Author + information
- Received July 12, 2000
- Revision received October 24, 2000
- Accepted December 1, 2000
- Published online March 15, 2001.
- Michel R Le May, MD, FACCa,* (, )
- Marino Labinaz, MD, FACCa,
- Richard F Davies, MD, FACCa,
- Jean-François Marquis, MDa,
- Louise A Laramée, MDa,
- Edward R O’Brien, MD, FACCa,
- William L Williams, MD, FACCa,
- Rob S Beanlands, MDa,
- Graham Nichol, MDa and
- Lyall A Higginson, MD, FACCa
- ↵*Reprint requests and correspondence:
Dr. Michel R. Le May, Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada K1Y 4W7
We sought to directly compare primary stenting with accelerated tissue plasminogen activator (t-PA) in patients presenting with acute ST-elevation myocardial infarction (AMI).
Thrombolysis remains the standard therapy for AMI. However, at some institutions primary angioplasty is favored. Randomized trials have shown that primary angioplasty is equal or superior to thrombolysis, while recent studies demonstrate that stent implantation improves the results of primary angioplasty.
Patients presenting with AMI were randomly assigned to primary stenting (n = 62) or accelerated t-PA (n = 61). The primary end point was the composite of death, reinfarction, stroke or repeat target vessel revascularization (TVR) for ischemia at six months.
The primary end point was significantly reduced in the stent group compared with the accelerated t-PA group, 24.2% versus 55.7% (p < 0.001). The event rates for other outcomes in the stent group versus the t-PA group were as follows: mortality: 4.8% versus 3.3% (p = 1.00); reinfarction: 6.5% versus 16.4% (p = 0.096); stroke: 1.6% versus 4.9% (p = 0.36); recurrent unstable ischemia: 9.7% versus 26.2% (p = 0.03) and repeat TVR for ischemia: 14.5% versus 49.2% (p < 0.001). The median length of the initial hospitalization was four days in the stent group and seven days in the t-PA group (p < 0.001).
Compared with accelerated t-PA, primary stenting reduces death, reinfarction, stroke or repeat TVR for ischemia. In centers where facilities and experienced interventionists are available, primary stenting offers an attractive alternative to thrombolysis.
Thrombolysis improves survival in acute ST-segment elevation myocardial infarction (AMI) (1,2). No other thrombolytic regimen has surpassed the survival benefit associated with accelerated tissue plasminogen activator (t-PA) (3–5). Several studies have found revascularization by primary percutaneous transluminal coronary angioplasty (PTCA) to be equal or superior to revascularization by thrombolysis (6–12). The largest of these compared primary PTCA with accelerated t-PA and found that PTCA reduced the composite of death, reinfarction or stroke at 30 days but failed to do so at six months (8). Primary stenting has clinical benefits beyond those of primary PTCA (13–17)but, as yet, has not been directly compared with thrombolysis. The objective of this study was, therefore, to directly compare primary stenting with accelerated t-PA.
The study was conducted at the University of Ottawa Heart Institute, a tertiary center where >1,200 angioplasties are performed per year. Potentially eligible were patients presenting with AMI defined as: 1) ischemic chest pain of ≥30 min duration within the previous 12 h and 2) ST-segment elevation ≥1 mm (0.1 mV) in ≥2 contiguous electrocardiographic leads or left bundle branch block (LBBB) not known to be old. Patients with any of the following were excluded: cardiogenic shock, active bleeding, history of stroke, major surgery or trauma within three months, systolic blood pressure ≥200 mm Hg or diastolic blood pressure ≥120 mm Hg, cardiopulmonary resuscitation >10 min, inadequate vascular access, PTCA within the preceding six months, previous stenting of the presumed infarct-related artery (IRA), previous coronary bypass surgery (CABG), international normalized ratio >2.0, platelet count <100,000/mm3, hematocrit <30%, creatinine >300 μmol/l, intolerance to aspirin, other medical condition likely to result in death within 12 months, participation in another study within the past four weeks, pregnancy or inability to provide informed consent. The protocol was approved by a duly constituted Institutional Review Board.
