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Original Contribution |

Evaluation of Prolonged Antithrombotic Pretreatment ("Cooling-Off" Strategy) Before Intervention in Patients With Unstable Coronary Syndromes:  A Randomized Controlled Trial FREE

Franz-Josef Neumann, MD; Adnan Kastrati, MD; Gisela Pogatsa-Murray, MD; Julinda Mehilli, MD; Hildegard Bollwein, MD; Hans-Peter Bestehorn, MD; Claus Schmitt, MD; Melchior Seyfarth, MD; Josef Dirschinger, MD; Albert Schömig, MD
[+] Author Affiliations

Author Affiliations: Medizinische Klinik (Drs Neumann, Seyfarth, and Schömig) and Deutsches Herzzentrum (Drs Kastrati, Pogatsa-Murray, Mehilli, Bollwein, Schmitt, Dirschinger, and Schömig), Technische Universität München, Munich, Germany; and Herz-Zentrum Bad Krozingen (Drs Neumann and Bestehorn), Bad Krozingen, Germany.


JAMA. 2003;290(12):1593-1599. doi:10.1001/jama.290.12.1593.
Text Size: A A A
Published online

Context In unstable coronary syndromes, catheter intervention is frequently preceded by antithrombotic treatment to reduce periprocedural risk; however, evidence from clinical trials to support antithrombotic pretreatment is sparse.

Objective To test the hypothesis that prolonged antithrombotic pretreatment improves the outcome of catheter intervention in patients with acute unstable coronary syndromes compared with early intervention.

Design, Setting, and Patients Randomized controlled trial conducted from February 27, 2000, to April 8, 2002, and including patients admitted to 2 German tertiary care centers with symptoms of unstable angina plus either ST-segment depression or elevation of cardiac troponin T levels.

Interventions Patients were randomly allocated to antithrombotic pretreatment for 3 to 5 days or to early intervention after pretreatment for less than 6 hours. In both groups, antithrombotic pretreatment consisted of intravenous unfractionated heparin (60-U/kg bolus followed by infusion adjusted to maintain partial thromboplastin time of 60 to 85 seconds), aspirin (500-mg intravenous bolus followed by 100-mg twice-daily oral dose), oral clopidogrel (600-mg loading dose followed by 75-mg twice-daily dose), and intravenous tirofiban (10-µg/kg bolus followed by continuous infusion of 0.10 µg/kg per min).

Main Outcome Measure Composite 30-day incidence of large nonfatal myocardial infarction or death from any cause.

Results Of the 410 patients enrolled, 207 were allocated to receive prolonged antithrombotic pretreatment and 203 to receive early intervention. Elevated levels of cardiac troponin T were present in 274 patients (67%), while 268 (65%) had ST-segment depression. The antithrombotic pretreatment and the early intervention groups were well matched with respect to major baseline characteristics and definitive treatment (catheter revascularization: 133 [64.3%] vs 143 [70.4%], respectively; coronary artery bypass graft surgery: 16 [7.7%] vs 16 [7.9%]). The primary end point was reached in 11.6% (3 deaths, 21 infarctions) of the group receiving prolonged antithrombotic pretreatment and in 5.9% (no deaths, 12 infarctions) of the group receiving early intervention (relative risk, 1.96 [95% confidence interval, 1.01-3.82]; P = .04). This outcome was attributable to events occurring before catheterization; after catheterization, both groups incurred 11 events each (P = .92).

Conclusion In patients with unstable coronary syndromes, deferral of intervention for prolonged antithrombotic pretreatment does not improve the outcome compared with immediate intervention accompanied by intense antiplatelet treatment.

