R. R. Azar1, S. Rinfret2, P. The ́roux2, P. H. Stone3, R. Dakshinamurthy4, Y.-J. Feng4, A. H. B. Wu4, G. Range ́2 and D. D. Waters
1Division of Cardiology, San Francisco General Hospital and the University of California, San Francisco, CA, U.S.A.; 2The Montreal Heart Institute, Montreal, Canada; 3The Brigham and Women’s Hospital, Boston, MA, U.S.A.; 4Hartford Hospital, Hartford, CT, U.S.A.
Aims The purpose of this study was to assess the efficacy of antiinflammatory therapy with methylprednisolone during the acute phase of unstable angina.
Methods This is a randomized ‘prospective’ double-blind, placebo-controlled trial. Patients with the diagnosis of unstable angina were randomized to a 48-h course of methylprednisolone (n=81) or placebo (n=85). Patient care and therapy were otherwise decided by their attending cardiologist. The primary end-point was a composite of in-hospital recurrence of angina, silent ischaemia on Holter recording, emergency coronary revascularization, readmission with unstable angina, and myocardial infarction or death during the 30-day follow-up.
Results The two groups were well balanced and had similar clinical characteristics at baseline. Forty-eight hours after randomization, mean C-reactive protein levels decreased by 2·6 mg . l-1 in the methylprednisolone group, but increased by 1·6 mg . l-1 in the placebo group (P = 0·03). The primary end-point occurred in 44% of the methylprednisolone patients and in 33% of the placebo patients (P = 0·12). Coronary revascularization rates were equal between the two groups (38% and 40%). When adjustment was made for the difference in revascularization times, a trend towards better event-free survival was seen in the control group (67% vs 57%; P=0·09).
Conclusion A 48 h course of antiinflammatory therapy with methylprednisolone given at the doses of this study did not improve the short-term outcome of patients with unstable angina.
(Eur Heart J 2000; 21: 2026–2032, doi:10.1053/ euhj.2000.2475)
© 2000 The European Society of Cardiology
Key Words: Acute coronary syndromes, inflammation, corticosteroids.
Inflammation has been implicated in the pathogenesis of coronary disease and acute coronary syndromes[1–4]. Histological studies support the concept that atherosclerosis is a chronic inflammatory process leading to progressive narrowing and obstruction of the arterial lumen. Unstable angina is a shift from this chronic indolent course to the acute catastrophic consequences of plaque rupture or erosion. Unstable angina is characterized by activated circulating white cells, high levels of inflammatory cytokines and acute phase reactant proteins[3,5–10]. A growing body of evidence has implicated inflammation in plaque instability, endothelial dysfunction and increased thrombogenesis[11–16]. Unstable angina patients with high levels of inflammatory markers are at high risk for adverse cardiac events and death during hospitalization and following discharge[8–10]. These complications occur despite aggressive antiplatelet and antithrombotic therapies.
These considerations raise the possibility that antiinflammatory therapy might reduce the event rate in unstable angina. As this therapeutic approach has not yet been investigated, a study was designed to test the hypothesis that a short course of potent antiinflammatory treatment during the early acute phase of unstable angina, combined with the usual antithrombotic and antiischaemic regimen, would improve short-term outcome.
This prospective, randomized, double-blind, placebo-controlled trial was designed to investigate the efficacy of 48 h treatment with intravenous methylprednisolone on the 30-day outcome of patients admitted with the diagnosis of unstable angina. Patients were recruited from Hartford Hospital in Hartford, Connecticut, and from the Montreal Heart Institute in Montreal, Canada. The study was approved by the institutional review boards of both hospitals. Informed consent was obtained from all patients prior to enrolment. Enrolment began in May 1996 and ended in April 1999.
All patients who were admitted to the two participating institutions with unstable angina, or who developed unstable angina while hospitalized were considered for the study. The most recent episode of chest pain had to have occurred less than 24 h prior to randomization and administration of the first dose of the study drug. The diagnosis of unstable angina was based on a clinical history of chest pain suggestive of myocardial ischaemia, occurring at rest, and lasting for more than 5 min, with normal serum levels of creatine kinase-MB on admission. Ischaemic electrocardiographic changes were defined as deeply inverted or newly peaked positive T waves, or horizontal or downsloping ST segment depression ≥1 mm, or horizontal or upsloping transient ST segment elevation ≥1 mm. In the absence of electrocardiographic changes compatible with ischaemia, inclusion in the study required independent confirmation of the diagnosis by two cardiologists.
