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To compare the efficacy and safety profile of dalteparin, a low-molecular-weight heparin with a standard unfractionated heparin in patients with unstable angina pectoris.
This was a 6-month, prospective, parallel, randomized and open-labeled study. Patients of angina pectoris were randomized to receive either unfractionated heparin or dalteparin for 5 days. They were followed for 21 days during three visits on 1st, 5th and 21st days. A series of resting electrocardiogram were undertaken in all patients on each visit.
The frequency of the combined clinical outcome of death, myocardial infarction and recurrence of angina was similar during 21 days of follow-up with either dalteparin or intravenous unfractionated heparin. In patients who received dalteparin 2.43% patients developed minor bleeding in the form of epistaxis and 2.5% patients who received unfractionated heparin developed minor bleeding in the form of macroscopic hematuria.
Dalteparin is as effective and safe as unfractionated heparin in the treatment of unstable angina. Dalteparin does not require routine laboratory monitoring as with unfractionated heparin.
Unstable angina is a severe form of angina pectoris, which may occur at rest as well as with minimal exertion. It is a serious, chronic life-threatening coronary artery disease. The disease process extends from coronary vasospasm to thrombus formation and from no significant stenosis to severe three-vessel disease.
Aspirin, an antiplatelet agent, effectively reduces short term and long-term risks of myocardial infarction after an episode of unstable coronary artery disease. Antithrombotic therapy, consisting of intravenous infusion of unfractionated heparin plus oral aspirin represents the current line of treatment for patients hospitalized with unstable angina. However, this treatment has a substantial failure rate, probably because of the unpredictable anticoagulant response to standard unfractionated heparin as well as its neutralization by protein binding and activated platelets. The low-molecular-weight heparins have several advantages over unfractionated heparin. They have a more predictable anticoagulant effect with a higher ratio of antifactor Xa to antifactor IIa. They do not require laboratory monitoring of anticoagulation, they are resistant to inhibition by activated platelets and have lower incidence of heparin-induced thrombocytopenia.
The purpose of present study was to evaluate and compare the efficacy and safety profile of dalteparin, a low-molecular-weight heparin with a standard unfractionated heparin in patients with unstable angina pectoris
This work was carried out for 6 months at a tertiary care hospital at Miraj. It was a prospective, parallel, randomized and open-labeled study. An approval was obtained from Institutional Ethics Committee. All the patients registered in the ‘In Patient Department’ and ‘Intensive Care Unit’ were screened. An informed, written and signed consent was obtained before enrollment. Patients with severe angina pectoris of either sex within the age group of 35–75 years were included. They were either newly diagnosed patients or having angina at rest or having severe and or frequent episodes of angina.
The following categories of patients were excluded from the study: Patients with increased risk of bleeding, ulcer disease or known gastrointestinal bleeding during last 5 years or those who had a surgery during previous week or a surgery of eye, ear or cerebroneuronal system during previous month or those with known defects of hemostasis, platelet count less than 50% of normal, left bundle branch block or pacemaker electrocardiogram, hypersensitivity to study drugs and pregnant or nursing women. A total of 81 patients fulfilled the inclusion criteria and were selected for the study. They were randomized into two parallel groups. Group I (41 patients) received treatment with dalteparin, 120 IU/kg body weight sc, twice a day for 5 days. Group II (40 patients) received unfractionated heparin initially as an intravenous bolus of 5000 IU followed within two hours by continuous infusion at a rate of 1000 IU/ hour adjusted according to activated partial thromboplastin time (aPTT).
The aPTT was measured 6 and 12 hours after the start of the infusion and daily thereafter. The infusion could be maintained for 5 days or stopped after a minimum of 48 hours and replaced within 8-12 hours with a subcutaneous regimen of unfractionated heparin (12,500 IU every 12 hours).
Aspirin was started in all patients as soon as possible after admission to hospital and continued throughout the study. Other antianginal drugs were started according to standard practice. The patients were followed up at three visits on 1st, 5th and 21st days. A series of resting electrocardiogram were undertaken in all patients on each visit. The primary analysis of efficacy was a comparison of frequency of recurrent angina, myocardial infarction, death and need for revascularization by percutaneous transluminal angioplasty or coronary artery bypass grafting in two study groups. The secondary analysis was a comparison of the composite of the principal outcomes i.e., death, myocardial infarction and recurrence of angina between two study 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. Angiography was indicated in all patients with refractory angina despite medication. Safety was monitored by studying the parameters like major or minor bleeding, stroke (hemorrhagic, nonhemorrhagic) thrombocytopenia and allergic reactions.
Statistical analysis for efficacy was based on 81 patients with unstable angina pectoris having completed the study. The efficacy parameters tested were frequency of recurrent angina, myocardial infarction, death and need for revascularization procedures and composite outcome of death, myocardial infarction and recurrent angina. Statistical analysis for safety was based on 81 patients (40 on unfractionated heparin and 41 on dalteparin) enrolled in the study. Z-test was applied for the analysis of efficacy and safety results and group comparisons. P-value<0.05 was considered statistically significant.
The baseline clinical characteristics of patients receiving unfractionated heparin and dalteparin were comparable with respect to type of angina, baseline ECG changes and associated risk factors [Tables [Tables11 and and22].
