Research

# Cost-utility analysis of antihypertensive medications in Nigeria: a decision analysis

Obinna Ikechukwu Ekwunife1*, Charles E Okafor1, Charles C Ezenduka2 and Patrick O Udeogaranya1

Author Affiliations

1 Department of Clinical Pharmacy and Pharmacy Management, Faculty of Pharmaceutical Sciences, University of Nigeria Nsukka, 410001, Enugu, Nigeria

2 Health Policy Research Group, University of Nigeria, Enugu Campus, P.O Box 1414, Enugu, Nigeria

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Cost Effectiveness and Resource Allocation 2013, 11:2  doi:10.1186/1478-7547-11-2

 Received: 24 October 2011 Accepted: 17 January 2013 Published: 23 January 2013

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### Abstract

#### Background

Many drugs are available for control of hypertension and its sequels in Nigeria but some are not affordable for majority of the populace. This serious pharmacoeconomic question has to be answered by the nation’s health economists. The objective of this study was to evaluate the cost-effectiveness of drugs from 4 classes of antihypertensive medications commonly used in Nigeria in management of hypertension without compelling indication to use a particular antihypertensive drug.

#### Methods

The study employed decision analytic modeling. Interventions were obtained from a meta-analysis. The Markov process model calculated clinical outcomes and costs during a life cycle of 30 years of 1000 hypertensive patients stratified by 3 cardiovascular risk groups, under the alternative intervention scenarios. Quality adjusted life year (QALY) was used to quantify clinical outcome. The average cost of treatment for the 1000 patient was tracked over the Markov cycle model of the alternative interventions and results were presented in 2010 US Dollars. Probabilistic cost-effectiveness analysis was performed using Monte Carlo simulation, and results presented as cost-effectiveness acceptability frontiers. Expected value of perfect information (EVPI) and expected value of parameter perfect information (EVPPI) analyses were also conducted for the hypothetical population.

#### Cost-effectiveness acceptability frontier

Cost-effectiveness acceptability frontiers were used to present the result of cost-effectiveness for the 3 different cardiovascular risk scenarios. The cost-effectiveness acceptability frontiers illustrate the probability of any intervention being optimal compared to all other competing alternatives. Cost-effectiveness frontier also illustrates the crossover when one intervention is substituted by the other as the one with the highest probability of being optimal and therefore provides useful information for policy makers [18]. The major difference between the frontier and curve is that the frontier takes into consideration the null scenarios in addition to the alternative interventions while the acceptability curve considers all the interventions except the null scenario. A total of 58 iterations of simulations were conducted for different willingness-to-pay threshold ratio. For each iteration, the probability that the cost-effectiveness of any intervention being optimal compared to the null scenario was calculated for all the alternative interventions from the NMB [12].

#### Assessment of population values of perfect information (EVPI)

Population Expected Value of Perfect Information (EVPI) was carried out for the three cardiovascular risk scenarios to determine the opportunity cost surrounding the conclusion of the analysis [12]. The population EVPI was conducted for 1000 patients over the life cycle of 30 years period. Simulation for 58 iterations were conducted for different willingness-to-pay threshold ratio and for each iteration, a value of perfect information for each willingness-to-pay threshold was calculated with the use of the effective population [12].

Across the four anti-HTs under evaluation including null scenario, the highest NMB for each iteration was selected. The highest NMBs for all the iterations were averaged. The difference between this average value obtained and the highest averaged NMB across the different interventions was noted. In calculating the Discount Population for the 1000 patients over a period of 30 years, a discount rate of 3% (range of 0% - 5%) was used. The sum of the discount population over 30 years is the Effective Population. The Population EVPI was obtained by multiplying the Effective Population with the difference in NMB noted.

#### Assessment of parameter value of perfect information (EVPPI)

The expected value of perfect information for parameters (EVPPI) was obtained by multiplying the effective population with the difference between the net-benefit with perfect information and the expected value with current information about the parameter(s) [12]. The EVPPI was also conducted for 1000 patients. This assessment was started by checking the threshold ratio and set to the maximum in order to give a high EVPI. The parameters assessed were relative risk (RR), utility and cost. A total of 100 iterations of Monte Carlo simulation were conducted and for each parameter, the net-benefit was obtained 10 times by repeating the process so as to calculate the mean net-value. The perfect information pay-off, given certainty over each parameter was determined in order to obtain the EVPPI.

#### Data analyses

All analyses (i.e. Markov chain analysis, Monte Carlo simulation, and assessment of value of perfect information) were carried out using Microsoft Excel (Microsoft Corporation, 2007).

