|Year : 2020 | Volume
| Issue : 3 | Page : 253-258
Cost Needed to Treat and Number Needed to Treat Analysis of Drugs for the Treatment of Heart Failure in India
Varghese George1, Krishnamohan Mullavelil1, Ancy Thannikkal Joseph1, Rajeev Aravindakshan2, Denny John3, Cheriyan Koshy1, Krishnan Nair Venugopal1
1 Department of Cardiology, Pushpagiri Medical College Hospital, Thiruvalla, Kerala, India
2 Department of Preventive and Social Medicine, All India Institute of Medical Sciences, Mangalagiri, Andhra Pradesh, India
3 Evidence Synthesis Specialist, Campbell Collaboration, New Delhi, India
|Date of Submission||16-Jun-2020|
|Date of Decision||27-Sep-2020|
|Date of Acceptance||15-Sep-2020|
|Date of Web Publication||23-Dec-2020|
Dr. Varghese George
Department of Cardiology, Pushpagiri Institute of Medical Sciences and Research Centre, Thiruvalla, Kerala
Source of Support: None, Conflict of Interest: None
Introduction: Our aim was to review the cost-effectiveness of guideline-directed medical therapy of heart failure in India and identify drugs that can be made available free of cost or at subsidized rates to the patient population. Methods: Data extracted from ten landmark trials in heart failure was used to compute the number needed to treat (NNT) and cost needed to treat (CNT) of drugs used in heart failure, to prevent cardiovascular mortality and heart failure re-hospitalization using the HDS Plotter-Incremental Cost Effectiveness Calculator. Since various brands (i.e., trade names) with a wide cost range are available in the Indian market, the average retail price in Indian Rupees for the year 2019 was used for the analysis. NNT and CNT of each drug were computed, and the cost-effectiveness was analyzed. The CNT of these drugs was compared with India's per capita Gross Domestic Product (GDP). The WHO recommendation of three times per capita GDP was used as the cost-effectiveness threshold. Results: Medications that were labeled as Class I for the treatment of heart failure were included in our analysis. Ivabradine, valsartan, and angiotensin receptor neprilysin inhibitor (ARNi) did not meet the cost-effectiveness criteria for preventing cardiovascular mortality. For the prevention of heart failure re-hospitalization, all drugs except ARNi met the cost-effectiveness threshold. Conclusion: Any future research would need to consider the compliance factor along with Willingness to Pay to understand the real acceptance of these drugs on the ground in India.
Keywords: Cost needed to treat, cost-effectiveness, heart failure, India, number needed to treat
|How to cite this article:|
George V, Mullavelil K, Joseph AT, Aravindakshan R, John D, Koshy C, Venugopal KN. Cost Needed to Treat and Number Needed to Treat Analysis of Drugs for the Treatment of Heart Failure in India. J Pract Cardiovasc Sci 2020;6:253-8
|How to cite this URL:|
George V, Mullavelil K, Joseph AT, Aravindakshan R, John D, Koshy C, Venugopal KN. Cost Needed to Treat and Number Needed to Treat Analysis of Drugs for the Treatment of Heart Failure in India. J Pract Cardiovasc Sci [serial online] 2020 [cited 2022 Jan 21];6:253-8. Available from: https://www.j-pcs.org/text.asp?2020/6/3/253/304529
| Introduction|| |
India has become the world capital of lifestyle and noncommunicable diseases due to its immense population size and scarce healthcare resources. Most of the national programs in India are targeted in controlling lifestyle diseases as well as in promoting early detection and treatment of infectious diseases. Little attention has been paid to treatment strategies of chronic disease conditions that require long-term treatment and repeated hospitalizations.
Heart failure curbs the patient off his productive days and affects the economic stability of his family. Mainly, this is due to catastrophic medical expenses on frequent hospitalizations and treatment. A large number of landmark trials have identified the mechanism of heart failure and detailed various drugs to reduce morbidity and mortality of chronic heart failure.,,,,,,,,, Drugs such as diuretics, angiotensin-converting enzyme inhibitors (ACEi) per angiotensin receptor blocker (ARB), beta-blockers (BB), mineralocorticoid receptor antagonist (MRA), angiotensin receptor neprilysin inhibitor (ARNi), ivabradine, and empagliflozin have been included in the treatment protocol of heart failure. Newer drugs are being added, and the list is ever-expanding. These drugs have imposed heavy financial burden on the patient population and health-care sector. Hence, new treatments have poor patient compliance, especially among people of lower economic status.
Data on heart failure prevalence and efficacy of various drugs in relation to the economic burden on the health care system in India is scarce. Various registries available for reference in India are geographically discrete; hence, the prevalence of heart failure is actually extrapolated from these available registries. For example, the trivandrum heart failure registry which is confined to a district of a state in India.According to current statistics, an average of 8–10 million of the Indian population suffers from heart failure. This number is expected to increase by an enormous proportion by 2030. The major cost of treatment of heart failure is due to repeated hospital admissions, especially in the elderly population. Most of these admissions are under-reported as well.
In India, the two ways of treating heart failure are dependent on the cost consideration of the patient. One way of treatment is to stick on to diuretics, ACEi and BB at effective doses along with nonpharmacological measures such as dietary advice and exercise. The second option is by prescribing all first-line drugs, including ARNi, ivabradine, empagliflozin, especially in advanced heart failure. Needless to mention that latter results in major economic drain on the health provider and patient alike. Hence, chronic heart failure is an ideal condition to study the effect of treatment in reducing mortality and morbidity in heart failure and also the economic burden it imposes on the health sector of a developing country like India.