Each patient immediately received 160 mg of chewable aspirin. After informed consent was obtained, candidates were randomized to primary stenting or thrombolysis. Patients were randomized in blocks of 10 using sealed opaque envelopes.
Coronary angiography was performed as soon as possible on patients randomized to stenting. Percutaneous transluminal coronary angioplasty alone was performed if the intraluminal diameter of the IRA was <2.5 mm or if technical difficulties could prevent delivery or expansion of a stent. Surgical treatment was recommended if angiography identified: 1) left main stenosis >50% or 2) Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 in the IRA and ≥70% stenosis of all three major epicardial vessels or 3) mechanical complications of AMI, such as papillary muscle or ventricular septal rupture. Medical therapy was recommended if angiography identified diffuse disease not amenable to revascularization or the IRA had TIMI flow grade 3 and the culprit site had a stenosis of <70%. Standard techniques were used to perform PTCA. After predilation, stenting of the IRA was performed using the ACS Multilink stent or the ACS Multilink Rx Duet stent (Guidant, Advanced Cardiovascular Systems, Inc., Temecula, California). The routine use of abciximab was discouraged early in the trial. When new data suggested benefit (18,19), its use was left to the discretion of the operator. It was recommended to stent only the IRA. Heparin was given to maintain an activated clotting time of ≥300 s during the procedure. Afterwards, heparin infusion was not initiated, and the femoral arterial sheath was removed within 6 h. Beginning on the day of the procedure, all patients received aspirin (325 mg daily continued indefinitely) and ticlopidine (250 mg twice daily for one month) or clopidogrel (75 mg daily for one month). Warfarin was not used routinely.
After stenting, patients free of significant arrhythmias, heart failure or recurrent ischemia were considered for very early discharge at 48 h with telephone follow-up at one and seven days.
Patients randomized to thrombolysis received accelerated t-PA and heparin as previously reported (3). Acute coronary angiography was recommended in the presence of: 1) unabated chest pain associated with persistent ST-segment elevation ≥2 h after initiation of thrombolysis or 2) deteriorating hemodynamic status. Routine coronary angiography was discouraged, and risk stratification was performed according to published guidelines (20).
Radionuclide ventriculography was performed within 10 days of AMI to determine the left ventricular ejection fraction. Quantitative coronary angiography was performed on the angiograms of patients who had primary stenting. Coronary flow was graded according to the TIMI trial classification (21). All patients had clinical follow-up at six weeks and at six months.
End points and definitions
The primary end point was the six-month composite of death, reinfarction, stroke or repeat target vessel revascularization (TVR) for ischemia. “Reinfarction” was defined as recurrent ischemic chest pain at rest lasting ≥30 min and accompanied by new or recurrent ST-segment elevation ≥0.1 mV in any two contiguous leads, or a new LBBB, or re-elevation of creatine kinase to greater than twice the upper limit of normal. If creatine kinase was measured before it returned to the normal range, a rise of ≥50% above the lowest level from the index AMI or a rise ≥50% above the sample drawn at the onset of new symptoms was considered evidence for reinfarction. Creatine kinase was not used to define reinfarction when chest pain recurred ≤18 h of onset of the index AMI. “Stroke” was defined as a focal neurological deficit, compatible with damage in the territory of a major cerebral artery with signs or symptoms persisting for ≥24 h and was classified as hemorrhagic or nonhemorrhagic according to the results of computerized tomography or magnetic resonance imaging. “Repeat TVR for ischemia” was defined as PTCA or CABG, done for failed thrombolysis, cardiogenic shock, reinfarction, angina at rest or with minimal exertion or ischemia on physiological testing. However, TVR initiated by physician preference only was not counted as an end point. In patients randomized to primary stenting, CABG done as a primary procedure or after failed PTCA constituted an end point. “Cardiogenic shock” was defined as a systolic blood pressure <80 mm Hg not responding to fluid expansion and requiring intravenous inotropic support or intra-aortic balloon counterpulsation. “Recurrent unstable ischemia” was defined as recurrent chest pain at rest associated with new ST-segment or T wave changes, hypotension or pulmonary edema. A drop in hemoglobin of ≥5 gm/dL from the baseline constituted severe bleeding.