### Results

For the three cardiovascular risk groups, the yearly cost in the null scenario was the least. The null scenario also had the least QALYs in the three groups. In all the cardiovascular risk states (CVRSs), ACEI has the highest annual cost if used followed by calcium-channel blocker. ACEI has a low QALY in the medium and high risk state but the highest QALY in the low CVRS. Thiazide diuretic has a very low annual cost in the three states, the highest QALYs in the medium and high risk state but not in the low CVRS. In the low CVRS, at any threshold ratio ($0 -$15,000), ACEI has the highest NMB followed by thiazide but in the medium and high CVRSs, thiazide has the highest NMB followed by calcium-channel blocker at any threshold ratio. For instance, in the medium risk, at threshold ratio of $15,000, the NMB of the various interventions are as follows: null scenario ($89799); thiazide ($101927); beta-blocker ($94094); ACEI ($98619); Calcium-channel blocker ($101780).

The null scenario in the three cardiovascular risk groups has a 0 (zero) probability of being cost effective. In the low CVRS, ACEI has the highest probability of being cost effective (about 0.526) followed by thiazide diuretic (about 0.278). In the medium and high CVRSs, calcium-channel blocker has the highest probability of being cost effective (about 0.47 and 0.53) followed by thiazide diuretic (about 0.45 and 0.41) respectively.

The application of cost-effectiveness acceptability frontier is to help determine which antihypertensive agent has the highest probability of being cost-effective when compared with other alternative drugs. For low cardiovascular risk state (Figure  2), at no willingness-to-pay, null scenario was the most cost-effective (if the provider is not willing to invest any money to achieve a higher health outcome). When the provider is ready to pay any amount above $2,600 but not more than$15,000 for additional QALY, thiazide diuretic emerged as the best intervention. If the provider is willing to pay greater than $15,000 for additional QALY, ACEI emerged as the best intervention. In Figure 3, cost-effectiveness frontier for patients in medium cardiovascular state is shown. At no willingness-to-pay, null scenario was the most cost-effective. When the provider is ready to pay any amount above$1,300 but not more than $15,000 for additional QALY, thiazide emerged as the best intervention. If the provider is willing to pay greater than$15,000 for additional QALY, calcium-channel blocker emerged as the best intervention. Similar result was also obtained for patient in high cardiovascular risk state (Figure  4). At no willingness-to-pay, null scenario was the most cost-effective. When the provider is ready to pay any amount above $1,300 but not more than$15,000 for additional QALY, thiazide emerged as the best intervention. If the provider is willing to pay greater than $12,500 for additional QALY, calcium-channel blocker emerged as the best intervention. Figure 2. Cost-effectiveness acceptability frontier for the alternative interventions in the low cardiovascular risk scenario. Figure 3. Cost-effectiveness acceptability frontier for the alternative interventions in the moderate cardiovascular risk scenario. Figure 4. Cost-effectiveness acceptability frontier for the alternative interventions in the high cardiovascular risk scenario. Population expected value of perfect information analysis (EVPI) in Table 5 showed that the opportunity cost surrounding the decision to implement any of the intervention that emerged cost-effective at a given willingness-to-pay threshold ranged from approximately$26,000,000 to $73,000,000. This range also implies the maximum that the providers will be willing to pay in order to obtain perfect information so as to obtain a perfect result. In Table 5, the interventions shown were the interventions which at a particular willingness-to-pay, becomes the most cost effective. For any of the risk states, interventions which are not cost-effective at any point are not included in the table. The willingness-to-pay used in Table 5 is the point from which an intervention emerges as the most cost-effective for a particular risk state. Analysis for the expected value of perfect information for parameters (EVPPI) in Table 6 showed that the population EVPPI for the various parameters was far below the population EVPI, indicating that the providers can easily pay-off such amount to obtain perfect information of the parameters. Parameters such as cost of managing stroke patients and yearly cost of using thiazide diuretic has negligible EVPPI for low risk and high risk state. Table 6. Expected Value of Perfect Information for Parameters ### Discussion From the result, thiazide diuretic among the four alternatives was the most cost-effective. This finding was consistent for the 3 cardiovascular risk scenarios. For low risk patients, lisinopril was the second most cost-effective option to implement but additional fund needs to be committed in order to achieve better health outcomes over thiazide diuretic. CCB was the second most cost-effective option for medium and high risk patients if additional fund is committed in order to achieve better health outcomes over thiazide diuretic. In the graphs, the probability that thiazide diuretic is cost-effective decreases as the CE threshold increases. This is so because beyond a willingness-to-pay of about$2,600/QALY, committing more funds does not yield a corresponding increase in QALY for thiazide. So, additional fund beyond \$15,000/QALY is a waste of resource since there is no increase in clinical outcome. Beyond that limit, CCB should be considered.

