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(Circulation. 1997;96:183-191.)
© 1997 American Heart Association, Inc.
Articles |
Beneficial Effects of Intravenous and Oral Carvedilol Treatment in Acute Myocardial Infarction
A Placebo-Controlled, Randomized Trial
From the Department of Cardiology, Northwick Park Hospital and Institute of Medical Research, Harrow, UK.
Correspondence to Dr Avijit Lahiri, Department of Cardiology, Northwick Park Hospital and Institute of Medical Research, Watford Rd, Harrow, Middlesex HA1 3 UJ, UK.
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Abstract |
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Background Evidence of efficacy and safety of ß-blockers after thrombolysis for acute myocardial infarction (AMI) is equivocal. Newer ß-blockers such as carvedilol have not been tested in this setting.
Methods and Results This study investigated the effects of acute (intravenous) and long-term (6 months, oral) treatment with carvedilol versus placebo in 151 consecutive patients with AMI. Exercise ECG, ambulatory monitoring, and two-dimensional echocardiography were performed before hospital discharge and at 3 and 6 months. All patients were followed up and cardiovascular events recorded. The Cox proportional hazards model was used to compare time from randomization with the occurrence of a cardiovascular event, and Kaplan-Meier survival curves were calculated. Carvedilol was found to be safe, and it significantly reduced cardiac events compared with placebo (18 on carvedilol and 31 on placebo, P<.02). Fifty-four patients had heart failure at study entry; 34 received carvedilol. There were no adverse effects of carvedilol therapy and no excess events in this subgroup. Carvedilol produced significant reductions in heart rate (P<.0001), blood pressure (P<.005) at rest, and rate-pressure product at peak exercise (P<.003), but exercise capacity was unchanged. Left ventricular ejection fraction was not altered significantly by carvedilol, but stroke volume was higher at pre–hospital discharge examination (63 versus 53 mL; P<.01). Diastolic filling of the left ventricle (E/A ratio) was also improved (1.2 versus 0.9; P<.001). In a subgroup with left ventricular ejection fraction <45% (n=49 patients; 24 on carvedilol and 25 on placebo), carvedilol showed attenuation of remodeling.
Conclusions Carvedilol was well tolerated and safe to use in patients immediately after AMI, including those with heart failure, and significantly improved outcome.
Key Words: myocardial infarction • thrombolysis • vasodilation • adrenergic beta antagonist
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The effect of early treatment with ß-blockers in reducing mortality and ischemic events after acute myocardial infarction (AMI) is well known. Trials with intravenous ß-blockers have shown reduction of early mortality by 13% when used within 24 hours of chest pain.1 2 3 Long-term treatment also has been shown to reduce both mortality and reinfarction.4 5 However, all these studies were conducted before the widespread use of thrombolysis and aspirin. One large-scale, randomized trial of intravenous versus oral ß-blockade in patients treated with thrombolytic drugs failed to show reduction in mortality but did show a reduction in ischemic events,6 while another showed increased adverse events in the group treated with intravenous atenolol.7 Furthermore, the negative inotropic effect of ß-blockers and their potential for aggravating heart failure have, in most cases, limited their use to patients who were not in heart failure at study entry.1
Carvedilol is a unique multiple-action drug, a nonselective ß-blocker
with additional vasodilating properties caused by 
1
blockade.8 It is an effective antianginal9
and antihypertensive agent.10 Previous studies have shown
that carvedilol improves both idiopathic and ischemic
congestive heart failure11 12 and confers beneficial
effects in patients with left ventricular
dysfunction.13 Furthermore, recent studies have shown a
large mortality benefit (65%) after carvedilol therapy14
when added to conventional treatment for congestive heart failure.
Additionally, carvedilol affects the lipid profile
favorably.15 It has also been shown to be beneficial in
renal dysfunction16 and significantly limit infarct size
in animal models.17 Furthermore, it is a potent
antioxidant and hence may reduce damage caused by free radical
generation.18
Thrombolysis and antiplatelet therapy have significantly reduced mortality after AMI.19 20 Reperfusion of the occluded coronary artery produces myocardial salvage; however, the "salvaged" myocardium remains at risk of future ischemic events.19 21 A drug with the properties demonstrated by carvedilol and one that may be safely given intravenously to most patients, including those in moderately severe heart failure,22 may be ideally suited to reduce both acute and long-term complications after AMI.