Each component event in the primary end point, as well as recurrent unstable ischemia, was adjudicated by a committee consisting of a chairperson and two members who were not investigators. To minimize bias, the research nurse coordinator masked the treatment group before providing relevant physician and nurses’ notes, electrocardiograms and laboratory test results to the adjudication committee. The data safety monitoring committee consisted of external members who reviewed the data at regular intervals.
It was expected that >75% of the patients randomized to the stent group would receive stent implantation. The sample size of 124 patients (62 randomized per group) was based on the assumption that the six month primary end point rate would be 40% in the thrombolytic group and 15% in the stent group, using a two-tailed α of 0.05 and β of 0.20.
Comparison between the two groups was performed on an intention-to-treat basis. Categorical variables were compared by the chi-square method, and continuous variables by the Student ttest. The Kaplan-Meier method was used to assess variables pertaining to time elapsed from entry to events. The analyses were conducted with Systat version 9.
Enrollment began August 1997 and ended June 1999. Of the 218 patients presenting to our hospital who met the inclusion criteria, 123 were randomized—62 to primary stenting and 61 to thrombolysis. The most common reasons for exclusion were: previous CABG (n = 17), patient refusal (n = 16), unavailable catheterization facilities (n = 12), missed enrollment (n = 12), previous stroke (n = 11), bleeding problems (n = 7) and inability to provide consent (n = 5).
Groups were well matched for baseline characteristics (Table 1). All patients assigned to thrombolysis received accelerated t-PA. In patients assigned to primary stenting, 61 (98%) had immediate angiography performed; the remaining patient was given t-PA because of a potential delay in accessing the catheterization laboratory. Stents were successfully deployed in 50 patients (81%), while PTCA alone was performed in two patients. Four patients had primary CABG, but none had emergency surgery after failed PTCA. The remaining five patients were treated with medical therapy. Abciximab was given to 12 patients (19.4%) assigned to the stent group.
For 36 patients treated during regular operating hours, the median interval between randomization and first balloon inflation was 62 min, compared with 94 min for 26 patients treated during off hours (1800 h to 0700 h, weekends and holidays) (p < 0.001).
In patients treated with stents, only one patient had TIMI flow grade 3 before dilation, compared with 46 patients (92%) after stenting (Table 2). A residual diameter stenosis <50% was achieved in all patients. The mean pressure for stent expansion was 14.2 ± 2.3 atm. An average of 1.3 stents was implanted per patient.
Radionuclide ventriculography was obtained in 49 patients in the stent group (79.0%) at 6.3 ± 4.2 days and in 48 patients in the t-PA group (78.6%) at 6.0 ± 3.5 days. Left ventricular ejection fraction at rest in the stent group was 50.5 ± 12.2, compared with 49.5 ± 10.7 in the t-PA group (p = 0.64).
Primary and secondary end points are shown in Table 3. The primary end point occurred less frequently in the stent group, 19.4% versus 47.5% (p < 0.001). All deaths were cardiac: three in the stent group (4.8%) and two in the t-PA group (3.3%) (p = 1.00). Reinfarction occurred in 4.8% of the patients in the stent group and 8.2% in the t-PA group (p = 0.49). One patient in each group experienced a stroke. Repeat TVR for ischemia was performed in 11.3% of the patients in the stent group and 42.6% of the t-PA group (p < 0.001).
Unscheduled coronary angiography was performed in 39 patients (63.9%) in the t-PA group, compared with seven (11.3%) in the stent group (p < 0.001) (Table 4). Seven patients (11.5%) who had angiography for failure of thrombolysis had an occluded IRA and required rescue PTCA.
Cardiogenic shock developed in four patients (6.6%) in each group. Intra-aortic balloon counterpulsation was used in one patient (1.6%) in the stent group and in three patients (4.9%) in the t-PA group. Severe bleeding occurred in four patients in the stent group (6.5%) and in seven (11.5%) in the t-PA group (p = 0.36); blood transfusion was required in three patients (4.9%) in the t-PA group and in four patients (6.5%) in the stent group. Severe bleeding was related to CABG in six patients (4.9%), gastrointestinal bleeding in two (1.6%), catheterization puncture site in two (1.6%) and retroperitoneal bleeding in one (0.8%). There were no intracranial hemorrhages.
