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(Circulation. 1997;96:61-68.)
© 1997 American Heart Association, Inc.
Articles |
Comparison of Low-Molecular-Weight Heparin With Unfractionated Heparin Acutely and With Placebo for 6 Weeks in the Management of Unstable Coronary Artery Disease
Fragmin in Unstable Coronary Artery Disease Study (FRIC)
From Graz, Austria (W.K.), Göttingen, Germany (A.B.), Glasgow, UK (S.E.H.), New York, NY ( S.M.), Barcelona, Spain (G.S.), Hamilton, Ontario, Canada (A.G.G.T.), Groningen, the Netherlands (J. van der M.), Pharmacia&Upjohn, Stockholm, Sweden (E.O., S.U.), and Pharmacia & Upjohn, Germany (K.L.).
Correspondence to Prof Werner Klein, MD, Division of Cardiology, Department of Internal Medicine, Auenbruggerplatz 15, A-8036 Graz, Austria.
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Abstract |
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Background Low-molecular-weight heparin has a number of pharmacological and pharmacokinetic advantages over unfractionated heparin that make it potentially suitable, when used in combination with aspirin, for the treatment of unstable coronary artery disease.
Method and Results Patients with unstable angina or non–Q-wave myocardial infarction (1482) were included in the study, which had two phases. In an open, acute phase (days 1 to 6), patients were assigned either twice-daily weight-adjusted subcutaneous injections of dalteparin (120 IU/kg) or dose-adjusted intravenous infusion of unfractionated heparin. In the double-blind, prolonged treatment phase (days 6 to 45), patients received subcutaneously either dalteparin (7500 IU once daily) or placebo. During the first 6 days, the rate of death, myocardial infarction, or recurrence of angina was 7.6% in the unfractionated heparin-treated patients and 9.3% in the dalteparin-treated patients (relative risk, 1.18; 95% confidence interval [CI], 0.84 to 1.66). The corresponding rates in the two treatment groups for the composite end point of death or myocardial infarction were 3.6% and 3.9%, respectively (relative risk, 1.07; 95% CI, 0.63 to 1.80). Revascularization procedures were undertaken in 5.3% and 4.8% of patients in unfractionated heparin and dalteparin groups, respectively (relative risk, 0.88; 95% CI, 0.57 to 1.35). Between days 6 and 45, the rate of death, myocardial infarction, or recurrence of angina was 12.3% in both the placebo and dalteparin groups (relative risk, 1.01; 95% CI, 0.74 to 1.38). The corresponding rates for death or myocardial infarction were 4.7% and 4.3% (relative risk, 0.92; 95% CI, 0.54 to 1.57). Revascularization procedures were undertaken in 14.2% and 14.3% of patients in the placebo and dalteparin groups, respectively.
Conclusions Our results add to previous evidence suggesting that the low-molecular-weight heparin dalteparin administered by twice-daily subcutaneous injection may be an alternative to unfractionated heparin in the acute treatment of unstable angina or non–Q-wave myocardial infarction. Prolonged treatment with dalteparin at a lower once-daily dose in our study did not confer any additional benefit over aspirin (75 to 165 mg) alone.
Key Words: heparin • angina • myocardial infarction
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionInvestigatorsReferences |
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In the treatment of unstable coronary artery disease, therapeutic-dose unfractionated heparin and aspirin are effective in reducing the adverse ischemic outcomes, including death and myocardial infarction.1 2 3 4 The combination of both drugs was found to be most effective.5 Unfractionated heparin has a number of limitations in this setting, however, and reactivation of disease or rebound hypercoagulability has been reported when the drug is discontinued after short-term therapy, although this may be prevented or reduced by the concomitant use of aspirin.6 Low-molecular-weight heparins have pharmacological and pharmacokinetic advantages over unfractionated heparin, including a predictable pharmacokinetic profile, high bioavailability, and long plasma half-life, all of which result in effective levels of anticoagulant activity after subcutaneous administration without laboratory monitoring.7 8 In addition, low-molecular-weight heparins have been found to be as effective or more effective than unfractionated heparin in the treatment of other thromboembolic disorders, including venous thromboembolism9 and ischemic stroke.10 Thus, low-molecular-weight heparins might also have the potential to improve the efficacy and safety of antithrombotic therapy in the management of unstable coronary artery disease.