The primary aim of the study was to compare a group of patients with proven myocardial infarction treated with carvedilol with a matched cohort on placebo with respect to the time of development of one of several cardiovascular end points. Secondary objectives included evaluation of the safety of the drug as judged by incidence and nature of side effects and hematologic, biochemical, and ECG screening as well as evaluation of efficacy as judged by exercise capacity, hemodynamics, and systolic and diastolic left ventricular function.
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Methods |
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Patient Selection
Patients admitted to the coronary care unit with typical signs and symptoms suggestive of AMI, ie, chest pain, ECG changes, and serum concentration of creatine kinase and MB isoform consistent with the diagnosis, were recruited to the study. Patients were subsequently withdrawn if the cardiac enzymes failed to show the typical pattern of acute myocardial necrosis. All patients gave informed consent, and the study was approved by the hospital ethics committee.
Exclusion Criteria
Patients were excluded if they were already on - or
ß-blockers and calcium antagonists or had
contraindications to - or ß-blockers; if they were in Killip class
IV heart failure or cardiogenic shock (classes I to III were not
excluded); or if they had severe bradycardia (heart rate <45 bpm),
hypotension (systolic blood pressure <90 mm Hg), second-
to third-degree heart block, left bundle-branch block, severe
valvular disease, insulin-dependent diabetes, renal failure
(creatine >159 µmol/L), known malignancy, or other severe
disease or pregnancy.
Study Design
The study was designed as a single-center, double-blind,
randomized, parallel-group, placebo-controlled study with
stratification for location of infarction (anterior or
inferior) and thrombolysis or no
thrombolysis.
Dosing and Concomitant Therapy
All patients were given aspirin and had subcutaneous heparin for
3 days. The decision regarding use of thrombolysis was
left entirely to the judgment of the admitting physician. Subsequently,
within 24 hours of chest pain, patients were injected
intravenously with 2.5 mg of carvedilol or placebo over 15
minutes. This was followed by an oral dose of 6.25 mg carvedilol or
matching placebo at 4 hours after injection and then 6.25 mg BID for 2
days. The dose was increased to 12.5 mg BID at day 3 and then
maintained at 12.5 mg to 25 mg BID for the duration of the study (6
months) or until a cardiovascular end point had been
reached when the drug was stopped (there was no down titration). Dose
titration was performed at day 14, with carvedilol being increased to
25 mg BID if blood pressure was >120/95 mm Hg and heart rate
>55 bpm. End points were defined as cardiac death; reinfarction;
unstable angina; heart failure; emergency
revascularization; ventricular
arrhythmia requiring intervention; stroke; and additional
cardiovascular therapy other than sublingual nitrates
for angina, diuretics for hypertension, or continuation of
preexisting ACE inhibitors, digitalis, or antiarrhythmics.
However, initiation of therapy with these latter three drugs after
recruitment to the study, for clinical reasons, was also considered an
end point. ACE inhibitors were not routinely administered
for asymptomatic left ventricular
dysfunction.
Study Procedures
All patients were assessed clinically at study entry for
presence or absence of heart failure on the basis of Killip criteria.
They had 12-lead ECGs daily for 3 days, at hospital discharge, and at
every visit (days 14, 42, 84, and 168). Exercise ECG,
echocardiography, and 24-hour ambulatory ECG
monitoring were performed at predischarge examination and then at days
84 and 168 (study completion). Cardiac enzymes were estimated daily for
3 days. Biochemistry and hematology were tested at admission and days
42 and 168.
Follow-up
All patients were followed up after discharge from the hospital
at days 14, 42, 84, and 168 (study completion). Subsequently, all
patients recruited were reviewed every 3 months (including those who
dropped out before study completion) until the last patient had
completed 6 months, and adverse cardiac events were
documented.
Twenty-Four–Hour Ambulatory Monitoring
This was carried out with the use of a Marquette Electronics
series 8500 recorder, utilizing leads CM5 and CC5. Analysis
was performed with the use of a Marquette Electronics Series 8000
analyzer. Tapes were analyzed for cardiac
arrhythmias, ventricular ectopic counts, and hourly
averaged heart rate.
Exercise ECG
Treadmill exercise testing was performed on a computer-assisted
ECG system (CASE 12, Marquette Electronics Inc). A 13-lead system (12
lead + CM5) and the modified Bruce protocol were used. The
ECG was continuously monitored throughout exercise and for 6 minutes
after exercise termination. Blood pressure was recorded manually
every 3 minutes, and ST-segment change was measured at J+60 ms.