Figures in this Article

The best treatment option for most patients with unstable coronary syndromes is angiographically guided revascularization, irrespective of the primary success of medical treatment.14 Compared with a conservative strategy that reserves coronary angiography for persisting spontaneous or inducible ischemia, an invasive strategy reduces risk of adverse events including large myocardial infarction (MI),13 severe recurrent angina,4 and death.2 This has been shown for patients with non–ST-segment elevation MI and for those with unstable angina and ST-segment depression.14

The risk associated with percutaneous coronary intervention as well as that of coronary artery bypass graft (CABG) surgery is, however, increased in patients with unstable coronary syndromes.58 To minimize this hazard, some have recommended passivating the plaque activity by means of extended antithrombotic treatment before intervention.9 Several observational studies comparing swift intervention vs antithrombotic pretreatment for unstable coronary syndromes have found a lower rate of complications in patients undergoing percutaneous intervention after more than 48 hours of antithrombotic pretreatment.1012 Pursuing such a "cooling-off" strategy, investigators in the second Fast Revascularization during Instability in Coronary Artery Disease (FRISC II) trial1 incorporated a 4-day medical stabilization period preceding intervention into the FRISC II protocol and speculated that this prolonged treatment period was a prerequisite for the substantial benefit of the invasive strategy. Other trials have demonstrated a reduction in intracoronary thrombus burden by prolonged pretreatment with glycoprotein IIb/IIIa inhibitors.13,14 Nevertheless, evidence in support of prolonged antithrombotic pretreatment is still largely observational, and potent platelet inhibition at the time of intervention only may suffice to optimize the outcome with early revascularization.1517 In the absence of dedicated clinical trials, current guidelines are equivocal as to the optimal timing of intervention in unstable coronary syndromes.12,18

To test the hypothesis that prolonged antithrombotic pretreatment is beneficial before catheter intervention in patients with unstable coronary syndromes, we conducted the Intracoronary Stenting With Antithrombotic Regimen Cooling-Off (ISAR-COOL) trial.

Patients

Our trial included patients with angina pectoris at rest or with minimal exertion, with the last episode occurring 24 hours or less before study entry. Myocardial ischemia had to be verified by horizontal or downsloping ST-segment depression of 0.1 mV or greater and/or cardiac troponin T concentration of 0.03 mg/L or greater (Roche Cardiac reader system, Roche-Boehringer-Mannheim, Mannheim, Germany). We excluded patients with evidence of large myocardial infarction, including ST-segment elevation of at least 1 mV in 2 or more contiguous leads or elevation of the catalytic activity of creatine kinase and its MB isoenzyme to 3 times the upper limit of normal or greater; those with hemodynamic instability; those with contraindications to study medication; or those unable to provide written informed consent for participation. The study was approved by the ethics committee of the medical faculty of the Technische Universität of Munich.

Randomization and Interventions

The trial was conducted at 2 German tertiary care centers. Allocation to early intervention or prolonged antithrombotic pretreatment was made by means of sealed envelopes containing a concealed computer-generated random sequence, which was set in blocks of 50 for each of the participating hospitals. The size of the block was preselected by the statistician and was unknown to the investigators and medical staff caring for the patients. Dedicated medical staff performed randomization and assigned participants to their groups immediately after establishing eligibility and obtaining written informed consent. Eligible patients were randomized to each of the 2 treatment groups in equal proportions and in the order that they qualified. The 2 treatment groups were studied concurrently. Time zero was defined as the time of randomization.

With the early intervention strategy we performed coronary angiography as soon as possible, at least within 6 hours, during which time antithrombotic pretreatment was instituted. With the prolonged antithrombotic pretreatment strategy, we continued pretreatment for at least 3 days, to a maximum of 5 days, after which all patients underwent coronary angiography. Patients assigned to the prolonged antithrombotic pretreatment strategy could undergo immediate intervention for severe refractory angina, hemodynamic instability, or when they reached the primary end point (see below). In both groups, our goal was immediate revascularization after coronary angiography, preferably by ad hoc percutaneous catheter intervention.

Apart from duration, antithrombotic pretreatment was identical in both study groups and was started immediately after randomization. Antithrombotic pretreatment consisted of (1) unfractionated heparin, initial bolus of 60 U/kg followed by infusion adjusted to a partial thromboplastin time of 60 to 85 seconds; (2) aspirin, initial intravenous bolus of 500 mg followed by 100-mg tablets twice daily; (3) oral clopidogrel, initial loading dose of 600 mg followed by 75 mg twice daily19; and (4) intravenous tirofiban, initial bolus of 10 µg/kg followed by continuous infusion of 0.10 µg/kg per minute.3 As soon as the decision was made to implement percutaneous catheter intervention, we administered an additional bolus of 60 U/kg of heparin and adjusted the infusion rate of tirofiban to 0.15 µg/kg per minute.20 We continued tirofiban for 24 hours and clopidogrel for 4 weeks after the intervention. At day 4 after catheter intervention, we reduced the dose of clopidogrel to 75 mg once daily. In patients assigned to conservative treatment (ie, medical treatment alone) or to CABG surgery, we stopped clopidogrel and tirofiban after catheterization; heparin could be continued until surgery if indicated clinically. For both groups, the study protocol mandated β-blockers, angiotensin-converting enzyme inhibitors, and statins as concomitant treatment. Nitrates were allowed if needed for suppression of angina.