Patients with any of the following conditions were excluded: persistent ST segment elevation consistent with acute myocardial infarction, left bundle branch block, myocardial infarction within 2 weeks, percutaneous revascularization within the preceding 6 months, bypass surgery within 3 months, any coexistent inflammatory or infectious condition, corticosteroid use within the previous month, digoxin therapy (because of interference with ST segment Holter monitoring) and any contraindication to steroid use (e.g. history of active peptic ulcer disease, uncontrolled diabetes mellitus). Patients older than 85 years and women of childbearing potential were also excluded.
Screening for the study was carried out in the emergency department or as soon as possible after admission. The trial medication was prepared by the pharmacy on a randomized double-blinded basis. Patients were divided into two equal groups. The active treatment group received methylprednisolone as a bolus followed by seven additional doses every 6 h. The dosage, given intravenously, was 125 mg for the bolus and 40 mg for the maintenance dose for patients with a weight ≥60 kg. Patients weighing <60 kg received half of the dosage (62·5 mg bolus and 20 mg maintenance dose). Control patients received a bolus and seven maintenance injections of placebo. The higher dose (125/40 mg) was given to 125 of the 166 study patients (75%) and the lower dose to the remaining 41 (25%). All efforts were made to inject the bolus as soon as possible after randomization. The mean time from the onset of the qualifying episode of chest pain to administration of the study drug bolus was 7·8 h in the steroid group and 8·4 h in the placebo group (P=ns). The mean number of doses of the study drug given per patient was 6±2·5 in the methylprednisolone group and 6±2·4 in the placebo arm. All eight doses required by the protocol were administered to 63% of the study patients. All patients randomized to methylprednisolone were treated with this drug. Three patients in the placebo group received intravenous methylprednisolone during their hospital stay. This was admin- istered to control asthma exacerbation in one case, prior to cardiac catheterization in one patient with a history of dye allergy, and in error by the nurse in one case.
All patients had cardiac enzymes performed prior to randomization and at 8–12 h and at 16–24 h. Additional enzymes were also ordered whenever an episode of chest pain, suspicious for myocardial ischaemia, occurred. Cardiac troponin I was checked on admission and 12–24 h later. C-reactive protein was measured in all patients, from the plasma prior to administration of the study drug bolus, using the Behring Nephelometer (Behring Diagnostics, Westwood, MA, U.S.A.). This assay has a detection limit of 2·0 mg . l-1 and a measurement range of up to 160 mg . l-1. Levels >5 mg . l-1 were considered elevated. To assess the antiinflammatory effects of methylprednisolone, C- reactive protein was also measured at 48 h following the study drug bolus in a subgroup of 39 randomly selected patients. All C-reactive protein results were blinded.
Holter monitoring for the detection of silent ischaemia was performed for a maximal duration of 24 h, starting 8 h after the study bolus. Holter recordings were sent to the Holter Core Laboratory at the Brigham and Women’s Hospital where they were read by an independent cardiologist blinded to treatment assignment.
Patient care decisions were made by the attending cardiologist, who was not involved in the study. In particular, no specific recommendations were made with regard to angiography or revascularization, which could be performed at any time.
The primary end-point of the study was a composite of any of the following during the 30-day follow-up: death from any cause, acute myocardial infarction, emergency revascularization driven by ischaemia, silent ischaemia on the Holter recording, chest pain recurrence during hospitalization, or readmission with unstable angina. The secondary end-points were each of the components of the primary end-point taken separately, as well as the number of episodes of recurrent chest pain. Because methylprednisolone requires 6–8 h to exert its full antiinflammatory effects, only events occurring 8 h after the study bolus were considered as end-points.