Exercise tests were used to assess angina, ST-segment changes, exercise
capacity, and rate-pressure product (heart rate times
systolic blood pressure).
Echocardiography
Two-dimensional, M-mode, and Doppler
echocardiography was performed with the use of a
digitized system (Ultramark 9, Advance Technology Laboratories).
Parasternal long- and short-axis and apical four- and two-chamber views
were obtained. Doppler recordings of left
ventricular inflow (peak early [E] and late [A])
velocities and outflow velocities were made from the apical
four-chamber view. Left ventricular volumes, ejection
fraction (Simpson's technique), and E/A ratio were calculated
according to methods described in detail elsewhere and validated in our
laboratory.23 24 Systolic wall thickening and
endocardial wall motion at rest were scored as grade 0, normal; grade
1, mild hypokinesia; grade 2, severe hypokinesia; grade 3, akinesia;
and grade 4, dyskinesia. This was graded using a 13-segment left
ventricular model. Global wall motion score index was
calculated by adding the wall motion score and then dividing it by the
number of left ventricular segments (n=13). Wall motion
score at the site of myocardial infarction was also calculated by
summing the wall motion score at the infarct site.
Statistical Analysis
Sample size calculations for the primary outcome variable,
time from randomization to development of any
cardiovascular end point, were based on two-sided tests
with a significance level of 5% and a power of 80%. It was calculated
that 144 patients (72 in each group) would be required to demonstrate a
20% difference between the groups.
Primary analysis was performed to compare the time from randomization with development of any one of the cardiovascular end points on an intention-to-treat basis in all patients with confirmed myocardial infarction and who had been given at least one dose of trial medication. The logistic regression test was applied before survival analysis was performed to identify factors that could have been related to the occurrence of cardiovascular end points. The factors analyzed were treatment group, sex, race, age, and site of infarction; previous history of diabetes, hyperlipidemia, hypertension, and smoking; and time from onset of pain to thrombolysis and to infusion of carvedilol or placebo. This showed that only the treatment group had a value of P<.05 and hence, thereafter, primary efficacy analysis was performed in the intention-to-treat population with the use of the Cox proportional hazards model, considering treatment as the only factor. Wilcoxon and log rank tests were also performed in the same cohort. Separate Cox analyses were also performed for "hard" end points—death and reinfarction— and also after exclusion of revascularization and need for nonpermitted cardiovascular medication. Additionally, a subgroup analysis was performed for patients who had clinical evidence of heart failure at study entry to assess the safety and efficacy of carvedilol in this group. Furthermore, the effects of drug therapy in patients with poor left ventricular function (ie, ejection fraction <45%) were also assessed by ANOVA and Fisher's exact test. Secondary variables were analyzed with descriptive statistics. Wilcoxon U tests were calculated in the case of continuous variables to detect differences between groups. A value of P<.05 was considered significant. The continuous variables are expressed as mean (standard deviations in parentheses).
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Demography
Duration of the study was from February 1992 to September 1994. Of the 416 patients screened, 265 were excluded. The main reasons for exclusion were preexisting therapy with either ß-blockers (n=41) or calcium blockers (n=45), elevated creatinine (n=28), delays in admission over 24 hours (n=28), poor mobility or inability to perform exercise for any other reason (n=22), declined consent (n=17), chronic obstructive airway disease (n=15), Killip class IV heart failure or death before recruitment (n=18), and patient residence outside our catchment area (n=11). The remaining 40 had miscellaneous reasons such as malignancy, left bundle-branch block, insulin-dependent diabetes, and advanced heart block.
A total of 151 patients were randomized to either carvedilol (n=77) or
placebo (n=74); 146 were analyzed for efficacy on an
intention-to-treat basis. Four patients (2 from each group) were
excluded because they were found not to have sustained a myocardial
infarction on the basis of the criteria used; 1 patient was found to
have renal failure and was not given study medication. Demographic data
for the 146 patients are given in Table 1
. There were no
differences between the carvedilol and placebo groups; neither were
there any differences between the two groups with respect to previous
drug therapy.
