|Year : 2015 | Volume
| Issue : 1 | Page : 90-94
A comparison of enoxaparin with unfractionated heparins in patients with coronary heart disease in an emergency department in rural South Indian tertiary care teaching hospital
Akram Ahmad1, Isha Patel2, Himani Asani3, M Jagadeesan3, S Parimalakrishnan3, S Selvamuthukumaran4
1 Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, UCSI University, No. 1 Jalan Menara Gading, UCSI Heights, Cheras 56000, Kuala Lumpur, Malaysia; Department of Pharmacy Practice, Annamalai University, Tamil Nadu, India
2 Department of Biopharmaceutical Sciences, Shenandoah University, Winchester, VA, USA
3 Department of Pharmacy Practice, Annamalai University, Tamil Nadu, India
4 Department of Medicine, Rajah Muthiah Medical College and Hospital, Annamalai University, Tamil Nadu, India
|Date of Submission||04-Aug-2014|
|Date of Decision||01-Oct-2014|
|Date of Acceptance||20-Dec-2014|
|Date of Web Publication||30-Jan-2015|
Dr. Akram Ahmad
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, UCSI University, No. 1 Jalan Menara Gading, UCSI Heights, Cheras 56000, Kuala Lumpur, Malaysia; Department of Pharmacy Practice, Annamalai University, Tamil Nadu, India
Source of Support: None, Conflict of Interest: None
Aim: Antithrombotic therapy with heparin plus antiplatelets reduces the rate of ischemic events in patients with coronary heart disease. Low molecular weight heparin has a more predictable anticoagulant effect than standard unfractionated heparin, is easier to administer, does not require monitoring and is associated with less ADRs.The purpose of the present study was to evaluate and compare the clinical and cost outcomes of Enoxaparin with a standard unfractionated heparin in patients with coronary heart disease.
Materials and Methods: This was a noninvasive prospective observational descriptive study carried out at a multi-specialty tertiary care teaching hospital situated in rural Tamil Nadu, India. Male and female coronary heart disease (CHD) patients aged 35-75 years newly diagnosed or those having a history of CHD were included. The intervention group received enoxaparin for 5 days. A series of resting the electrocardiogram, prothrombin time and ADRs were measured in all patients during days 1 and 21 respectively.
Results: Compared to unfractionated heparin group of patients, the average prothrombin time was significantly higher (P < 0.0001) whereas hypokalemia was significantly lower (P < 0.02) in enoxaparin group of patients. Even though recurrence of angina and ADRs such as bleeding, nausea, headache and sudden cough occurred less frequently in the enoxaparin group of patients compared to unfractionated heparin group of patients, the differences were not significant.
Conclusions: Antithrombotic therapy with enoxaparin plus aspirin was safer and more effective than unfractionated heparin plus aspirin, in reducing the incidence of ischemic events in patients with unstable angina or myocardial infarction in the early phase.
Keywords: Anticoagulant, coronary heart disease, enoxaparin, safety, and efficacy, unfractionated heparin
|How to cite this article:|
Ahmad A, Patel I, Asani H, Jagadeesan M, Parimalakrishnan S, Selvamuthukumaran S. A comparison of enoxaparin with unfractionated heparins in patients with coronary heart disease in an emergency department in rural South Indian tertiary care teaching hospital. Indian J Pharmacol 2015;47:90-4
|How to cite this URL:|
Ahmad A, Patel I, Asani H, Jagadeesan M, Parimalakrishnan S, Selvamuthukumaran S. A comparison of enoxaparin with unfractionated heparins in patients with coronary heart disease in an emergency department in rural South Indian tertiary care teaching hospital. Indian J Pharmacol [serial online] 2015 [cited 2021 Feb 26];47:90-4. Available from: https://www.ijp-online.com/text.asp?2015/47/1/90/150360
| » Introduction|| |
The burden of non-communicable diseases (NCDs) has increased considerably over the past few decades compared to communicable diseases. Moreover, the majority of people suffering from NCDs reside in developing countries including India. The already inadequate and stretched healthcare systems in these countries are an indication that the mortality due to NCDs is also higher; Nearly 80% people die prematurely in countries that are low income and middle-income. , Coronary heart disease (CHD), a NCD and also called coronary artery disease (CAD) is the leading cause of death in India and worldwide. CHD is a condition where the vascular supply to the heart is impeded by atheroma, thrombosis or spasm of coronary arteries. This may impair sufficient supply of oxygenated blood to cardiac tissue to cause myocardial ischemia that, if severe or prolonged, may cause the death of cardiac muscle cells (myocardial infraction). 