Data were collected on case-report forms by study coordinators at the clinical sites. Follow-up after hospital discharge was obtained by telephone or by a visit to the research clinic. Whenever an event was reported, it was confirmed by a review of hospital records. All patients completed the 30-day follow-up. All events were reviewed and confirmed by an independent investigator (D.D.W.) blinded to treatment allocation. Myocardial infarction was defined as typical chest pain associated with new Q waves on the 12-lead electrocardiogram, or with an at least twofold elevation above normal of the creatine kinase MB subfraction associated with abnor- mal total creatine kinase. Emergency revascularization was defined as recurrence of chest pain refractory to medical therapy requiring immediate coronary angiography and revascularization. Angina recurrence was defined as recurrence of chest pain similar to that on admission. If electrocardiographic changes suggestive of ischaemia were present, the chest pain was automatically retained as an end-point; however, in the absence of electrocardiographic changes, two cardiologists had to agree that the pain was due to myocardial ischaemia. Ischaemic ST changes on Holter recording analysis were defined as the development of reversible horizontal or downsloping ST segment depression ≥1 mm below the isoelectric line and ≥1 mm below the baseline ST segment, or as ST segment elevation ≥1 mm above the isoelectric line and ≥1 mm above the baseline ST segment. An episode of ischaemia had to last more than 1 min in order to be regarded as an end-point and at least 1 min had to elapse between episodes for them to be counted as separate events.
Because corticosteroid therapy has been reported to cause complications when used in acute myocardial infarction, the study protocol required that the study drug (whether methyprednisolone or placebo) be stopped immediately whenever there was any enzymatic evidence of myocardial infarction.
During the trial, a total of 21 acute myocardial infarctions were reported, 15 of which occurred during the first 48 h when the patient was still on the study drug. The drug was discontinued before completion of the full eight doses of treatment in 13 of these 15 patients and continued until the last dose (in violation of the protocol) in the remaining two. The 13 patients who did not complete the treatment because of early acute myocardial infarction received a mean of 2·1 ± 1·7 doses per patient.
Sample size and statistical analysis
The event rate for the primary end-point in the placebo group was predicted to be 40%, based on recent studies of unstable angina that included Holter-based ischaemic events and had comparable follow-up periods[18,19]. A sample size of 82 patients per group was required to detect a 50% reduction in the primary end-point in the active treatment group, using a two-tailed chi-square test with a significance level of 5% and a power of 80%.
Continuous variables were expressed as the mean value ±1 SD and were compared with a Student t-test. Categorical variables were presented as absolute values and percent, and were compared with a chi-square test. There was no interim data analysis. Statistical analyses of end-points were performed at the end of the trial based on the intention-to-treat principle. The 30-day outcomes in the two groups were compared using the chi-square test. To adjust for the finding that coronary revascularization was performed much earlier in the methylprednisolone group, the primary end-point was also analysed using Kaplan–Meier survival curves. Event-free survival for each group was plotted to the time of coronary revascularization or to completion of the 30-day follow-up (in cases where revascularization was not performed) and was compared using the log-rank method. All statistical tests were two-tailed, and a P value <0·05 was considered significant.
A total of 166 patients met entry criteria and were included in the trial. Of these, 81 were randomized to methylprednisolone and 85 to placebo. The baseline demographic and clinical characteristics of the two groups are summarized in Table 1. Randomization achieved a good balance between the groups. Of the 17 inter-group comparisons in Table 1, the only difference with a P value <0·05 is history of coronary angioplasty (>6 months prior to randomization). On admission, 88 patients (53%) had electrocardiographic changes suggestive of ischaemia. Of the 78 patients without ischaemic electrocardiographic changes on admission, 39 (50%) had elevated levels of cardiac troponin I, or an abnormal exercise stress test, or a new reversible perfusion defect on nuclear imaging, or ischaemic electrocardiographic changes during episodes of chest pain recurrence, or on Holter recording. Thus, objective evidence of myocardial ischaemia was documented in 77% of the study patients.
The in-hospital treatment of patients was similar in both groups, as summarized in Table 2. Of note, >90% of patients in both groups received aspirin and heparin.
Coronary angiography was performed in 104 patients (63%) and revealed at least one vessel disease (stenosis >50%) in 90% of cases.
C-reactive protein levels
Immediately prior to randomization, C-reactive protein levels were similar between the steroid and the placebo group (7·9 ± 10·7 vs 8·3 ± 8·3; P = ns). In the 39 patients who had C-reactive protein measured at the time of randomization and 48 h later, mean C-reactive protein levels decreased by 2·6±2·7 mg . l-1 in the methylprednisolone group but increased by 1·6±7·3 mg . l-1 in the placebo group (P=0·03; Table 3).
