Statins: Cost analysis in Indian scenario from eight major clinical trialsJ Sanmukhani1, V Shah2
1 Department of Pharmacology, Government Medical College, Bhavnagar, Gujarat- 364001, India
2 Department of Endocrinology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.68649
Source of Support: None, Conflict of Interest: None
Background and Aims: Coronary heart disease (CHD) is the leading cause of death in India resulting in loss of young Indians. Statins have proved to reduce the CHD mortality in various clinical trials. The aim of the study is to find the cost-effectiveness ratio (CER) for each major coronary event averted and a coronary death avoided by use of statins in different clinical settings based on the data from the major clinical trials on statins. Materials and Methods: Using electronic database and as per our inclusion and exclusion criteria we selected the West of Scotland Coronary Prevention Study (WOSCOPS), the Air Force Coronary Atherosclerosis Prevention Study (AFCAPS) and the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA) study for primary prevention; the Cholesterol and Recurrent Events Trial (CARE), the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study and the Scandinavian Simvastatin Survival Study (4S) for secondary prevention and two studies, the Heart Protection Study (HPS) and the Pravastatin in elderly individuals at risk of vascular disease (PROSPER) study for high-risk patients. The results of these studies were used for cost-effectiveness analysis of statins in different patient groups. Statistical Analysis: Absolute risk reduction, Number Needed to Benefit (NNTB), NNTB/year for total sample and in subgroups of males, females and age >65 was derived. CER for branded and generic versions was calculated by using the prices of statins listed in Indian Drug Review Triple i. Results: Cost-effectiveness ratio (CER) in primary prevention studies i.e., the WOSCOPS, the AFCAPS and the ASCOT-LLA was Rs. 25.8 lacs, Rs. 23.8 lacs and Rs. 7.9 lacs per major coronary event averted respectively. CER in secondary prevention studies i.e., the CARE and the LIPID was approximately Rs. 20 lacs per major coronary event averted while it was Rs. 52.4 lacs and Rs. 37 lacs per coronary heart disease (CHD) death avoided. CER from the 4S was Rs. 6.9 lacs per major coronary event and Rs. 16.9 lacs per CHD death averted. CER in the HPS and the PROSPER study was Rs. 17.9 lacs and Rs. 27.1 lacs per major coronary event avoided in high-risk patients. Conclusion: Cost associated with the use of statins is higher in primary prevention as compared to secondary prevention. More studies are needed to confirm the cost-effectiveness of statins to make any decision for health policy.
Keywords: Cost-effectiveness ratio, Indian scenario, statins
According to the World Health Organization (WHO), coronary heart disease (CHD) is the leading cause of death, accounting for 29% of all deaths in 2005 in India.  The prevalence of CHD in adults has risen fourfold over the last 40 years (to the present level of around 10%), and also in rural areas the prevalence has doubled over the past 30 years (to the present level of around 4%). There will be around 47 million cases of CHD in India by the year 2010 (around 47% being in rural areas and 52% of them being women).  The WHO estimates that, over the next 10 years, India will lose 237 billion US dollars due to heart disease, stroke, and diabetes.  To prevent this increasing prevalence of CHD a large number of preventive measures are being taken. Several large-scale randomized controlled trials ,,,,,,, have impressively proven the effect of 3-hydroxy-2-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) in the prevention of CHD. Based on evidence and influenced by the results in these trials, statins are now being prescribed to most of the CHD cases without taking into account the economic status of the diseased.  Forty-seven per cent cases of CHD in India are from rural areas.  The average annual income in many of these areas is more or less equal to the money spent on statin therapy in a year. This widespread use has made statins the largest selling drug worldwide and its market in India is presently estimated at about Rs. 300 crore (Rs. 3000 million). 
There are several studies showing cost-effectiveness of statins in developed economies , where the majority of the healthcare receivers are insured or the health is taken care of by the government itself; however, there is not a single study form developing economies like India where most of the health expenditure is borne by the patient themselves. The aim of the study is to find the cost-effectiveness ratio (CER) for each major coronary event averted and a CHD death avoided by use of statins in different clinical settings based on the data from the major clinical trials on statins.