The recurrence of angina was seen in 2.5% patients of each group within 5 days. During the next follow-up it was found that 2.5% patients of unfractionated heparin group and 4.87% patients of dalteparin group. The total rate of recurrence was 7.31% in dalteparin group and 5.0% in unfractionated heparin group. The frequency of recurrent angina in two study groups was found to be statistically insignificant (P>0.05).
Nearly the same number of patients who received unfractionated heparin (2.5%) and those who received dalteparin (2.4%) developed a fresh episode of myocardial infarction within 5 days of therapy. The frequency of the combined clinical outcome of death, myocardial infarction and recurrence of angina was similar during 21 days of follow-up with the either regimen (9.75% in dalteparin group and 7.5% in unfractionated heparin group). Moreover, 5% patients who received unfractionated heparin were posted for revascularization as compared to 4.87% of patients who received dalteparin. There was no statistical significant difference between these two groups as far as myocardial infarction, combined clinical outcome and need for revascularization were concerned.
In the present study, no serious adverse effects were encountered in any patient of either group that warranted stoppage of medication. In patients who received dalteparin 2.43% patients developed minor bleeding in the form of epistaxis and 2.5% patients who received unfractionated heparin developed minor bleeding in the form of macroscopic hematuria. This difference in the frequency of adverse effects between the two groups was statistically insignificant (P>0.05).
Several randomized clinical trials have demonstrated that low-molecular–weight heparins are at least as good as, if not better than, unfractionated heparin in preventing perioperative deep venous thrombosis and thromboembolism after major abdominal surgery and total hip or knee arthroplasty.[6–8] Recently, clinical trials have been published indicating that low-molecular–weight heparins may be beneficial in arterial diseases.[9–12]
The present study was undertaken to evaluate and compare the efficacy and safety profile of dalteparin and unfractionated heparin in patients with unstable angina. Out of 81 patients included in the study 41 were randomized to receive dalteparin and 40 were randomized to receive unfractionated heparin. The two groups were similar with respect to demographic characteristics like age, sex, weight, Braunwald class of angina and medication at entry. The base-line electrocardiographic changes and risk factors associated with the disease did not differ significantly among the two study groups. The parameters of primary importance to compare the efficacy of dalteparin with unfractionated heparin were incidence of recurrent angina, incidence of myocardial infarction, measurement of composite outcome of death, myocardial infarction and recurrent angina and the need for revascularization procedures.
The total rate of recurrence of angina was 7.31% in dalteparin group and 5.0% in unfractionated heparin group. Similar rate of recurrent angina 8.4% in the dalteparin group was noted in a study conducted by FRISC (Fragmin during Instability in coronary artery disease) study group. Similar to the present study, this also showed an initial reduction in recurrence of angina maintained during acute phase of the trial while there was loss of protection from recurrent angina after withdrawal of low-molecular-weight heparin.
In FRIC (Fragmin in unstable coronary artery disease) study, prolonged treatment with dalteparin led to a trend towards the reduced recurrence of angina even though the dose of dalteparin was reduced to half of that, which was found to be effective in the acute phase of trial. Klein et al, concluded that greater benefits would have been observed if body weight adjusted dose of dalteparin had been used twice daily for prolonged treatment.
We observed that similar number of patients on unfractionated heparin and dalteparin developed a fresh episode of myocardial infarction within 5 days of therapy. These findings are also in accordance with the study conducted by Klein et al, wherein frequency of myocardial infarction was 2.6% in patients who received dalteparin during the acute phase of the trial. Similarity of these results might be due to the same dosage regimen and same duration of therapy used during the trials.
The frequency of the combined clinical outcome of death, myocardial infarction and recurrence of angina was similar during 21 days of follow-up with either dalteparin or aPTT-monitored intravenous unfractionated heparin. These results are also similar to those reported by Klein et al, wherein the composite outcome of death, myocardial infarction and recurrent angina was 9.3% in dalteparin group and 7.6% in unfractionated heparin group, during the acute phase of the trial. We also observed that the need for revascularization was about 5% in both the groups. It was found to be significantly more in a study conducted by Cohen et al, (27% in low-molecular-weight heparin group as compared to 32% in unfractionated heparin group). The higher need for revascularization in that study was probably because of greater number of of high-risk patients therein. After studying the above stated efficacy parameters it can be concluded that the efficacy of dalteparin was comparable to unfractionated heparin. Our observations also indicate that the safety of dalteparin was comparable to that of unfractionated heparin, in the treatment of unstable angina pectoris. It has been noted by others that dalteprin has a predictable dose response and can be administered as a standard single daily subcutaneous dose for all patients. The long-term dalteparin treatment is also not associated with any increased risk of thrombocytopenia, allergic reactions or fractures.[14,15] Hence, it can be concluded that treatment with dalteparin 120 IU/kg sc, twice daily, in addition to aspirin along with other antianginal drugs, should be considered for at least 5 days in all patients with unstable angina to ameliorate symptoms and reduce the risk of new cardiac events. As per the results of FRIC study, a prolonged treatment with body weight adjusted dose of dalteparin twice daily can also be advocated.
Source of Support: Nil.
Conflict of Interest: None declared.