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Concomitant Therapy
Most patients (95%) underwent thrombolysis with
streptokinase; 7 patients received tissue plasminogen
activator. All patients received aspirin, 97% received
heparin, and 80% received either oral or intravenous
nitrates. Diuretics were allowed during the acute phase but
later only for the control of hypertension. There were no differences
between the groups regarding concomitant medication. No patients were
on calcium channel blockers, long-acting nitrates, or ACE
inhibitors during the course of the study, since clinical
requirement for these drugs was a designated end point. The majority
(91%) of patients on carvedilol were on 12.5 mg BID during the
study.
Cardiac End Points
Treatment Period
There were significantly fewer serious cardiac events in the group
treated with carvedilol (n=18) compared with placebo (n=31)
(P<.02; Cox proportional hazards model, Wilcoxon
and log rank tests) despite the small number of patients studied
(n=146). The breakdown of events is shown in Fig 1. Even
after excluding the soft end points of
revascularization and requirement for nonpermitted
cardiovascular medication, the effect of carvedilol
therapy remained significant, with 24 events on placebo compared with
14 events on carvedilol (P<.03). This study was not powered
to detect differences between hard events; however, there was a trend
toward benefit, with 11 deaths or reinfarctions on placebo compared
with 6 on carvedilol—a 45% reduction (P=.12). Of the 12
patients (n=8 on placebo and 4 on carvedilol) who had reinfarction, 11
occurred in the original infarct territory.
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In the subgroup presenting with acute heart failure at study entry, 34 were on carvedilol and 20 on placebo. None of these patients had any adverse events related to intravenous infusion of the drug, and there was no excess of cardiac events with carvedilol during either the in-hospital phase (6 events on carvedilol, 4 on placebo) or during subsequent follow-up (13 events on carvedilol compared with 9 events on placebo) (P=NS for both). Requirement for intravenous nitrates or diuretics during the acute phase did not differ between the two groups. Additionally, in this subgroup with acute heart failure, patients on carvedilol had significantly greater left ventricular ejection fraction: 45% (10) versus 35% (12), P=.005; lower end-systolic volume: 62 (23) mL versus 80 (30) mL, P=.03; lower wall motion score index: 0.85 (0.47) versus 1.46 (0.62), P<.001; and lower wall motion score at infarct site: 7.7 (3.3) versus 12.2 (4.3), P<.001, compared with placebo, before discharge.
Kaplan-Meier survival curves for carvedilol and placebo groups are
shown in Fig 2. It is clear that separation between the
two groups begins as early as the in-hospital (within day 7) phase, and
the lines continue to separate throughout the treatment phase (6
months).
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Follow-up Period
After withdrawal of treatment at 6 months, 10 patients who had
been on carvedilol had cardiovascular events.
Interestingly, the majority (8) of the events were ischemic
(unstable angina or reinfarction), and 7 of the 10 patients had been
started on treatment with either atenolol (n=4), diltiazem (n=2),
nicardipine (n=3), long-acting nitrates (n=4), or a
combination at study completion. The Kaplan-Meier survival curves for
the full duration of the study are shown in Fig 3; it is evident that
the curves start to converge after carvedilol was withdrawn and that
the difference between the groups no longer remains statistically
significant (P>.05) despite the use of other standard
anti-ischemic drugs.
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Electrocardiography
Carvedilol produced a significant reduction in 24-hour heart rate
trend compared with placebo (Fig 4) during all visits.
Cardiac arrhythmia was not significantly reduced by carvedilol,
but there was wide variability and this may account for the lack of
difference. There were no differences between the groups at any visit
regarding exercise time or ST-segment change (Table 2).
However, patients on carvedilol had a lower heart rate, blood pressure,
and rate-pressure product at peak exercise and at maximal
comparable workloads at all visits (Fig 5).
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Echocardiography
There were no differences in left ventricular ejection
fraction (Table 2
) between the groups at any visit, but stroke volume
values were greater in patients on carvedilol (P<.01) (Fig 6). The diastolic function
parameter, E/A ratio, was significantly greater on
carvedilol than placebo at predischarge examination
(P<.001), demonstrating improved left
ventricular filling (Fig 7).