Previously CHD was thought to affect people only in developed countries, but now CHD is responsible for higher mortality and morbidity rates even in developing countries such as India, especially in younger people, with increasingly disproportionate rates.  Data on CHD incidence rates is not available in prospective national cohort registries of CHD in India. In a study by Gupta et al. 2008, it was found that unadjusted CHD rates ranged from 1.6% to 7.4% among people residing in rural areas and 1-13.2% among urban residents respectively.  Gaziano et al., 2006, concluded that the age-standardized CVD mortality rates per 100,000 in people aged 30-69 years were180 in Britain, 280 in China, and 405 in India respectively. Also, 50% of CHD-related deaths in India occur in people <70 years of age compared to only 22% in western countries in a similar age group.  In developed countries, ischemic heart disease is predicted to rise by 30-60% between 1990 and 2020. In developing countries, rates are predicted to increase by 120% in women and 137% in men from 1990 to 2020. 
The most common risk factor for CHD is smoking, diabetes, and hypertension.  Aspirin or clopidogrel (if patients are allergic to aspirin), are antiplatelet agents that effectively reduce short term and long term risks of myocardial infarction after an episode of unstable CAD. Various agents like cholesterol modifiers, antiplatelets, beta blockers, nitroglycerin, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and calcium channel blockers (CCB) are prescribed as monotherapy or combination therapy to treat CAD. , According to standard treatment guidelines (STGs), antithrombotic therapy, consisting of intravenous infusion of unfractionated heparin (UFH) plus oral antiplatelet therapy (aspirin or clopidogrel) represent the current therapy for hospitalized patients with coronary heart disease. ,, This treatment has a high likelihood of being unsuccessful due to unpredictable anticoagulation caused be using standard unfractionated heparin. Also, the standard unfractionated heparin may be neutralized by protein binding and activated platelet. The low molecular weight heparins (LMWH) have several advantages over UFH. They have a more predictable anticoagulant effect with a high ratio of anti-factor Xa to anti-factor IIa, do not require monitoring for anticoagulation, are less likely to cause heparin induced thrombocytopenia and exhibit resistance to activated platelet inhibition. ,
The purpose of the present study was to evaluate and compare the clinical and cost outcomes of CAD patients treated with Enoxaparin versus CAD patients treated with a standard UFH.
| » Materials and Methods|| |
This was a noninvasive prospective observational descriptive study. It was carried out in a multi-specialty tertiary care teaching hospital situated in a rural part of Tamil Nadu, India. It was carried out over a 6 months period; from November 2011 to April 2012.
- Patients with CHD either who were newly diagnosed or those with a history of CHD who have received unfractionated heparin or enoxaparin in the past
- Patients able to give informed consent
- Male and female patients aged 35-75 years.
- Patients receiving anticoagulants other than Enoxaparin and UFH
- Patients with increased risk of bleeding, ulcer disease or known gastro intestinal bleeding during the last 5 years
- Patients who have had an eye, ear or cerebro neuronal system surgery during the previous month
- Patients with known defects of hemostasis, platelet count <50% of normal
- Patients with hypersensitivity to study drugs
- Pregnant or nursing women.