We analyzed biochemical markers of myocardial damage every 8 hours before catheterization and up to 48 hours after surgical or percutaneous catheter revascularization. Thereafter and in patients treated conservatively after catheterization, myocardial marker proteins were analyzed daily and for new episodes of severe chest pain until hospital discharge. Patients underwent conventional 12-lead electrocardiography on admission, immediately after revascularization, and at least once daily thereafter, until hospital discharge. We performed a telephone interview at 30 days. For patients reporting cardiac symptoms, at least 1 clinical and electrocardiographic examination was performed in the outpatient clinic or by the referring physician. Thirty-day follow-up was complete in all surviving patients; in addition, 330 patients (80.5%) subsequently had direct visits to our institutions. All information derived from contingent hospital readmission records or provided by the referring physician or by the outpatient clinic was entered into a computer database.

Outcomes

Our primary end point was the combined cumulative incidence of large MI or death from any cause during 30 days of follow-up. Large MI was defined by the occurence of any of the following: new Q waves in 2 or more contiguous electrocardiographic leads, new left bundle branch block, or elevation of the catalytic activity of creatine kinase and its MB isoenzyme to at least 5 times the upper limit of normal. After CABG surgery, we diagnosed large MI if the catalytic activity of creatinine kinase MB isoenzyme exceeded 30 U/L.

In addition, we assessed bleeding complications. According to the Thrombolysis in Myocarcardial Infarction (TIMI) trial definitions,3 a bleeding event was defined as major if it was intracranial or if there were clinically significant overt signs of hemorrhage associated with a drop in hemoglobin of more than 5 g/dL. To account for transfusion, an increase of 1 g/dL in hemoglobin was assumed for each unit of blood. All end points were adjudicated by an independent blinded committee.

Statistical Methods

For calculation of sample size, we assumed a 7% 30-day incidence of death and MI with prolonged antithrombotic pretreatment and hypothesized that this represented a 60% relative risk reduction compared with early intervention. We designed the study to have a power of 80% to test this hypothesis, with a 2-sided P value of less than .05 indicating statistical significance. According to these assumptions, 203 patients were required in each treatment group. In a prespecified secondary analysis, we compared the incidence of our primary end point after catheterization between the 2 treatment strategies. According to the intention-to-treat principle, all primary analyses were based on data from all patients as randomized.

Continuous variables are presented as median (interquartile range). We report categorical variables as counts and proportions and assessed differences between the groups with use of a 2-sided χ2 test or Fisher exact test as appropriate. In addition, we report our primary end point as an information-preserving composite end point.21 We analyzed survival by the Kaplan-Meier method. We calculated a multivariate logistic regression model adjusting for age, sex, smoking, serum cholesterol level, hypertension, diabetes, insulin-dependent diabetes, prior angioplasty, prior CABG surgery, prior MI, ST-segment depression, cardiac troponin T level, coronary stenosis of 50% or greater, and left ventricular ejection fraction. Some of the relative risks and 95% confidence intervals (CIs) were calculated by conventional methods included in the crosstabs procedure of SPSS version 11.5 (SPSS Inc, Chicago, Ill). We also used S-Plus version 4.5 (Insightful Corp, Seattle, Wash) for statistical analyses.

The trial profile is shown in Figure 1. From February 27, 2000, until April 8, 2002, we enrolled 410 patients, of whom 207 were allocated to receive prolonged antithrombotic pretreatment and 203 to receive early intervention. There were no significant differences between the study groups with respect to entry criteria and other baseline characteristics (Table 1). Elevated levels of cardiac troponin T were present in 274 patients (67%) while 268 (65%) had ST-segment depression. In both groups, half of the patients were aged 70 years and older, and one third (136/410) were women. Patients with diabetes mellitus constituted 29% (118/410) of our study cohort.