A computerized literature search was performed using the PubMed database. The following search terms were used: statin, HMG-CoA reductase inhibitor, atorvastatin, pravastatin, simvastatin, coronary disease, coronary heart disease and myocardial infarction. In addition, the references cited in articles on statins were examined. Only clinical trials of statins conducted in humans and reported in English were selected. The criteria for inclusion in our study were: (1) randomized treatment allocation; (2) a placebo arm; (3) no other specified differences in management; (4) double-blinding at least in the assessment of endpoints; (5) follow-up of at least three years; (6) a hard endpoint that is a cardiovascular event as the primary or secondary endpoint; (7) number of participants in the study should be at least 4000. Eight trials fulfilled our criteria and were included in the analysis. ,,,,,,, The West of Scotland Coronary Prevention Study Group (WOSCOPS),  the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS)  and the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA)  recruited subjects having raised blood cholesterol levels, diabetes and hypertension but without any prior history of myocardial infarction or angina and were thus considered for analysis of statins in primary prevention. The Scandinavian Simvastatin Survival Study (4S),  the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group  and Cholesterol and Recurrent Events Trial (CARE)  recruited patients with prior history of myocardial infarction and were considered for analysis of statins in secondary prevention. The Heart Protection Study (HPS)  and the Pravastatin in elderly individuals at risk of vascular disease (PROSPER)  study group had recruited patients with high risk i.e. those who have already had an episode of myocardial infarction or angina (secondary prevention) and those with diabetes, hypertension or raised cholesterol levels (primary prevention).
The main variables extracted from the trials were: number of subjects (subgrouped by sex and age >65), prior history of cardiovascular disease, type of statin, dosage and duration, major coronary events and CHD deaths. Major coronary events included cases of fatal and nonfatal myocardial infarction and sudden cardiac deaths.
The primary endpoint in all the eight studies varied but all these trials gave separate data of total major coronary events and CHD deaths which was used for analysis. Subgrouped data of major coronary events based on sex and age >65 was available only in the AFCAPS,  the ASCOT-LLA,  the 4S,  and the LIPID  and thus was analyzed and compared for these four trials only. The subgroup data of other trials was not analyzed as it resulted in invalid comparisons due to the following issues: In the WOSCOPS only male patients were recruited and they were divided into age groups with age >55. In the CARE trial the subgroup data included cases of coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA). In both the HPS and the PROSPER the subgroup data included cases of fatal and nonfatal stroke while the HPS additionally had cases of revascularization.
Based on the variables abstracted from the eight studies mentioned above, we derived absolute risk reduction (ARR), Number Needed To Benefit (NNTB), NNTB/year for major coronary events in total sample and subgroups of males, females and age >65. The same parameters were derived for CHD deaths in the total sample studied. NNTB is the number of patients a medical practitioner needs to treat to prevent one additional person from having the event (NNTB = 1/ARR). NNTB from various trials differ as they follow the patients for different time periods so NNTB/year was calculated which tells the number of patients to be treated for a period of one year to prevent one additional person from having the event. CER for each death avoided and for each major coronary event averted was calculated using the prices listed in Indian Drug Review (IDR) Triple i.  Separate CER was calculated for branded and generic version of the drugs. All the calculations were done using Microsoft Office Excel 2007® . For calculation of CER we took into account the cost of therapy alone (statins). We did not include the cost of hospital admissions, procedural charges, consultation fees, laboratory charges, treatment of complications, loss of daily wages and other indirect costs for want of data. This is because we could not find any Indian data on this issue and there are wide differences in the cost of these issues from state to state and institute to institute.
Results of the cost analysis were divided into three parts: primary prevention, secondary prevention and high-risk group (primary and secondary prevention put together).
Cost-effectiveness analysis of statins in primary prevention [Table 1]: As per our inclusion criteria, three studies were included in the analysis as described under methodology. In the WOSCOPS,  3302 male patients received pravastatin in a dose of 40 mg/day and were followed for 4.9 years. The CER with branded pravastatin was Rs. 25 lacs (Rs. 2.5 million) per major coronary event averted while it was Rs. 93.7 lacs per CHD death prevented.
The AFCAPS  had recruited 6605 patients (females-15%) and followed them for 5.1 years treating them with lovastatin 40 mg/day. Cost of per day treatment with lovastatin was Rs. 26 with branded drugs while it was Rs. 10 with the generic version of the drug. To prevent one major coronary event in the total sample NNTB/year was 251, CER being Rs.23.8 lacs with branded drugs. In the AFCAPS only 15% of the total recruited patients were females and they showed a poor response with lovastatin, the NNTB/year was 422 with CER of Rs.40 lacs per major coronary event prevented.
The third trial for primary prevention was the ASCOT-LLA.  It recruited 10,305 patients and followed them for 3.3 years with 10 mg atorvastatin/day. This trial showed that to prevent a major coronary event the NNTB/year was 310 and the CER was Rs.7.9 lacs per event prevented. In the subgroup analysis, males and subjects with age >65 showed similar results with NNTB/year being 245 and 266 respectively. Females in this trial did not show any improvement with statins and gave a negative value for NNTB/year which signifies number needed to harm (NNTH/year). To prevent a CHD death with atorvastatin NNTB/year was found to be more than 2000 with CER of Rs.51.2 lacs per death avoided.