In a recent study in acute unstable coronary artery disease (FRISC), the low-molecular-weight heparin dalteparin (120 IU/kg) administered twice daily subcutaneously with aspirin was shown to reduce the frequency of death and new myocardial infarction in the acute phase by 63% in comparison with aspirin alone.11 The reduction in ischemic outcomes in this study was similar to that demonstrated in other smaller studies with adjusted therapeutic-dose intravenous unfractionated heparin,1 2 4 5 but large-scale comparisons of the two types of heparin in this indication have yet to be reported.
There are several reasons to believe that prolonged anticoagulant therapy might improve the outcome in unstable angina. First, the risk of ongoing or recurrent ischemia after acute presentation of unstable angina remains increased for 6 to 12 weeks.2 Second, reactivation of the disease process may occur after cessation of short-term heparinization.6 Third, coagulant activity and thrombin generation in this group of patients are increased for several months after the acute event.12 13 Low-molecular-weight heparins have pharmacokinetic properties that allow long-term treatment through subcutaneous injection at home without monitoring and may be beneficial during a prolonged treatment phase.
The aims of this study were to compare the efficacy and safety of weight-adjusted subcutaneous dalteparin, administered twice daily, with those of intravenous unfractionated heparin in the acute treatment of unstable angina or non–Q-wave myocardial infarction and, primarily, to investigate the value of prolonged treatment with dalteparin at a lower dose in comparison with placebo in patients initially anticoagulated for a period of 5 to 8 days. All patients received aspirin throughout the study.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionInvestigatorsReferences |
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Study Design
The FRIC study was prospective, randomized, multinational, and parallel group in design and had two phases. In the acute phase, between days 1 and
6 after randomization, patients with unstable
coronary artery disease received open treatment with either
dalteparin, administered by twice-daily subcutaneous injection, or
unfractionated heparin, administered at first by continuous
intravenous infusion (for 
48 hours) and then by
subcutaneous injection. In the double-blinded prolonged-treatment
phase, between days 6 and 45 after randomization, dalteparin,
administered by once-daily subcutaneous injection, was compared with
placebo. Randomization for each of the two phases was performed once at
the beginning of the study. Clinical follow-up and resting ECGs were undertaken in all patients at 3 months after randomization.
Eighty-one centers in nine countries (Austria, Canada, Germany, Italy, the Netherlands, Norway, Spain, UK, and the United States of America) participated in the study. Approval of the protocol was obtained at each center from the appropriate authority.
Patients
Consecutive male or female patients presenting with chest
pain were potentially eligible for inclusion in the study if they
satisfied the clinical criteria for unstable coronary artery
disease according to a modified Braunwald
classification.14 Admission to the study had to be within
72 hours of the last episode of chest pain, and the ECG on admission
had to show either one or both of the following abnormalities in at
least two adjacent leads: temporary or persistent ST-segment depression
of 0.1 mV and/or temporary or persistent T-wave inversion of 0.1 mV
below baseline without corresponding Q waves. Patients who subsequently
had biochemical evidence of a non–Q-wave myocardial infarction
remained eligible.
Patients were excluded if they had any of the following: newly
developed Q waves; left bundle-branch block on ECG; an indication for
thrombolytic therapy; a pacemaker; known primary
myocardial disease, septic endocarditis, pericarditis, or aortic
valvular disease of hemodynamic significance;
any known defect of hemostasis; ongoing treatment with oral
anticoagulants or heparin (if administered for >12 hours or if the
total dose received was >10 000 IU); diastolic blood
pressure >120 mm Hg or systolic blood pressure <90
mm Hg; fever with temperature 39°C; hemoglobin <125 g/L if male
or <110 g/L if female; known renal or liver insufficiency; a history
of a cerebrovascular event, peptic ulceration, or gastrointestinal
bleeding within 3 months of admission; surgery of any type within 1
week or eye or ear surgery or neurosurgery within 1 month of admission;
malignancy or other diseases of unfavorable prognosis; or known
hypersensitivity to aspirin, unfractionated heparin, or
low-molecular-weight heparin.