Table Graphic Jump LocationTable 1. Baseline Demographic, Clinical, and Angiographic Characteristics of the Study Cohort

The median time to catheterization with prolonged antithrombotic pretreatment was 86 hours; we catheterized only 12 patients in this group (5.8%) prematurely according to the prespecified criteria. Of the patients assigned to early intervention, 87.2% (177/203) underwent coronary angiography within 6 hours, while the median time to catheterization was only 2.4 hours (Figure 2).

Figure 2. Time to Catheterization
Graphic Jump Location

The angiographic baseline characteristics were not significantly different between the 2 treatment groups (Table 1). More than two thirds (69.5% [285]) of our patient population had multivessel disease and 89% (364) had coronary artery stenosis of 50% or greater. The definitive treatment did not differ significantly between the antithrombotic pretreatment and the early intervention groups (catheter revascularization: 133 [64.3%] vs 143 [70.4%]; CABG surgery: 16 [7.7%] vs 16 [7.9%]), nor did concomitant medication (Table 2). We did not use drug-eluting stents, atherectomy, or brachytherapy.

Table Graphic Jump LocationTable 2. Definitive Treatment and Concomitant Therapy

At 30 days, the cumulative incidence of large MI or death from any cause differed significantly between the 2 treatment strategies (Figure 3); this combined end point was reached in 11.6% (3 deaths, 21 infarctions) of the antithrombotic pretreatment group and in 5.9% (no deaths, 12 infarctions) of the early intervention group (relative risk [95% CI], 1.96 [1.01-3.82]; P = .04 [Fisher exact test, P = .05]). The observed incidences of both death and MI tended to be higher with prolonged antithrombotic pretreatment as compared with early intervention when we analyzed each component of the primary end point separately (Table 3). If we present our primary end point in an information-preserving form, the number of patients in each of 3 categories (death, nonfatal MI, neither event) was 3, 21, and 183, respectively, in the antithrombotic pretreatment group and 0, 12, and 191, respectively, in the early intervention group.

Figure 3. Cumulative Incidence of Death and Myocardial Infarction at 30 Days
Graphic Jump Location
P value is from unadjusted χ2 test.
Table Graphic Jump LocationTable 3. Incidence of Clinical Events During 30 Days

In a multivariable logistic regression model that took into account baseline variables listed in Table 1, the adjusted odds ratio (OR) was 2.17 (95% CI, 1.01-4.76) (P = .047) for the primary end point comparing the prolonged antithrombotic pretreatment strategy with the early intervention strategy. This was similar to the unadjusted OR of 2.09 (95% CI, 1.01-4.30) (P = .046) for the primary end point comparing prolonged antithriombotic pretreatment with early intervention.

Findings in subgroups defined by entry criteria or definite treatment were consistent with the main study results. We found no significant effect on our primary end point when comparing prolonged antithrombotic pretreatment vs early intervention, either in patients with elevated levels of cardiac troponin T (OR, 1.65 [95% CI, 0.75-3.64]) or in those with ST-segment depression (OR, 1.50 [95% CI, 0.67-3.37]). Similarly, in patients undergoing percutaneous catheter intervention there was no detectable benefit of prolonged antithrombotic pretreatment compared with early intervention (OR, 1.64 [95% CI, 0.73-3.68]).

Irrespective of the duration of pretreatment, the event rate after catheterization was similar in both study groups (P = .92), with 11 events occurring in each of the 2 treatment groups (Figure 4). In the early intervention group only 1 event occurred before catheterization, whereas the longer duration of pretreatment in the prolonged antithrombotic pretreatment group resulted in 13 precatheterization events. Major bleeding and severe thrombocytopenia occurred at a similar rate in both groups (Table 3). None of our patients experienced cerebral hemorrhage.