Cost-effectiveness analysis of statins in secondary prevention [Table 2]: As per our criteria we included and analyzed the CARE,  the LIPID  using pravastatin and the 4S  using simvastatin for secondary prevention. The CARE  and the LIPID  trials used pravastatin in a dose of 40 mg/day, costing around Rs.32/day. They showed similar results for secondary prevention of a major coronary event when both males and females were taken together. The NNTB/year in CARE trial was 167 and for LIPID trial it was 172. The CER in both the trials was Rs.20 lacs per major coronary event averted. In the subgroup analysis males and subjects with age >65 showed similar results with NNTB/year being 157 and 146 respectively while the females again showed a poorer result with NNTB/year of 342. For secondary prevention of a CHD death, the LIPID trial had a NNTB/year of 317, while the CARE trial showed a poorer response with a NNTB/year of 449. The 4S  used simvastatin 40 mg/day and followed the 4444 patients for 5.4 years. The CER with the branded version was Rs.6.9 lacs per major coronary event averted and Rs.16.9 lacs per CHD death avoided.
Cost-effectiveness analysis of statins in the high-risk group (primary and secondary prevention taken together) [Table 3]: The HPS  and the PROSPER  recruited subjects with high risk and thus took patients with both primary and secondary prevention together. The HPS recruited 20,536 cases (drug-10,269) and followed them up for five years using simvastatin 40 mg/day, while the PROSPER recruited 5804 subjects (drug-2891) and followed them for 3.2 years using pravastatin 40 mg/day. CER in the HPS trial was Rs.17 lacs per major coronary event avoided and Rs.46.8 lacs per CHD death with branded simvastatin. The PROSPER showed that to prevent a major coronary event NNTB/year was 181 with CER of Rs.21 lacs per event and to prevent a CHD death NNTB/year was 341 with CER of Rs.40 lacs.
Statins have now become one of the most prescribed drugs for both primary and secondary prevention of CHD, therefore we decided to evaluate the cost-effectiveness of stains in Indian currency.
All data we have analyzed are from large randomized trials carried out in the Western population and extrapolated to India. The trials we analyzed have used simvastatin, lovastatin or pravastatin which are quite expensive in India. Atorvastatin is the cheapest available statin in India but its cost cannot be analyzed due to lack of data for secondary prevention from any large randomized trial. We have included only the cost of statins in our analysis and have not taken costs of laboratory tests, hospital admissions, treatment of complications and other indirect and intangible costs as a result of cardiovascular events. If all these costs are taken into consideration the cost-effectiveness ratio with statins will further improve with a larger impact in studies with a high absolute risk of events as more events would be avoided there in absolute terms as compared to the placebo groups.
The primary prevention trials show that males respond better to statins than females in prevention of major coronary events. Among the three drugs used for primary prevention pravastatin was the most effective drug but is less cost effective in India due to its high cost and unavailability of cheaper generic versions. On the other hand atorvastatin has a higher NNTB/year but is more cost-effective due its lesser cost and availability of generic versions. These trials also suggested that statins may not be very useful in preventing CHD deaths in primary prevention as the NNTB/year was very large in all the trials. The secondary prevention trials showed much better results with the use of statins than the primary prevention trials, simvastatin being the most effective. Females again showed a poorer response than males but it was far better than in case of primary prevention.
For primary prevention, CER of statins was very high and thus other methods like lifestyle modification, including dietary changes, exercise,  mental relaxation  techniques and meditation  should be stressed upon. Moreover lifestyle modification also helps in preventing many other diseases including some of the cancers. Though lifestyle modification is difficult to incorporate and does not come absolutely free of cost, it has been found to be cost-effective, , especially for primary prevention of CHD.
Statins have become an integral part of the regimen for secondary prevention of CHD. National health accounts show that 71% of all health expenditure is made by individuals in a household,  which is one of the highest proportions in the world. In India 75% of the population resides in rural areas with 27.5% of the population living below the poverty line in 2004-05. , Thus the huge costs affect the healthcare receivers directly and it is a major problem in treating poor patients. After introduction of generics the CERs of statins have significantly improved but still a decrease in cost or inclusion of statins in the essential drug list and all hospital formularies will greatly reduce burden on individuals.
Thus we conclude that cost associated with the use of statins is higher in primary prevention as compared to secondary prevention. More studies with data on efficacy from the Indian population are needed to confirm the cost-effectiveness of statins for policy decisions.
We sincerely thank Dr. C. B. Tripathi, Professor and Head, Department of Pharmacology, Government Medical College, Bhavnagar, Gujarat and Dr. Vikas Vaishnavi, Research and Development Department, Cadila Pharmaceuticals, Ahmedabad, Gujarat, India for their great support in this study. We also extend our sincere thanks to Dr. J.C. Sanmukhani, Head, Department of Medicine, Pushpa Mission Hospital, Ujjain, Madhya Pradesh for critical review of this manuscript.
[Table 1], [Table 2], [Table 3]