Patients in whom PTCA or CABG was planned within 3 weeks of admission were also excluded, as were women who were pregnant or lactating and any person for whom the at-home administration of study treatment was likely to be difficult.
Eligible patients who gave their written informed consent were randomized at entry to treatment in both phases of the study. Instructions for treatment allocation during the open phase and coded treatment during the double-blinded phase were obtained for each patient by telephone from a randomization center in each country.
Treatment Regimens
Aspirin (75 to 165 mg/d) was started in all patients as soon as
possible after admission to hospital and continued throughout the
study. Other antianginal medications were administered according to the
standard practice at each center.
Treatment was started as soon as possible after randomization and within 72 hours of the last episode of chest pain. In the open phase of the study, patients randomized to weight-adjusted low-molecular-weight heparin received dalteparin (120 IU/kg) by subcutaneous injection every 12 hours. Those randomized to unfractionated heparin received an initial intravenous bolus of 5000 IU followed, within 2 hours, by a continuous infusion at a rate of 1000 IU/h adjusted to maintain the aPTT at 1.5-fold the control value. The aPTT was measured 6 and 12 hours after the start of the infusion and daily thereafter. The infusion could be maintained throughout the acute phase or stopped after a minimum of 48 hours and replaced within 8 to 12 hours with a subcutaneous regimen of unfractionated heparin (12 500 IU every 12 hours).
Low-molecular-weight heparin (dalteparin [Fragmin], Pharmacia & Upjohn) was provided at a concentration of 10 000 IU/mL. Unfractionated heparin was provided by Pharmacia & Upjohn according to local preference.
In the second, double-blind phase of the study, dalteparin (7500 IU) or saline in prefilled syringes (0.3 mL) was administered subcutaneously in a fixed single-daily dose. Before discharge from hospital, all patients were instructed in the self-injection technique.
Outcomes
The principal outcomes of the study were death, myocardial
infarction, and recurrence of angina during the double-blinded
phase (days 6 to 45) of the study. The primary analysis of
efficacy was a comparison of the composite of the principal outcomes
between the two treatment groups. Only one outcome was counted for
each patient; where two occurred, death was counted before myocardial
infarction, and myocardial infarction was counted before recurrent
angina.
A patient was considered to have had a myocardial infarction if the event was confirmed by serial ECG examination or if two of three other diagnostic criteria were met: prolonged ischemic chest pain, ECG evolution suggestive of myocardial infarction according to the Minnesota code, and elevation of relevant cardiac enzymes (CK-MB greater than the upper normal limit or total CK greater than twice the usual upper limit). (The final decision was made by the blinded Steering Committee, which did not include Pharmacia & Upjohn personnel.) In hospitalized patients, recurrence of angina was defined as any anginal chest pain that required a nitroglycerin infusion to be restarted. The decision was made by the treating physician. The episode had to be new and unrelated to the event that led to the inclusion of the patient in the study. In patients who had been discharged from hospital, recurrence of angina was defined as any new episode of angina requiring readmission to hospital and the institution of a nitroglycerin or heparin infusion.
The secondary outcomes were death, myocardial infarction, and recurrence of angina occurring in the acute phase of the study (before the first injection of dalteparin or placebo in the double-blinded phase), revascularization by PTCA or CABG during either phase of the study, and ischemia during exercise testing. The indications for angiography and revascularization were predetermined and were the same in all the study centers. Thus, angiography was indicated in all patients with refractory angina despite medication or significant ischemia or inadequate circulatory response during the initial exercise test evaluation. Revascularization was indicated in those patients subsequently shown to have left main vessel disease, three-vessel disease, left anterior descending coronary artery stenosis (75%), or disabling angina with significant coronary stenosis. Exercise tests were undertaken in all suitable patients at the end of the first and second phases of the study; these results will be reported separately.
Safety was also considered a secondary outcome; the main variables
that were studied were major or minor bleeding, thrombocytopenia
(platelet count <100x109/L), and allergic reactions.
A bleeding event was classified as major if it led to a fall in the
hemoglobin level of 20 g/L, required transfusion, was intracranial,
or caused death or cessation of the study treatment.