The patients who fulfilled the study criteria were selected for the study. They were divided into two parallel groups. Group 1 received treatment with enoxaparin and group 2 received treatment with unfractionated heparins initially as an IV bolus of 5000 IU followed by a continuous infusion at a rate of 1000 IU/h adjusted according to activated partial thromboplastin time, administered within 2 h. American Heart Association recommends treatment with 75-162 mg of aspirin daily is recommended for type I patients with stable CHD or high-risk type IIb patients with stable CHD.  Aspirin and other medications were administered to both the groups immediately, in accordance with the standard practice after admission to hospital and were continued throughout the study. The patients were followed for two visits on the 1 st and 21 st day respectively. Resting electrocardiogram was administered in all patients during each visit. The choice of the medication (enoxaparin versus unfractionated heparin) received by the patients was made by their physician based on the patient's affordability. An approval for conducting the study was obtained from the Institutional Human Ethics Committee of the hospital. All the patients registered in the Inpatient Department and Coronary Cardiac Intensive Care Unit (CCICU) were screened. An informed consent form was given to the patients.
Clinical parameters such as the average prothrombin time, occurrence of myocardial infarction, recurrence of angina and occurrence of death were analyzed. Occurrence of major or minor bleeding, stroke (hemorrhagic, nonhemorrhagic) thrombocytopenia, hypokalemia and allergic reactions were monitored. Cost comparison analysis was performed by equating individual costs of initial treatment with Enoxaparin and Unfractionated heparin comprising of the costs of hospital services, physician services and 5 days of medication costs (unfractionated heparin/enoxaparin). T-test and the Chi-square test were applied to compare the clinical and costs outcomes of both the drug groups.
| » Results|| |
A total of 113 patients was selected for the study. Patients were divided into two groups: one receiving enoxaparin comprising of 62 patients and other receiving unfractionated heparin comprising of 51 patients. Two groups were similar with respect to demographics such as age, sex, and weight. The baseline electrocardiographic changes and risk factors associated with the disease did not differ among the two study groups. Initially, 152 patients were admitted in CCICU out of which 113 (74.34%) patients were treated with heparins. Remaining participants were excluded from the study due to various reasons such as lack of interest in participating in the study and having received heparins for <5 days. Totally, 68 (60%) participants were males and 45 (40%) participants were females. Majority of the patients (both males and females) had coronary heart disease and were aged below 60 years. Out of 113 patients enrolled in the study, CHD was mostly observed in patients with myocardial infraction (n = 42, 37%) followed by patients with ischemia (n = 39, 35%), patients with unstable angina (n = 20, 17%) and patients with stable angina (n = 12, 11%) respectively. The average weight of the patients was 60.20 kg in unfractionated heparin group and was 59.42 kg in the enoxaparin group. The average number of medications consumed by patients in the unfractionated heparin and enoxaparin group was 9.33 and 8.85, respectively. The most commonly prescribed medications in both the groups were antilipidemics, ACE inhibitors, antiplatelets, nitrates, digitoxin, diuretics and beta blockers. The common comorbidities found in our study were diabetes mellitus, hypertension, bronchial asthma, hypothyroidism and pulmonary edema [Table 1].
[Table 2] represents average prothrombin time, ADRs, and cost comparison analysis in both the unfractionated heparin and enoxaparin groups. Compared to unfractionated heparin group of patients, the average prothrombin time in the enoxaparin group of patients was significantly higher (P < 0.0001). Bleeding (13.72%), hypokalemia (11.76%) and other minor ADRs (nausea, headache and sudden cough) (15.68%) were found more in the unfractionated group of patients compared to bleeding (6.45%), hypokalemia (0%) and other minor ADRs (nausea, headache and sudden cough) (9.67%) in patients consuming enoxaparin. Compared to unfractionated heparin group of patients, hypokalemia was significantly lower in the enoxaparin group of patients (P < 0.02). The cost of illness was calculated for 5 days that the patients stayed in the hospital (costs of hospital care + physician services + 5 days treatment with heparin). The LMWH was given twice a day for 5 days, and the average cost of all three brands was Rs. 457.32 and for unfractionated heparin, it was Rs. 268.72. The medications were given to both the groups 3 times a day for 5 days. The expenditure of the remaining services such as physician fees, laboratory tests and hospital charges were the same for both the groups. The total average cost of the illness of unfractionated group of patients was Rs. 7830.8 and for the LMWH group of patients, it was Rs. 8373.1 [Table 3].