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Subgroup With Ventricular Dysfunction
There were 49 patients with left ventricular ejection
fraction <45% (24 on carvedilol and 25 on placebo) (Table 3). Despite similar infarct size and
hemodynamic status at study entry, the left
ventricular end-systolic and diastolic
volumes were smaller in the carvedilol group; 79 (22) mL and 121 (29)
mL, respectively, compared with placebo; and 91 (32) mL and 137 (38)
mL, respectively, at predischarge examination. At 3 months, carvedilol
significantly reduced both end-systolic (P<.01) and
end-diastolic (P=.01) volumes; 74 (30) mL and
122 (34) mL, respectively, compared with placebo; and 100 (45) mL and
148 (53) mL, respectively (Fig 8). Carvedilol improved
left ventricular ejection fraction from 35 (8)% at
predischarge examination to 39 (9)% at 3 months compared with placebo
32 (7)% and 34 (10)%, respectively, but the difference was not
significant (P=.06). Wall motion score at the site of
infarction was 11.6 (3.4) in the carvedilol group compared with 12.7
(3.2) in the placebo group at predischarge examination. By 3 months,
there was a significant improvement with carvedilol, 8.3 (4.3) compared
with placebo, 11.4 (5) (P=.02). Similarly, global wall
motion score index was also improved by carvedilol (P=.03)
(Fig 8).
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Serious cardiac events (death, reinfarction, unstable angina,
congestive heart failure, and ventricular
tachycardia) were reduced significantly (n=5 on carvedilol,
n=13 on placebo, P=.04) (Fig 9).
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Safety Data
Hematologic and biochemical evaluations were performed three times
during the study, and there were no differences between the groups.
There were also no differences between the groups regarding creatine
kinase levels. There were no serious adverse events related to
intravenous administration of carvedilol. Adverse events
requiring withdrawal unrelated to cardiac end points were similar (ie,
4 on carvedilol and 3 on placebo). Dizziness was slightly more frequent
on carvedilol (6.5% compared with 1.4%) but did not cause withdrawal
from the study.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In canine models, pretreatment with ß-blocker has been shown to redistribute blood flow to the endocardium, which is usually more jeopardized by the process of ischemia.25 ß-Blockers reduce rate-pressure product, thus reducing oxygen requirement, and may limit infarct size. The progress of infarction, from vessel occlusion to myocardial necrosis, is usually complete within a few hours of onset of symptoms26 and hence any intervention aimed at limiting infarct size and preventing events needs to be initiated early.
In the prethrombolytic era, a large number of trials of ß-blockers, used early, intravenously, and over longer periods, showed benefits such as improvement in chest pain and reduction in infarction size27 as well as reduction in mortality.1 2 3 4 5
However, there has been a quantum change in the management of myocardial infarction since the majority of these studies were performed. The widespread use of thrombolytic therapy and aspirin has greatly reduced mortality. It is not known whether the benefits obtained previously with ß-blockers are still likely to be present. Indeed, in the TIMI II-B study there was no difference in 6-day mortality between the immediate intravenous metoprolol and delayed oral metroprolol groups, but a reduction in nonfatal reinfarction and chest pain was observed.6 However, results from the GUSTO study appear to indicate that in patients given atenolol intravenously there was an increased incidence of shock, congestive heart failure, myocardial ischemia, and requirement for pacing.7 These factors have clearly restricted the widespread use of the standard ß-blocker therapy after AMI. In the GISSI-3 study,28 just 31% of patients were prescribed ß-blockers after myocardial infarction, while in the AIRE study,29 the figure was even lower (22%). While the use of thrombolysis has greatly reduced mortality,19 20 the salvaged myocardium in the infarct-related artery territory is likely to remain at higher risk of future events. An area of such viable but ischemic myocardium may be the cause of angina, myocardial infarction, arrhythmia, and sudden death.19 21 Thus, in the thrombolytic era it may be more difficult to show mortality benefits, and one must investigate the incidence of serious ischemic complications in the postinfarction phase.
Carvedilol has demonstrated potent anti-ischemic,9 cardioprotective,17 and antioxidant18 properties. Its beneficial effects in left ventricular dysfunction are manifested in both idiopathic and ischemic heart failure,12 13 unlike metoprolol30 and bisoprolol,31 which have shown benefits only in dilated cardiomyopathy. This may be due to the effect of carvedilol in improving regional wall motion abnormality in patients with ischemic left ventricular dysfunction.32 This is likely to result in functional improvement in patients with hibernating myocardium, which is often present in patients with ischemic cardiomyopathy33 and after myocardial infarction with thrombolysis.34 Alternatively, the "protective" action of carvedilol may actually lie in its effect of reducing neurohormonal activation.35
Carvedilol significantly reduced double product as the result of
its combined - and ß-blocking activity; it also improved stroke
volume and left ventricular diastolic function
(A/E ratio) but not exercise duration or left ventricular
ejection fraction. However, these patients had relatively good left
ventricular function and exercise capacity, and at each
stage there were fewer patients in the placebo group because of larger
dropouts after events. Hence, patient selection, with clinically better
patients continuing in the placebo group, may have caused this lack of
difference.