Additional Investigations
Resting ECG was performed before and 2 days after inclusion in
the study. It was repeated at the end of the first (days 5 to 8) and
second (day 45) phases of the study and after 3 months. Hemoglobin
levels and platelet counts were measured according to a similar
schedule. Serial cardiac enzymes (CK, CK-MB, ASAT according to local
routine), serum creatinine, and the international
normalized ratio (INR) were measured at the start of the study. Cardiac
enzymes were also measured in the event of a new episode of angina or
myocardial infarction. aPTT was measured according to the standard
method of each study center and at the times previously described.
Anti–factor Xa activity in patients receiving dalteparin in the acute
phase was measured in blood samples taken before the injection and at 2
and 6 days after randomization for retrospective
analysis.
Statistical Analysis
Sample sizes were based on the assumption that the composite
incidence of the primary outcomes would be 10% in placebo-treated
patients and 5% in dalteparin-treated patients during the prolonged
treatment phase of the study (days 6 to 45). It was also assumed that
40% of patients would have a primary outcome or be withdrawn for some
other reason in the first phase of the study and would not progress to
the second phase. We therefore calculated that 1500 patients would need
to be randomized to detect a treatment difference in a two-sided test
with significance level of .05 and a power of .80. The trial did not
have sufficient power to show equivalence of heparin and dalteparin in
the acute phase.
Efficacy variables were analyzed according to the intention-to-treat principle, and 95% CIs were calculated for the incidence of all events. Treatment comparisons were made using the Cochran-Mantel-Haenszel test and Fisher's exact test. The time to occurrence of cardiac events was analyzed by a log rank test.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionInvestigatorsReferences |
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Between March 1993 and April 1995, 1499 patients entered the study and were randomized to treatment in both phases. Of these, 17 were randomized but excluded from all subsequent analyses because they did not receive any study treatment. Of the remaining 1482 patients, 731 were assigned to initial treatment with unfractionated heparin and 751 were assigned to receive dalteparin.
During the acute phase (days 1 to 6), 350 patients (166 in the
dalteparin group and 184 in the heparin group) were withdrawn from the
study on account of thrombolytic therapy (4 to 1) due
to myocardial infarction, myocardial infarction (22 to 30) or need for
heparin infusion (29 to 19), a serious adverse event (11 to 13),
coronary revascularization (45 to 48),
patient request (28 to 29), or other reasons (eg, intercurrent illness,
epidural anesthesia, renal insufficiency) (27 to 40). Thus,
1132 patients entered the second, prolonged-treatment phase of the
study, and 1126 were included in the intention-to-treat evaluation (562
in the dalteparin group and 564 in the placebo group). The
characteristics of the patients (median age, 65 years) in the two
treatment groups of each phase of the study were comparable at baseline
(Table 1
). Overall, 64% of patients were male and 36%
were female. Eighty-four percent had unstable angina, and 16% had a
non–Q-wave infarction. A history of hypertension or previous
myocardial infarction was recorded in 39% and 25% of patients,
respectively, and 56% of patients were receiving aspirin at entry.
Current smokers represented 27% of the study population at
baseline. During the acute phase, 56% of patients received a
ß-blocker; 52%, a calcium channel blocker; 70%, an oral nitrate;
and 8%, digitalis. As stipulated in the protocol, all patients
received aspirin.
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Acute Phase
During the first 6 days, comparable rates of the individual or
combined outcomes of death, myocardial infarction, or
recurrence of angina were observed in the two treatment groups
(Table 2). The combined outcome occurred in 7.6% and
9.3% of patients treated with intravenous unfractionated
heparin and dalteparin, respectively (relative risk, 1.18; 95% CI,
0.84 to 1.66). The corresponding rates of the composite of end point of
death or myocardial infarction were 3.6% and 3.9% (relative risk,
1.07; 95% CI, 0.63 to 1.80). Revascularization
procedures were undertaken in 5.3% of unfractionated heparin-treated
and 4.8% of dalteparin-treated patients. The hazard curves showed no
difference in the timing of the clinical outcomes in each group (Fig 1). P values are listed in Table 2.
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Adverse events during the acute phase were rare and are summarized in
Table 3.