Figure 4. Cumulative Incidence of Death and Myocardial Infarction at 30 Days After Catheterization
Graphic Jump Location

In our randomized controlled trial in patients with unstable coronary syndromes, deferral of intervention for prolonged antithrombotic pretreatment did not improve outcome compared with immediate intervention accompanied by intense antiplatelet treatment. On the contrary, we observed a significant increase in the cumulative 30-day incidence of large MI or death from any cause in patients who underwent prolonged antithrombotic pretreatment. The cardiac event rate after catheterization was almost identical irrespective of the duration of antithrombotic pretreatment. The intense antithrombotic treatment including triple antiplatelet therapy at the time of catheter intervention may have contributed substantially to outcome after catheterization. Without this antiplatelet regimen the prevention of excessive peri-interventional MIs in the early intervention group might not have occurred.

In trials on the peri-interventional use of abciximab, the excessive risk of catheter intervention in unstable coronary syndromes was reduced to close to that observed among patients with stable angina.1517 Thus, abciximab administered at the time of intervention appeared to achieve plaque passivation.22 In our study, the high loading dose of clopidogrel in combination with tirofiban afforded even stronger platelet inhibition at the time of intervention.19 Whereas earlier trials used the 300-mg loading dose of clopidogrel, the 600-mg loading dose used in the ISAR-COOL trial had been tested in 2 more recent studies—a large registry23 as well as the ISAR-REACT (Intracoronary Stenting and Antithrombotic Regimen–Rapid Early Action For Coronary Treatment) trial.24 The ISAR-REACT trial addressed peri-interventional antithrombotic therapy in patients without myocardial marker proteins or ischemic ST-segment changes. In the low to intermediate–risk cohort of the ISAR-REACT trial, clopidogrel alone with a 600-mg loading dose was highly effective because abciximab was no longer needed to reduce the risk of peri-interventional ischemic events. With a 600-mg loading dose, a 2-hour delay, as in the early intervention group, suffices to achieve an almost full effect of adenosine diphosphate–receptor inhibition.19 Within the same time frame, tirofiban would have achieved a steady-state concentration that enables a robust potent antiaggregatory effect.25 Our study shows that the plaque passivation achieved by such intense antiplatelet therapy at the time of intervention cannot be surpassed by extended pretreatment; ie, extended pretreatment does not improve outcome.

Compared with the early intervention strategy, the excessive event rate with the antithrombotic pretreatment strategy was incurred exclusively during pretreatment, presumably as a consequence of its differential duration. During the pretreatment phase (median duration, 3.6 days), 6.3% of the patients receiving prolonged antithrombotic pretreatment experienced an event. Reflecting the high-risk characteristics of our study population, this rate was higher than the daily rate of 1.3% in the Chimeric 7E3 Anti-Platelet Therapy in Refractory Unstable Angina Treatment (CAPTURE) trial26 or the approximate daily rate of 1% found in other studies during conservative treatment.2729 Compared with other trials,2629 our patient population was the oldest, comprised the highest proportion of patients with ST-segment abnormalities, and had the highest prevalence of diabetes mellitus. Our study demonstrates that despite recent advances in antithrombotic therapy the risk of large MI or death from any cause is still substantial during conservative treatment of unstable coronary syndromes in unselected high-risk patient settings.

When we designed our study, we chose the duration of the pretreatment phase based on FRISC II.1 Shorter pretreatment phases lasting a median of 1 or 2 days have been instituted in more recent trials.3,4 Nevertheless, the principle message of our study would not have been altered had we chosen a shorter duration of pretreatment. In our study, there was no trade-off between a reduction in postcatheterization events and the incidence of precatheterization events that could be optimized by choosing another duration of pretreatment. On the contrary, our study suggests that the shorter the pretreatment phase the lower the incidence of adverse events.

As in other contemporary studies, 30-day mortality in the entire population was below 1%.14,27 Thus, our primary end point and the benefit from early intervention were driven largely by the incidence of MI; one-third of patients with MI will develop new Q waves and two-thirds will not. Consistent with the outcome for nonfatal MI, the observed mortality rates also favored early intervention. These analyses need to be interpreted cautiously, because our study was not powered to analyze each component of our primary end point. In our admittedly underpowered subgroup analyses we did not find any indication that the benefit from early intervention was linked to patients with elevated levels of cardiac troponin T or to those with ST-segment depression, or to a specific modality of definite treatment, such as catheter revascularization or CABG surgery.