From the report of a recent Meta analysis aimed to quantify the benefits and harm of the major first-line anti-hypertensive drug classes, thiazide diuretic was the best choice for hypertension [5]. Most of the evidence demonstrated that first-line low dose thiazide diuretic reduces mortality and morbidity (stroke, heart attack and heart failure). No other drug improved health outcomes better than low-dose thiazide [5]. This analysis shows that with cost consideration, low dose thiazide diuretic is very cost-effective. Thus, in low resource settings such as in Nigeria and other developing countries, thiazide diuretic should be considered the drug of first choice especially in patients that respond well to it and those that do not have other co-morbidities that will necessitate the use of a particular antihypertensive agent.

That an intervention is most cost-effective depends on what the providers are willing to pay per outcome. As a guide, WHO considers interventions to be cost-effective if they have incremental cost-effectiveness ratios (ICERs) that are less than three times the gross national income (GNI) per capita [19]. It is pertinent to state that at 50% probability of cost-effectiveness, the willingness-to-pay is less than three times the GNI per capita. The national income per capita for Nigeria in 2009 was USD1, 190 or USD3, 370 when multiplied by three. Based on the above premise, thiazide diuretic could be judged a cost-effective option.

From the University of Toronto, in a published cost-effectiveness analysis of routine echocardiography in patients starting antihypertensive drug therapy, the result of the model showed that ACE-inhibitors cannot be recommended as antihypertensive first-line therapy in the patients under study [20]. This was because ACE-inhibitors were very expensive and the gain in unadjusted and quality-adjusted life-years was small and clinically irrelevant [20]. From the author’s result, prescribing conventional antihypertensive therapies (diuretics and beta-blockers) to everybody can be recommended as strategies of choice [20]. This is in line with the result of this study because the result showed that ACE-inhibitors are very expensive with low QALYs and their ICERs are far more than three times the GNI of Nigeria.

However, the result of this study does not completely support the guideline by the Sixth Report of the Joint National committee on prevention, detection, evaluation and treatment of high blood pressure (JNC- 6) which recommends the use of diuretics and beta-blockers as first-line antihypertensive drugs in the absence of compelling reasons to use other antihypertensive drugs [21]. The result of this study does not also completely support the result in the cost-effectiveness study from the University of Toronto which recommended the prescribing of diuretics and beta-blockers to everybody [20]. This is evidently because, in the result of this study, beta-blocker was never a contender for cost-effectiveness. For Nigerians, in place of beta-blocker, calcium-channel-blocker should be considered a second-line therapy after diuretics.

In the context of research, with respect to this study, EVPI represent the maximum that providers can willingly pay for additional research, to inform the decision they make [22]. The EVPI analysis showed that the opportunity cost surrounding the choice of thiazide diuretic for all the cardiovascular risk state is lower compared to the choice to use ACEI or CCB. A reason for this is because the willingness-to-pay from which thiazide diuretic becomes most cost-effective is relatively small. This supports the fact that thiazide could be judged a cost-effective option compared to the other antihypertensive drugs. On the other hand, analysis for the expected value of perfect information for parameters (EVPPI) showed that there may not be need of further experimental research to get perfect parameter estimates since the population EVPPI for the various parameters was far below the population EVPI. Change in the parameters caused an infinitesimal changed in the result showing that the result is insensitive to the parameters which invariably means that the result is robust.

This analysis has some limitations which have to be considered when interpreting the results. In our Markov model to show a typical timeline of events consequent on hypertension, we made use of an algorithm designed from data obtained from Africans in Britain, which may not hold true for indigenous Africans and Nigerians in particular. The reason for use of those data in the model was because there was no published study that predicted cardiovascular events over time in Africans that could be used for this model.

In conclusion, the result of this study shows that thiazide diuretic followed by calcium-channel blocker especially for medium and high risk patients is a cost-effective option in the management of patients with high blood pressure in Nigeria.

### Competing interests

Funding for this research, a project in partial fulfillment of the requirement for the award of a Bachelor of Pharmacy (B.Pharm) was provided partly by parents and friends of Okafor, C.E. The authors declare no conflict of interest.

### Authors’ contributions

OIE, CEO and CCE designed the study. OIE designed the model while CEO and PO helped in gathering data. CEO wrote the first draft of the manuscript. All authors read and approved the final manuscript.

### Acknowledgement

The authors are grateful to Obinna Ugwu and Stanley Ibeme, for their help in data collection.