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Prolonged-Treatment Phase
Between days 6 and 45, the frequency of the combined clinical
outcomes of death, myocardial infarction, or recurrence of
angina was 12.3% in both treatment groups (relative risk, 1.01; 95%
CI, 0.74 to 1.38) (Table 4). The frequencies of the
individual outcomes were also similar. The composite end point of death
or myocardial infarction occurred in 4.7% and 4.3% of patients
assigned to receive placebo and dalteparin, respectively (relative
risk, 0.92; 95% CI, 0.54 to 1.57).
Revascularization procedures were undertaken in
14% of patients in each group.
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The hazard curves showed no difference throughout the 6-week period in
the occurrence of death or myocardial infarction or the
recurrence of angina in the two groups (Fig 2).
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The similarity of the event rates in the two treatment groups was
consistent across all the predefined subgroups, including those
with non–Q-wave infarction, smokers, and nonsmokers (Table 5).
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As in the acute phase, adverse events occurred infrequently
(Table 3
). The two groups differed only in the frequency of minor
bleeding events; these occurred in 2.8% of the patients receiving
placebo compared with 5.1% of those receiving dalteparin. No patient
in either group developed thrombocytopenia in this phase of the
study.
The results of the exercise tests will be reported elsewhere.
Compliance and Withdrawals
Compliance during the prolonged-treatment phase with the
once-daily injection of either dalteparin or placebo was good. The
median number of self-administered injections recorded during this
period was 38 (range, 0 to 50) in the placebo group and 38 (range, 0 to
52) in the dalteparin group. In total, 27 patients withdrew from the
study between days 6 and 45 at their own request, of whom 19 and 8 had
been assigned to dalteparin and placebo, respectively. Other reasons
accounted for the withdrawal of an additional 50 patients (27 on
dalteparin and 23 on heparin), mostly minor adverse events such as
hematoma.
Anti–Factor Xa Activity and aPTT Values in the Acute
Phase
The median preinjection anti–factor Xa activity in the
dalteparin-treated patients was 0.35 IU/mL (range, 0.0 to 1.50) on day
2 and 0.37 (range, 0.00 to 1.46) on day 6.5 6 7 8 Of the
patients assigned unfractionated heparin in the acute phase, 21%
received an intravenous infusion throughout, whereas 79%
went on to receive subcutaneous injections at a mean time of 57 hours
after the initial infusion.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionInvestigatorsReferences |
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The approach to treatment in the present study was the conservative one outlined in treatment guidelines that were prevalent when the study was started.14 Thus, although our purpose was to compare dalteparin and unfractionated heparin in the acute phase and dalteparin and placebo in the prolonged-treatment phase, patients considered to be at high risk of death or myocardial infarction underwent PTCA or CABG at any time, at the discretion of the local investigator. During the study,
7% of the patients died or had an
acute myocardial infarction, with approximately half of these events
occurring during the acute phase and half during the subsequent 5
weeks. Revascularization procedures were undertaken
in 15% of the entire population. Whether a greater readiness to
undertake PTCA or CABG in this group of patients would result in a
lower rate of serious complications is being debated currently but no
large-scale comparisons of the conservative and aggressive strategies
have been reported. The frequency of the combined clinical outcome of death, myocardial infarction, and recurrence of angina was similar during 6 days of treatment with either dalteparin (120 IU/kg twice daily) or aPTT-monitored intravenous unfractionated heparin, and the rates of revascularization procedures in the two groups were comparable. In view of the relatively small number of deaths in either group, the marginally significant excess early mortality with dalteparin was, in our opinion, probably a chance finding. Therefore, although not dimensioned to show equivalence of these two anticoagulant regimens in the acute phase, this study supports the evidence suggesting that body weight–adjusted low-molecular-weight heparins administered subcutaneously twice daily can be used as an alternative to intravenous unfractionated heparin in this indication.15 This is an important practical advance over current therapy. Low-molecular-weight heparins can be administered subcutaneously to give a predictable anticoagulant response without laboratory monitoring. Thus, they have the potential to markedly improve the clinical utility of anticoagulant therapy.