During the first 8 h after the study drug bolus (time when events were not retained as end-points according to the study protocol), 30 patients (37%) in the methylprednisolone group and 23 patients (27%) in the placebo group had chest pain recurrence (P = ns) and one patient (in the methylprednisolone group) sustained a new myocardial infarction.
All end-points were measured 8 h after the first dose of the study medication and were not statistically different between the two groups (Table 4). Slightly more patients in the methylprednisolone group had pain recurrence >8 h after the study drug bolus (33% vs 27%; P = ns), but the median number of chest pain recurrences in either group was two episodes. Holter recordings of adequate technical quality were obtained on 144 patients. Ischaemic ST segment changes were detected in nine patients (13%) in the methylprednisolone group (23 episodes, mean ischaemic time 81 ± 180 min) and seven patients (9%) in the placebo group (13 episodes, mean ischaemic time 15 ± 9·3 min; P = ns for all comparisons).
The incidence of coronary revascularization in the two groups was equal, 38% vs 40% (Table 2). However, revascularization was performed much earlier in the methylprednisolone group than in the placebo group, at a mean of 3·4 ± 2·2 compared to 6·1 ± 3·8 days following the study drug bolus; (P = 0·002). The incidence of emergency revascularization, a component of the primary end-point, was 2% in each group.
Overall, 21 patients sustained an acute myocardial infarction. Of these infarctions, 11 occurred <8 h after randomization and did not count as end-points, as pre-specified by the protocol. These were patients with non-Q wave acute myocardial infarction on admission and a negative first set of cardiac enzymes, who, mistakenly, were diagnosed as having unstable angina and enrolled in the study. The diagnosis was corrected to that of non-Q wave acute myocardial infarction once the second set of cardiac enzymes was obtained 8–12 h later. A total of 11 patients sustained an acute infarction >8 h after the study drug bolus (six in the methylprednisolone and five in the placebo group) of which two in each group were of the Q-wave type. These 11 acute myocardial infarctions were retained as end-points. They occurred before coronary revascularization in seven cases and were a complication of the revascularization procedure in four patients (two patients in each group). Nine of these acute myocardial infarctions occurred during the initial hospitalization and two after hospital discharge. Overall, the interval between study drug initiation and acute myocardial infarction was similar in the two groups (mean 5·1 ± 8·7 days in the methylprednisolone group vs 6·4 ± 2·9 days in the placebo group; P = ns). However, in the nine patients who had their infarct prior to hospital discharge, the time from randomization to acute myocardial infarction was shorter in the methylprednisolone group (1·6 ± 0·5 vs 6·4 ± 2·9 days; P = 0·02).
After hospital discharge, four patients in each group were readmitted with unstable angina. The 30-day mortality rate was 2% in the two groups. The causes of death were acute myocardial infarction and cardiogenic shock in three cases (one in the methylprednisolone and two in the placebo group) and septic shock following coronary artery bypass graft surgery in one patient (methylprednisolone group).
Overall, methylprednisolone-treated patients had slightly more events than patients in the placebo group, both during hospitalization (42% vs 31%; P = ns) and at 30-day follow-up (primary end-point of the study; 44% vs 33%; P = ns). Kaplan–Meier event-free survival curves (Fig. 1) revealed that the majority of events occurred within the first 48 h after randomization. There was a trend toward better outcome in the placebo group (event-free survival 67% vs 57%; P = 0·09).
This is the first randomized clinical trial assessing the efficacy of antiinflammatory therapy in unstable angina. The hypothesis of the study was that treatment with methylprednisolone would result in a 50% reduction in event rates at 30-day follow-up. The two groups were well matched for baseline clinical characteristics and for in-hospital medical therapy. The study drug was well tolerated and significantly reduced C-reactive protein levels in actively treated patients compared to controls. Contrary to expectation however, all the components of the primary end-point were either equal or slightly worse in the methylprednisolone group. The difference in the primary composite end-point was not statistically significant.