### References

1. Aguwa CN:

Therapeutic Basis of Clinical Pharmacy in the Tropics. 3rd edition. 2004, 102-136.

2. Chobian AV, Bakris JL, Black HR, Cushman WC, Green LA, Izzo JL, Jones WD, Materson BJ, Oparil S, Wright JT, Roccella EJ: National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure.

Hypertension 2003, 42:1206-1252. PubMed Abstract | Publisher Full Text

3. World Health Organisation:

Evidence for Action [Online]. 2003 [Cited 2008 August 22]; Available from: URL: http://whqlibdoc.who.int/publications/2003/9241545992.pdf Accessed 2 August 2011

4. Ekwunife OI, Aguwa CN: A Meta Analysis of Prevalence of Rate of Hypertension in Nigerian Populations.

J Publ Health Epidemiol 2011, 13:604-607.

5. Wright JM, Musini VM: First-line drugs for hypertension.

Cochrane Database Syst Rev 2009, Art. No.: CD001841(Issue 3):CD001841.pub2. Publisher Full Text

6. Yusuff KB, Balogun OB: Pattern of drug utilization among hypertensives in a Nigerian teaching hospital.

Pharmacoepidemiol Drug Saf 2005, 14:69-74. PubMed Abstract | Publisher Full Text

7. Lopez AD, Salomon J, Ahmad O, Murray CJL: Life tables for 191 countries: data, methods and results (GPE discussion Paper No. 9). Geneva: World Health Organization; 2000.

8. Ekwunife OI, Aguwa CN, Adibe MO, Barikpaoar E, Onwuka CJ: Health state utilities of a population of Nigerian hypertensive patients.

BMC Res Note 2011, 12(4):528. BioMed Central Full Text

9. Brindle P, May M, Gill P, Cappuccio F, D'Agostino R Sr, Fischbacher C, Ebrahim S: Primary prevention of cardiovascular disease: a web-based risk score for seven British black and minority ethnic groups.

Heart 2006, 92(11):1592-1602.

10. Whitworth JA, World Health Organization International Society of Hypertension Writing Group: 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension.

J Hypertens 2003, 21(11):983-1992.

11. Akpa MR, Agomouh DI, Alasia DD: Lipid profile of health adult Nigerians in Port Harcourt, Nigeria.

Niger J Med 2006, 15(2):137-140. PubMed Abstract

12. Briggs A, Claxton K, Sculpher M: Decision modeling for health economic evaluation. New York: Oxford University Press Inc; 2006.

13. Tan-Torres Edejer T, Baltussen R, Adam T, Hutubessy R, Acharya A, Evans DB, Murray CJL: Making choices in health: WHO guide to cost-effectiveness analysis. Geneva: World Health Organization; 2003.

14. Nigerian Health Insurance Scheme:

NHIS Healthcare Providers Service Price List. 2005.

Power Purchasing Parity conversion factor (GDP) to market exchange rate ratio in Nigeria. 2010.

16. CBN Data and Statistics:

Monthly Average Exchange Rates of the Naira (Naira Per Unit of Foreign Currency) - 2010 (Interbank Foreign Exchange Market - IFEM). 2011.

17. World Health Organization:

International Drug Price Indicator Guide. 2010.

http://apps.who.int/medicinedocs/en/m/abstract/Js18714en/ Accessed 15 July 2011

18. Robberstad B, Hemed Y, Norheim OF: Cost-effectiveness of medical interventions to prevent cardiovascular disease in a sub-Saharan African country - the case of Tanzania.

Cost Effectiveness and Resource Allocation 2007, 5:3. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text

19. Edejer T, Baltussen R, Adam T, Hutubessy R, Acharya A, Evans D, et al.: Making Choice in Health: WHO Guide to Cost-effectiveness Analysis. Geneva: World Health Organisation; 2003.

20. Nordmann AJ:

Cost-effectiveness of Routine Echocardiography in Hypertensive Patients starting Antihypertensive Drug Therapy. 2001.

http://tspace.library.utoronto.ca/bitstream/1807/15428/1/MQ58821.pdf Accessed 15 December, 2012

21. The Sixth Report of the Joint National Committee on Prevention:

Detection, Evaluation and Treatment of High Blood Pressure. 1997.

http://www.nhlbi.nih.gov/guidelines/archives/jnc6/jnc6_archive.pdf Accessed 15 December, 2012

22. Bravo Vergel Y, Hawkins NS, Claxton K, Asseburg C, Palmer S, Woolacott N, Bruce IN, Sculpher MJ: The cost-effectiveness of etanercept and infliximab for the treatment.

Rheumatology 2007, 46(11):1729-1735. PubMed Abstract | Publisher Full Text