In the prolonged-treatment phase, between days 6 and 45, the frequency of the combined outcome of death, myocardial infarction, or recurrence of angina was similar in both dalteparin- and placebo-treated patients, a finding that was consistent across all the predefined subgroups, including those with or without non–Q-wave infarction, smokers, and nonsmokers. There were no differences between the two treatment groups in the rates of revascularization procedures.
Given the clear added benefit over aspirin alone of initial anticoagulation with either unfractionated or low-molecular-weight heparin in patients with unstable coronary artery disease1 2 6 11 and evidence that the underlying lesion remains active with accompanying thrombin generation for several weeks after the initial event,2 12 13 the reason for the apparent lack of benefit of prolonged treatment with low-molecular-weight heparin in this study is unclear. It is possible that after initial treatment with aspirin plus unfractionated heparin or low-molecular-weight heparin, continued treatment with aspirin may be sufficient to prevent important clinical outcomes in a low risk subset of patients—an inevitable feature of the conservative strategy used in this study was that high-risk patients were filtered out during the acute phase. This would seem unlikely, however, as aspirin has no direct effect on thrombin generation or action.
Another explanation is that the dose of low-molecular-weight heparin used in the prolonged-treatment phase of our study was too low or the interval between injections was too long to provide 24-hour anticoagulant cover. When this study was designed, it was hypothesized that thrombotic activity associated with acute unstable coronary artery disease decreased after the acute phase and that lower doses of anticoagulant would suffice. Our results indicate that this is not the case and that periods of inadequate anticoagulant activity in some patients might have permitted the reemergence of thrombosis. In FRISC, prolonged treatment with dalteparin led to a trend toward reduced death and myocardial infarction even when the dose of dalteparin was reduced to half that which was found to be effective in the acute phase.11 It is possible, however, that greater benefits would have been observed if weight-adjusted twice-daily dalteparin had also been used for the prolonged treatment. This is supported by the results of a study of low-molecular-weight heparin in ischemic stroke in which greater efficacy was achieved with twice-daily than with once-daily dosing.10
How patients would view twice-daily injections is open to speculation, although compliance with the once-daily regimen used in this study was excellent. This suggests that a future study with higher and more frequent doses of dalteparin is at least feasible.
Study Limitations
It should be stated that the trial was not powered to detect a
difference between heparin and dalteparin in the acute phase.
Furthermore, this part of the study was not blinded. However, the
almost identical incidence of recurrent angina, myocardial infarction,
and need for revascularization in both groups
(Table 2) strongly suggests equivalence of both treatment regimens,
despite a borderline difference in mortality. Intravenous
heparin obviously is very effective in acute coronary syndromes
but is usually discontinued after 48 to 72 hours, whereas there clearly
is ongoing risk for cardiovascular complications for
7 days.
Conclusions
The present study indicates that the low-molecular-weight
heparin dalteparin administered by twice-daily subcutaneous injection
is a safe and effective alternative to unfractionated heparin in the
acute treatment of unstable coronary heart disease. There is,
however, no evidence from this study that prolonged treatment with
dalteparin at a reduced dose in addition to aspirin confers any
additional benefit over aspirin alone. These data do not preclude a
benefit to prolonged treatment with a more intense level of
anticoagulation.