Methylprednisolone-treated patients underwent coronary revascularization earlier than control patients (P=0·001). Their rates of recurrent angina, number of ischaemic episodes and total ischaemia time on Holter monitoring were all slightly higher than the rates in the placebo group, even though the placebo patients were left without revascularization for nearly twice as long, a mean of 6·1 vs 3·4 days. A trend toward better event-free survival was seen in the control group (Fig. 1). Thus, the results of this study support the conclusion that methylprednisolone therapy is of no benefit in unstable angina. It should be emphasized however, that most of the events that comprised the primary end-point were episodes of chest pain or myocardial ischaemia on Holter recording. The incidence of hard end-point events, such as death or acute myocardial infarction, was similar between the two groups but too low to eliminate the possibility of a treatment benefit.
Rational for antiinflammatory therapy in unstable angina
Recent studies have provided convincing evidence that unstable angina is an acute inflammatory state. Atherectomy specimens from patients with unstable angina have revealed a more abundant inflammatory cell infiltrate than was seen in specimens from patients with stable angina. Degradative enzymes, such as the metalloproteinases, are actively synthesized and secreted during unstable angina and can undermine the structural integrity of the plaque[20–22]. Patients with unstable angina exhibit activated circulating leukocytes, increased leukocyte function and secretion, and high levels of interleukins and leukotrienes, and acute phase reactant proteins such as C-reactive protein[5–10]. Monocytes from patients with unstable angina have an increased expression of tissue factor[14–16]. This contributes toward shifting the thrombosis–fibrinolysis balance toward thrombosis. Inflammatory cytokines and oxygen free radicals can cause direct endothelial dysfunction, resulting in an increased propensity for thrombosis and vasospasm. They can also directly depress myocardial function. Unstable angina patients with high levels of inflammatory markers are at higher risk for adverse cardiac events[8–10]. All these findings suggest that antiinflammatory drugs might be useful in unstable angina.
Methylprednisolone is a potent antiinflammatory agent with an excellent safety profile, especially during short-term use. In this study, methylprednisolone decreased C-reactive protein levels at 48 h following initiation of treatment, while C-reactive protein levels increased in controls. This is direct evidence that a substantial antiinflammatory effect was achieved with therapy. The major mechanisms for this antiinflammatory action are inhibition of phospholipases and transcription of various cytokines[24,25]. Glucocorticoids also inhibit polymorphonuclear leukocyte accumulation in inflamed tissue. The full antiinflammatory effects of methylprednisolone via these mechanisms are delayed for many hours following administration of the drug.
Possible reasons for the lack of efficacy of methylprednisolone
There are several potential explanations for the lack of benefit from methylprednisolone in this study. The duration of therapy might have been too short. Also, treatment may have been initiated too late; the delay from the onset of chest pain to treatment was 8 h, and an additional 8 h probably elapsed before the full antiinflammatory activity of the drug would take effect. By this time, plaque erosion or rupture had already occurred, and significant and possibly irreversible damage may have been caused by activated leukocytes.
In addition to its antiinflammatory activity, methylprednisolone is also an immunosupressant. Prior studies have shown that unstable angina is accompanied by activation of humoral and cellular immunities, and that inadequate activation of these systems is associated with higher event rates. The recent reports linking infectious agents to acute coronary syndromes is rele- vant to these findings. If this link is confirmed, immunosuppressive agents may turn out to be contraindicated in unstable angina, and antibiotics might become a component of routine care[28,29]. Finally, the systemic acute inflammatory response seen in unstable angina may be a consequence of plaque rupture rather than its cause, and may not be incriminated in the pathogenesis of complications, but only be a marker of increased risk.
This study is limited by its small sample size. The routine use of aspirin and heparin have reduced the incidence of acute myocardial infarction and death in unstable angina to less than 4%. This trial was not powered to show a significant difference in these hard events. The primary end-point was a composite of clinical events, including chest pain recurrence. Coronary angiography and revascularization were allowed any time during the study course. Early revascularization might have masked the full effect of corticosteroid therapy, either beneficial or detrimental. However, early intervention and discharge are a common approach in patients with acute coronary syndromes. The results of this trial are thus applicable in the context of how unstable angina is currently managed.
A 48-h course of antiinflammatory therapy with methylprednisolone given at the doses of this study does not improve the short-term outcome of patients with unstable angina. This, however, does not prove that suppression of acute inflammation is of no value in acute coronary syndromes. Other more selective antiinflammatory drugs with a more rapid onset of action and without immunosuppressive activity may yield different results and may be a safe and synergistic addition to the current antithrombotic and antiischaemic therapies.
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