The median length of stay was four days (interquartile range: three to seven days) in the stent group and seven days (interquartile range: 5 to 10 days) in the t-PA group (p < 0.001). In the stent group, fifteen patients (24%) were discharged within 48 h of admission and 26 within 72 h (42%); in the t-PA group, none were discharged within 48 h and five (8%) within 72 h.
Discharge to six weeks
None of the patients in the stent group experienced death, reinfarction, stroke or TVR for ischemia between discharge and six weeks. However, events continued to accrue in the t-PA group (Table 3).
Follow-up at six months
The primary end point was reduced in the stent group: 24.2% versus 55.7% (p < 0.001) (Fig. 1). This difference is largely explained by the lower rate of repeat TVR for ischemia in the stent group: 14.5% versus 49.2% (p < 0.001) (Table 3). Among the 50 patients treated with primary stenting, 10.0% required repeat TVR. No other deaths ensued from discharge to follow-up. All strokes were nonhemorrhagic. By six months, recurrent unstable ischemia occurred less frequently in the stent group: 9.7% versus 26.2% (p = 0.019). The composite of death, stroke reinfarction or recurrent unstable ischemia was also lower in the stent group: 16.1% compared with 32.8% in patients assigned to the t-PA group (p = 0.032) (Fig. 2). There were no primary or secondary events in the 26 patients discharged within 72 h after randomization to primary stenting. At discharge, lipid-lowering medications were prescribed less frequently in the stent group (p = 0.02), while nitrates (p = 0.03) and ticlopidine (p < 0.001) were prescribed more frequently. However, at six months after enrollment, there was no difference between the two groups in the cardiac medications prescribed (Table 5).
Compared with thrombolysis, primary stenting was associated with a significant reduction in the combined end point of death, reinfarction, stroke or repeat TVR for ischemia at six months, as well as in recurrent unstable ischemia. The median length of initial hospitalization was also reduced in the stent group, suggesting that the costs associated with primary stenting may be offset by reductions in the need for subsequent care.
Several trials have compared PTCA with thrombolysis for AMI (6–8,10–12,22,23). Percutaneous transluminal coronary angioplasty versus streptokinase improves survival over five years (12)and versus standard t-PA reduces death or reinfarction in-hospital (6)and at two years (11). These benefits may not have been evident if accelerated t-PA had been used instead. The Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO) IIb trial reported that PTCA compared with accelerated t-PA reduces death, reinfarction or stroke at 30 days but not at six months (8). The loss of benefit was attributed to reocclusion after PTCA (8), which occurs in 10% to 15% of patients within six months (24,25).
Stent implantation in the IRA is feasible, safe and a useful adjunct to primary PTCA (13–17,26,27). Stenting leads to a large intraluminal gain. This may produce a more rapid and complete restoration of flow in the IRA, an important determinant of survival (1,3,28).
Five randomized trials have shown that primary stenting provides clinical benefits beyond those of primary PTCA (13–17). In three of these trials, randomization was performed only after the guidewire crossed the occlusion (14,15)or after successful balloon dilation was performed (13). The Stent Primary Angioplasty in Myocardial Infarction (PAMI) study (16)and the STENTing In acute Myocardial infarction (STENTIM) 2 study (17)randomized patients after angiography, thus avoiding a bias toward more favorable lesions. Primary stenting reduced the six-month composite of death, reinfarction, stroke or repeat TVR for ischemia in Stent-PAMI and was associated with a trend towards fewer clinical events in STENTIM-2; angiographic restenosis was lower with primary stenting in both studies. Still, the clinical benefit obtained by stenting may not have been fully appreciated, because 15% of the patients assigned to PTCA in Stent-PAMI and 36% in STENTIM-2 crossed over to stenting. Patients undergoing primary stenting in this study had similar initial angiographic results and subsequent rates of repeat TVR for ischemia as reported in Stent-PAMI and STENTIM-2. Because our study randomized patients in the emergency room before angiography and showed stenting to be feasible in a high percentage of patients, the results may be more directly applicable to clinical decisions regarding the optimal strategy in AMI.