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Investigators |
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TopAbstractIntroductionMethodsResultsDiscussionInvestigatorsReferences |
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Spain: J. Bosch (Barcelona), L. Saenz (Barcelona), J. Masip (Barcelona), V. Valle (Badalona), M. Garcia Moll (Barcelona), A. Cabadés (Valencia), A. Pajarón (Santander), A. Loma-Osorio (Vitoria), F. Malpartida (Málaga), L. Lopéz Bescos (Madrid), R. Masia (Gerona); Austria: K. Silberbauer (Eisenstadt), N. Elbl (Wolfsberg), W. Rainer (Knittelfeld), K. Zeuschner (Voitsberg), G. Stöckl (Feldbach), W. Kronik (Krems), J. Borkenstein (Leoben), W. Weihs (Graz), H. Seewann (Fürstenfeld), L. Marosi (Wr. Neustadt), H. Wimmer (Villach), W. Schellnegger (Bruck an der Mur); Germany: A. Buchwald (Göttingen), K. Möller (Göttingen), Ch. Unterberg (Göttingen), J. Neubaur (Wolfenbüttel), P. Mysliwietz (Wolfenbüttel), U. Leithäuser (Wolfenbüttel), W. Lieb (Alfeld), H. Duwald (Alfeld), H. Krönert (Eschwege), T. Eggeling (Eschwege), M. Kunze (Suhl), P. Kindler (Suhl), S. Müller (Jena), R. Thiele (Jena), H.P. Pohl (Jena), A. Schmidt (Stuttgart), U. Kroschel (Stuttgart), W. Jansen (Leverkuen), B. Engels (Leverkusen), R. Prenzel (Leverkusen), W. Petermann (Paderborn), R. Kröning (Paderborn), M. Sude (Paderborn), J. Dyckmans (St Ingbert), B. Trapp (St Ingbert), O. Schöne (St Ingbert), G. Rettig-Stümmer (Sulzbach), F. Heieck (Sulzbach); UK: B. Vallance (East Kilbride), H. McAlpine (Glasgow), T. Fyfe (Glasgow), A.P. Rae (Glasgow), F.G. Dunn (Glasgow), D. Matthews (Stone House), C. Rodger (Airdrie), J. Gemmill (Ayr), A. Scriven (Leicester), C. Forfar (Oxford), S. Campbell (Sheffield), D. Birnie (Glasgow), S. Hood (Glasgow), M. Carpenter (Leicester), S. Firoozan (Oxford), M. Malekianpour (Glasgow), J. Ahmed (Sheffield); Canada: T.D. Ruddy (Ottawa), R.M. Prewitt (Winnipeg), J.R. Leclerc (Montreal), B.A. Sussex (St Johns), D.L. Roth (Calgary), S. Nawaz (Sudbury), C. Pilon (Hamilton), J.B. Gill (Hamilton), S.N. Sinha (Winnipeg), Y. Latour (Montreal); United States of America: P. Mehta (Greenville), A. Kahn (Greenville), E.K. Weir (Minneapolis, Minn), S. Archer (Minneapolis, Minn), E. Amsterdam (Sacramento, Calif), C.T. Kappagoda (Sacramento, Calif), J.T. Holder (Bellevue), R.W. Lee (Scottsdale, Ariz), C. Eng (New York, NY); the Netherlands: E.J.A.M. Göbel (Groningen), D. Rehorst (Delft), J.P.M. Saelman (Hoogeveen), L.M. Van Wijk (Stadskanaal), M.R. Van der Linde (Drachten), J.J. De Graaf (Drachten), A.C.M. Ligtenberg (Drachten), A.J. Funke Küpper (Haarlem), S.P.M. Twisk (Delzijl); Italy: F. Acquati (Varese), I.S. Caico (Varese), A.F. Cozzi (Varese), C. Carella (Varese), C. Brunelli (Genova), A. Iannone (Genova), P. Chiavacci (Padova), A.V. Mattioli (Modena), A. Maresta (Faenza), L. Pirazzini (Faenza), E. Varani (Faenza), R. Fusco (Milano), S. Savonitto (Milano), G. Colonna (Roma), A. Rebuzzi (Roma), F. Stazi (Roma), D. Bracchetti (Bologna), A. Rubboli (Bologna), A. Maseri (Roma), A. Mafrici (Roma), M. Paolucci (Roma); Norway: A. Rollag (Nordbyhagen), B. Henestam (Stavanger), F. Kontny (Oslo), J. Erikssen (Nordbyhagen), B. Wik (Kristiansand), D.W.T. Nilsen (Stavanger); additional country coordinators: A. Maseri, Italy, and J. Dale, Norway; Safety Committee: D. Julian (London, UK), W. Rutishauser (Geneva, Switzerland), and B. Schneider (Hannover, Germany); data management and statistics: K. Wiklund and G. Ekman (Pharmacia & Upjohn).
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by Pharmacia & Upjohn (Stockholm, Sweden). We thank the many physicians, nurses, and monitoring personnel who made this study possible and, above all, the patients for their participation.
Received September 12, 1996; revision received December 10, 1996; accepted January 1, 1997.
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TopAbstractIntroductionMethodsResultsDiscussionInvestigatorsReferences |
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