|Table 2: Baseline clinical and cost outcomes in the two treatment groups|
Click here to view
| » Discussion|| |
The present study was undertaken to evaluate and compare the clinical and cost outcomes of enoxaparin and UFH in patients with CAD. CAD patients have several comorbidities such as diabetes, hypertension, and bronchial asthma. As a result, the phenomenon of poly pharmacy is seen in these patients. Previous studies have shown that poly pharmacy leads to more ADRs, drug-drug interactions and increases the disease burden of the patient. The most common medications prescribed in our study were lipid lowering medication, ACE inhibitors, and antiplatelets. Previous studies have shown similar results. 
Coronary heart disease can normally be managed by primary care doctors in outpatient clinics and standard treatment should involve usage of drugs like antiplatelets, antianginals, beta blockers and antilipidemics but during emergency, anticoagulants are used for prophylactic treatment.  Previous randomized clinical trials have shown that LMWH is at least as good as, if not better than, UFH in preventing preoperative deep venous thrombosis and thromboembolism after major abdominal surgery and total hip or knee arthroplasty. , The benefit of LMWHs is not canceled by an increase in hemorrhagic complications. At least two studies , have also documented the superior efficacy and safety of LMWH administered at home as compared to in-hospital intravenous UFH, in treating patients with established deep vein thrombosis. Recently, clinical trials have also been published indicating that LMWH may be beneficial in treating arterial diseases. ,
The parameters of primary importance were to compare the clinical and cost outcomes of enoxaparin and UFH by monitoring incidences of recurrence of angina, myocardial infraction, measurement of the composite outcome of death and monitoring prothrombin time. By comparing the prothrombin time after the therapy with LMWH and UFH, we found that LMWH had better clinical outcomes than UFH. In our study, there was a decrease in recurrence of angina in the enoxaparin group compared to the UFH group when patients were monitored on the 21 st day (7.84% UFH and 4.83% enoxaparin group of patients). However, the results were not statistically significant. No death had occurred during our study period in both the groups.
Our results suggest enoxaparin is as effective as unfractionated heparin for the treatment of CHD and in addition is a safer choice. We conducted a follow up on 1 st and 21 st day since previous studies had shown that complications may occur when UFHs are used. During the first 3-5 days after treatment, there were no complications. Thrombocytopenia occurs after about 6 days of treatment and often results in much more profound decrease in platelet count and an increased risk of thromboembolism.  LMWH is less likely to cause thrombocytopenia, but this complication has been reported, including individuals who have previously developed thrombocytopenia after using UFH. For these reasons, patients should have a platelet count on the day of starting UFH and then platelet counts should be performed from days 4 to 14 every alternate day. In patients taking LMWH, the platelet count should be performed at a 2-4 day interval from day 4 to 14.  In our study we performed platelet count for both groups of patients taking LMWH and UFH on 1 st and 21 st day platelet count but did not find any adverse effects of heparin induced thrombocytopenia in both group of patients.
We studied clinical parameters like major or minor bleeding, stroke (hemorrhagic, non-hemorrhagic), thrombocytopenia, hypokalemia and allergic reactions. In our study we found that patients taking UFH developed hypokalemia, minor bleeding and other ADRs such as nausea, headache and cough to a greater extent compared to patients taking enoxaparin. Previous studies also show several advantages of LMWH over UFH, when it is used as a sole antithrombotic agent. Previous studies have shown that LMWH has a more expected pharmacological profile than UFH, and there is no need for close therapeutic drug monitoring. , In disparity, UFH shows an impulsive pharmacological profile which needs close monitoring of anticoagulation levels. ,,
The present study was an observational study, and we included only those patients who were admitted to the coronary care unit of the hospital in the study. This could affect the generalizability of the study. Our study also had a short study duration that represented few prescribers and meant smaller sample size. No follow up was performed after 21 days of administering the medications.