Despite the small number of patients and a dose of carvedilol at the lower end of the therapeutic range, there was a potent effect in reducing serious cardiac events during the treatment phase (42%). The main reduction was of the ischemic events, ie, reinfarction, unstable angina, and urgent revascularization, thus demonstrating the effect of the drug on ischemic and jeopardized myocardium after infarction. In this context, it is of note that of the 12 patients with reinfarction (8 on placebo and 4 on carvedilol), 11 occurred at the site of the original infarction. The reduction of "hard events" was 45%, but in view of the small numbers, this failed to reach statistical significance (P=.12). Since introduction of softer events such as revascularization and nonpermitted cardiovascular medication may dilute the results, analysis was also performed with the exclusion of these end points. However, the study still remained statistically significant, with a 42% reduction in events (P<.03).
Patients with heart failure at study entry were unevenly distributed (34 on carvedilol, 20 on placebo), and this may have a bearing on the apparent failure of the drug to reduce the number of patients having heart failure as an end point. It is also worth noting that despite the large number of patients with heart failure at entry, intravenous carvedilol was well tolerated, with no dropouts after infusion. Furthermore, the patients on carvedilol derived benefit in terms of left ventricular ejection fraction improvement and decreased wall motion abnormality. The majority of earlier studies of ß-blockers in AMI have excluded such patients.1 Treatment with intravenous carvedilol in patients with severe chronic congestive heart failure has shown that carvedilol reduces filling pressure.22 This finding is likely to be of influence in the design of future trials of carvedilol in high-risk patients with higher grades of heart failure who may be safely included, thus expanding the therapeutic window to patients who are likely to derive the greatest benefit.
Remodeling, associated with AMI, is characterized by deleterious alterations of left ventricular size, shape, and thickness involving the infarcted and noninfarcted segments of the myocardium,36 and this is affected by infarct size, infarct healing, and loading characteristics (left ventricular distending pressure, inotropic state, heart rate, and neuroendocrine activation).37 38 Progressive remodeling is associated with worsening left ventricular function and poor prognosis.36 39 Acute reperfusion (eg, thrombolysis) and ACE inhibitors reduce remodeling.37 40 Preliminary studies have shown that carvedilol may reverse left ventricular wall motion abnormality in patients with ischemic heart disease with myocardial infarction.32 Furthermore, this drug produces significant reduction in neurohormonal activation in congestive heart failure.41 Our data in the subgroup of patients with ejection fraction <45% after AMI show that carvedilol may have an effect on attenuation of remodeling by decreasing left ventricular size and wall motion abnormality at the infarct site. These effects are associated with a 65% reduction in serious cardiac events.
After stopping carvedilol, 10 patients who had been on the drug subsequently had cardiac events, 8 of which were ischemic (unstable angina and reinfarction). None of the events occurred immediately after withdrawal; thus, a "rebound" phenomenon was absent. Furthermore, 6 patients had events despite treatment with atenolol or diltiazem. Finally, carvedilol had an excellent safety profile.
Conclusions
Carvedilol is a novel, multiple-action vasodilating ß- and
1-blocker with additional properties of cardioprotection
and free radical suppression. This study demonstrates that carvedilol
is safe to use after AMI with or without associated heart failure.
Carvedilol also has the potential to reduce ischemic events and
mortality, but larger trials are required to further elucidate its
beneficial effects.
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Acknowledgments |
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The study was supported by educational grants from the NPH Cardiac Research Fund, Harrow, UK, and Boehringer Mannheim GmbH, Mannheim, Germany. We would like to acknowledge the assistance of Christopher Kinsey, Rita Hamill, Jenny Ralph, Minoo Shah, and Catherine Belling. We would like to thank Caroline Dore and the nursing staff of the coronary care unit. We also would like to acknowledge the late Dr Edward B. Raftery.
Received October 2, 1996; revision received December 16, 1996; accepted January 1, 1997.
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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