In patients with unstable coronary syndromes, intense antithrombotic pretreatment with triple antiplatelet therapy reduces the risk of adverse cardiac events during an unavoidable conservative treatment phase,29 but does not appear to have any further benefit. Conservative pretreatment consumes considerable resources, including an increase in length of hospital stay (median [interquartile range] for prolonged vs early intervention, 7 [6-11] days vs 5 [3-7] days; P<.001) is associated with a substantial risk of cardiac complications, and does not reduce the risk of subsequent revascularization procedures. In patients with unstable coronary syndromes, antithrombotic pretreatment should therefore be kept to the minimum duration required to organize early cardiac catheterization and revascularization.

FRISC II Investigators.  Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study.  Lancet.1999;354:708-715.
PubMed
Wallentin L, Lagerqvist B, Husted S, Kontny F, Stahle E, Swahn E. Outcome at 1 year after an invasive compared with a non-invasive strategy in unstable coronary-artery disease: the FRISC II invasive randomised trial.  Lancet.2000;356:9-16.
PubMed
Cannon CP, Weintraub WS, Demopoulos LA.  et al.  Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban.  N Engl J Med.2001;344:1879-1887.
PubMed
Fox KA, Poole-Wilson PA, Henderson RA.  et al.  Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial.  Lancet.2002;360:743-751.
PubMed
Bjessmo S, Ivert T, Flink H, Hammar N. Early and late mortality after surgery for unstable angina in relation to Braunwald class.  Am Heart J.2001;141:9-14.
PubMed
Boden W, O'Rourke R, Crawford M.  et al.  Outcomes in patients with acute non-Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy.  N Engl J Med.1998;338:1785-1792.
PubMed
de Feyter PJ, van den Brand M, Laarman GJ, van Domburg R, Serruys PW, Suryapranata H. Acute coronary artery occlusion during and after percutaneous transluminal coronary angioplasty: frequency, prediction, clinical course, management, and follow-up.  Circulation.1991;83:927-936.
PubMed
Schühlen H, Kastrati A, Dirschinger J.  et al.  Intracoronary stenting and risk for major adverse cardiac events during the first month.  Circulation.1998;98:104-111.
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Figures

Figure 2. Time to Catheterization
Graphic Jump Location
Figure 3. Cumulative Incidence of Death and Myocardial Infarction at 30 Days
Graphic Jump Location
P value is from unadjusted χ2 test.
Figure 4. Cumulative Incidence of Death and Myocardial Infarction at 30 Days After Catheterization
Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline Demographic, Clinical, and Angiographic Characteristics of the Study Cohort
Table Graphic Jump LocationTable 2. Definitive Treatment and Concomitant Therapy
Table Graphic Jump LocationTable 3. Incidence of Clinical Events During 30 Days

References

FRISC II Investigators.  Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study.  Lancet.1999;354:708-715.
PubMed
Wallentin L, Lagerqvist B, Husted S, Kontny F, Stahle E, Swahn E. Outcome at 1 year after an invasive compared with a non-invasive strategy in unstable coronary-artery disease: the FRISC II invasive randomised trial.  Lancet.2000;356:9-16.
PubMed
Cannon CP, Weintraub WS, Demopoulos LA.  et al.  Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban.  N Engl J Med.2001;344:1879-1887.
PubMed
Fox KA, Poole-Wilson PA, Henderson RA.  et al.  Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial.  Lancet.2002;360:743-751.
PubMed
Bjessmo S, Ivert T, Flink H, Hammar N. Early and late mortality after surgery for unstable angina in relation to Braunwald class.  Am Heart J.2001;141:9-14.
PubMed
Boden W, O'Rourke R, Crawford M.  et al.  Outcomes in patients with acute non-Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy.  N Engl J Med.1998;338:1785-1792.
PubMed
de Feyter PJ, van den Brand M, Laarman GJ, van Domburg R, Serruys PW, Suryapranata H. Acute coronary artery occlusion during and after percutaneous transluminal coronary angioplasty: frequency, prediction, clinical course, management, and follow-up.  Circulation.1991;83:927-936.
PubMed
Schühlen H, Kastrati A, Dirschinger J.  et al.  Intracoronary stenting and risk for major adverse cardiac events during the first month.  Circulation.1998;98:104-111.
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