheterization team (Joelle Cabanes, Jacqueline Latulipe, Cecile Potier, Francois Dubroca) and to the nurses of the Coronary Care Unit of Hôpital Bichat for their participation in round the clock catheterization effort.
- Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries
- National Registry of Myocardial Infarction
- percutaneous transluminal coronary angioplasty
- recombinant tissue-type plasminogen activator
- Thrombolysis in Myocardial Infarction
- tissue-type plasminogen activator
- Received December 16, 1996.
- Revision received March 5, 1997.
- Accepted March 12, 1997.
- The American College of Cardiology
- for the GUSTO-I Investigators,
- Simes RJ,
- Topol EJ,
- Holmes DR,
- et al.
- Kennedy JW
- Stadius ML
- White HD,
- Cross DB,
- Elliot JM,
- Norris RM,
- Wee TN
- ISIS-3 (Third International Study of Infarct Survival) Collaborative Group).
- for the Participants in the National Registry of Myocardial Infarction,
- Rogers WJ,
- Bowlby LJ,
- Chandra NC,
- et al.
- Topol EJ
- Chesebro JH,
- Knatterud G,
- Roberts R,
- et al.
- Hosmer DW Jr.,
- Lemeshow S
- The Urokinase and Alteplase in Myocardial Infarction Collaborative Group
- for the Gruppo Italiano per lo Studio della Sopravivenza nell’Infarto Miocardico (GISSI-2), the International Study Group,
- Maggioni AP,
- Franzosi MG,
- Santoro E,
- White H,
- Van de Werf F,
- Tognoni G
- Himbert D,
- Steg PG,
- Juliard JM,
- Neukirch F,
- Aumont MC,
- Gourgon R
- Fibrinolytic Therapy Trialists (FTT) Collaborative Group
- Sobel BE
- Lee L,
- Erbel R,
- Brown TM,
- Laufer N,
- Meyer J,
- O’Neill WW
- Gacioch GM,
- Ellis SG,
- Lee L,
- et al.
- Zabel M,
- Hohnloser SH,
- Köster W,
- Prinz M,
- Kasper W,
- Just H
- for the PERM Study Group,
- Laperche Th,
- Steg PG,
- Dehoux M,
- et al.
- for the TAMI 7 Study Group,
- Krucoff MW,
- Croll MA,
- Pope JA,
- et al.
- Dellborg M,
- Steg PG,
- Simoons ML,
- et al.
- for the TAMI Study Group,
- Califf RM,
- Topol EJ,
- Stack RS,
- et al.
- Ellis SG,
- van de Werf F,
- da Silva ER,
- Topol EJ
- for the RESCUE Investigators,
- Ellis SG,
- da Silva ER,
- Heyndricks G,
- et al.
- for the TEAM-3 Investigators,
- Anderson JL,
- Karagounis LA,
- Becker LC,
- Sorensen SG,
- Menlove RL
- Lincoff AM,
- Topol EJ