| » Conclusions|| |
The recommended treatment of angina, myocardial infarction, and ischemic heart disease should comprise of enoxaparin with antiplatelets. The present report has shown that enoxaparin has more benefits than UFH. By observing clinical outcomes and cost comparison analysis we conclude that although UFH is less expensive than enoxaparin, enoxaparin has better overall clinical outcomes such as higher prothrombin time, less recurrence of angina and less occurrence of ADRs compared to UFH.
| » Acknowledgment|| |
We extend our sincere thanks to Dr. P. K. Manna, Prof. and Coordinator for Pharm. D program, and Dr. R. Manavalan, Ex-HOD, Department of Pharmacy, Annamalai University, for their support in carrying out the research work and giving valuable comments on an earlier version of this manuscript.
| » References|| |
Engelgau MM, Karan A, Mahal A. The Economic impact of non-communicable diseases on households in India. Global Health 2012;8:9.
Ghaffar A, Reddy KS, Singhi M. Burden of non-communicable diseases in South Asia. BMJ 2004;328:807-10.
Walker R, Whittlesea C. Clinical Pharmacy and Therapeutics. 4 th
ed. Churchill Livingstone Elsevier Ltd. 2008. p. 280, 336-7.
Gupta R, Joshi P, Mohan V, Reddy KS, Yusuf S. Epidemiology and causation of coronary heart disease and stroke in India. Heart 2008;94:16-26.
Gaziano TA. Cardiovascular disease in the developing world and its cost-effective management. Circulation 2005;112:3547-53.
Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 1997;349:1498-504.
Sharma S, Sethi GR, Gupta U. Standard Treatment Guidelines - A Manual for Medical Therapeutics. 3 rd
ed. New Delhi: Delhi Society for Promotion of Rational Use of Drugs, B I Publishing House Pvt. Ltd.; 2009. p. 116-24.
Misra UK, Kalita J, Chandra S, Kumar B, Bansal V. Low molecular weight heparin versus unfractionated heparin in cerebral venous sinus thrombosis: A randomized controlled trial. Eur J Neurol 2012;19:1030-6.
Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, et al
. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2012;126:3097-137.
Amane HS, Burte NP. A comparative study of dalteparin and unfractionated heparin in patients with unstable angina pectoris. Indian J Pharmacol 2011;43:703-6.
Comp PC, Spiro TE, Friedman RJ, Whitsett TL, Johnson GJ, Gardiner GA Jr, et al.
Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement. Enoxaparin Clinical Trial Group. J Bone Joint Surg Am 2001;83-A: 336-45.
Levine M, Gent M, Hirsh J, Leclerc J, Anderson D, Weitz J, et al.
A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996;334:677-81.
Koopman MM, Prandoni P, Piovella F, Ockelford PA, Brandjes DP, van der Meer J, et al.
Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. N Engl J Med 1996;334:682-7.
Korovesis S, Karvouni E, Karabinos I, Giazitzoglou E, Papadopoulos A, Katritsis D. Comparison of enoxaparin and unfractionated heparin in coronary angioplasty. Hellenic J Cardiol 2005;46:46-51.
Keeling D, Davidson S, Watson H, Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. The management of heparin-induced thrombocytopenia. Br J Haematol 2006;133:259-69.
Antman EM. The search for replacements for unfractionated heparin. Circulation 2001;103:2310-4.
Montalescot G, Philippe F, Ankri A, Vicaut E, Bearez E, Poulard JE, et al.
Early increase of von Willebrand factor predicts adverse outcome in unstable coronary artery disease: Beneficial effects of enoxaparin. French Investigators of the ESSENCE Trial. Circulation 1998;98:294-9.
Montalescot G, Collet JP, Choussat R, Ankri A, Thomas D. A rise of troponin and/or von Willebrand factor over the first 48 h is associated with a poorer 1-year outcome in unstable angina patients. Int J Cardiol 2000;72:293-4.
Montalescot G, Collet JP, Lison L, Choussat R, Ankri A, Vicaut E, et al.
Effects of various anticoagulant treatments on von Willebrand factor release in unstable angina. J Am Coll Cardiol 2000;36:110-4.
[Table 1], [Table 2], [Table 3]