Some believe that primary stenting puts excessive strain on available resources. However, angiograms were performed during initial hospitalization in 63.9% of patients randomized to t-PA and rescue PTCA in 11.5%, rates similar to previous reports (8). Treatment with accelerated t-PA mandates intravenous heparin for ≥48 h after initiating therapy, and subsequent risk stratification after thrombolysis may further extend the length of hospitalization. In our study, 24% of the patients in the stent group were discharged within 48 h of admission and 42% within 72 h. This resulted in a reduced median length of hospitalization in the stent group (6).
Abciximab reduces urgent TVR after primary PTCA (18). Recently, the effect of primary stenting plus abciximab was compared with t-PA in 140 patients (29). Improved myocardial salvage and a better clinical outcome were obtained in the group that received stent with abciximab. The composite of death, reinfarction or stroke at six months was lower in the stent group, 8.5% versus 23.2%. In our study, platelet glycoprotein IIb/IIIa inhibitors were not used routinely, yet the clinical outcomes were similar. The Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications trial (CADILLAC) will determine if abciximab provides additional clinical benefit to primary angioplasty with and without stent implantation.
Because of its small sample size, our study was not powered to address the effect of primary stenting on mortality or reinfarction. Although there was a trend towards less reinfarction in the stent group, repeat TVR for ischemia was predominantly responsible for the reduction in the primary outcome in the stent group. The composite of death, stroke, reinfarction and recurrent unstable ischemia was also lower in the stent group. Our results are, therefore, clinically important.
The promising results on the primary outcome, combined with the demonstrated reductions in recurrent unstable ischemia, repeat TVR for ischemia and length of hospitalization suggest that primary stenting is a very attractive alternative to thrombolysis. Larger randomized trials, and studies evaluating the cost-effectiveness of primary stenting, will define its role in AMI.
The authors are indebted to our research nurses, Donna Orchard and Allyson Feres, for their diligent work, Kathryn Calladine for assistance with QCA and to our catheterization laboratory personnel for their dedication.
☆ Supported by Guidant, Advanced Cardiovascular Systems Inc., Temecula, California.
- acute ST-elevation myocardial infarction
- coronary bypass surgery
- Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes trial
- infarct-related artery
- left bundle branch block
- Primary Angioplasty in Myocardial Infarction trial
- percutaneous transluminal coronary angioplasty
- STENTing In acute Myocardial infarction trial
- tissue plasminogen activator
- Thrombolysis In Myocardial Infarction
- target vessel revascularization
- Received July 12, 2000.
- Revision received October 24, 2000.
- Accepted December 1, 2000.
- American College of Cardiology
- Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) Angioplasty Substudy Investigators
- Garcia E.,
- Elizaga J.,
- Perez-Castellano N.,
- et al.
- Nunn C.M.,
- O’Neill W.W.,
- Rothbaum D.,
- et al.
- Antoniucci D.,
- Santoro G.M.,
- Bolognese L.,
- Valenti R.,
- Trapani M.,
- Fazzini P.F.
- Suryapranata H.,
- van’t Hof A.W.,
- Hoorntje J.C.,
- de Boer M.J.,
- Zijlstra F.
- Maillard L.,
- Hamon M.,
- Khalife K.,
- et al.
- Brener S.J.,
- Barr L.A.,
- Burchenal J.E.,
- et al.
- van den Merkhof L.F.,
- Zijlstra F.,
- Olsson H.,
- et al.
- Gibbons R.J.,
- Holmes D.R.,
- Reeder G.S.,
- Bailey K.R.,
- Hopfenspirger M.R.,
- Gersh B.J.
- Ribeiro E.E.,
- Silva L.A.,
- Carneiro R.,
- et al.
- Brodie B.R.,
- Grines C.L.,
- Ivanhoe R.,
- et al.
- Stone G.W.,
- Brodie B.R.,
- Griffin J.J.,
- et al.