It is to be assessed whether allocation and rationing of treatment resources in the health sector is based on priority, disease prevalence, and, most importantly on cost-effectiveness principles. This study is a cost-effectiveness analysis in the treatment of heart failure by analyzing the cost needed to treat (CNT) and number needed to treat (NNT) of various drugs available in the Indian market for treating heart failure.
| Methods|| |
We conducted an intensive internet search via Pubmed for trials on the treatment of heart failure from 1990 to 2019. As there are no studies from India related to cardiovascular mortality of heart failure that are available, we extracted data from ten international landmark trials.,,,,,,,,, These are in the field of heart failure treatment that included endpoints of cardiovascular mortality such as hospitalizations due to heart failure. These were used to calculate the NNT, which is the average number of patients to be treated to prevent one event (mortality per hospitalization of heart failure) and CNT to prevent mortality or heart failure hospitalization.
NNT can be calculated taking the inverse of the absolute risk reduction (ARR). The ARR is the absolute difference in the rates of events between the incidence of events in the control group and treatment group. We calculated NNT and CNT using “HDS Plotter-ICE Box-NNT-Incremental Cost-Effectiveness Calculator”-Copyright, Health Decision Strategies, LLC.
For calculating the CNT, we used the cost of the lowest and highest dose of the drug in the ICE box plotter. Since various brands (i.e., trade names) with wide cost range are available in the Indian market, the average retail price in Indian Rupees for the year 2019 was considered and used for the analysis.
On the basis of this, we computed NNT and CNT and analyzed the cost-effectiveness of enalapril, bisoprolol, carvedilol, nebivolol, spironolactone, valsartan, ivabradine, ARNi (sacubitril and valsartan), and empagliflozin. We compared CNT of these drugs with India's per capita Gross Domestic Product (GDP), and we fixed the WHO recommendation of three times per capita GDP as the limit to ascertain whether a drug meets cost-effectiveness thresholds.
| Results|| |
Enalapril (ACEi) in India is the class leading drug in the treatment of heart failure. In the “Studies of Left Ventricular Dysfunction” (SOLVD) trial published in 1991, the addition of Enalapril to conventional therapy significantly reduced the mortality and hospitalization for heart failure in patients with congestive heart failure and reduced ejection fraction. Based on this trial, to prevent one CV death, five patients had to be on enalapril per year (NNT), amounting to an expense of $143.50(Rs. 10,260) for 1 year (CNT). To reduce heart failure admissions, enalapril had values of four and $109.60 (Rs. 7836) as its NNT per year and CNT per year, respectively [Table 1].
|Table 1: Number needed to treat per year and cost needed to treat per year of cardiovascular mortality and heart failure hospitalization for various heart failure medications in India|
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The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II) published in 1999 investigated the efficacy of Bisoprolol, a beta selective adrenoreceptor blocker, in decreasing all-cause mortality in chronic heart failure with reduced ejection fraction. The NNT per year of bisoprolol for preventing CV mortality was 24 at a CNT per year of $1095.40 (Rs. 78,320). Results from [Table 1] state that for preventing one heart failure hospitalization using bisoprolol, NNT per year was fourteen, and CNT per year turned out to be $632.30 (Rs. 45,208).
The Randomized Aldactone Evaluation Study published in the same year as CIBIS-II concluded that blockade of aldosterone receptors by Spironolactone, in addition to the standard therapy, substantially reduced the risk of both morbidity and mortality in patients with severe heart failure. The NNT per year of spironolactone to prevent CV mortality was considerably lower at five and that too at a lower CNT of $78 (Rs. 5577) per year [Table 1]. Spironolactone could also reduce heart failure hospitalization with NNT per year of five and with a significantly reduced CNT of $84 (Rs. 6006) per year. This emphasized the importance of spironolactone in the treatment of heart failure with reduced ejection fraction.
CIBIS-II, MERIT-HF trials have demonstrated the mortality benefits of beta-adrenergic blockade in patients with mild to moderate heart failure. The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial showed similar benefits in mortality and morbidity in patients with severe heart failure. Carvedilol had an NNT per year of twelve, which showed its effectiveness at a CNT of $193 (Rs. 13,799) for preventing CV mortality. CAPRICORN (Carvedilol Post-Infarct Survival Control in LV Dysfunction) trial was analyzed for obtaining NNT per year and CNT per year of carvedilol for preventing heart failure hospitalization. Carvedilol had NNT per year of forty but a higher CNT per year of $640 (Rs. 45,759) for preventing heart failure re-hospitalization when compared with CNT per year of mortality prevention.
Valsartan Heart Failure Trial (Val-HeFT) was a 1 year 9 month trial published in 2001 which showed the beneficial effects in morbidity, clinical signs and symptoms in patients with heart failure when Valsartan is the ARB prescribed in heart failure treatment regimen. The NNT per year of Valsartan to prevent CV mortality from this trial was 273 at a CNT per year of $54620.5 (Rs. 3,905,311), which implies the huge cost valsartan adds to attain mortality benefit, whereas to prevent heart failure hospitalization, valsartan had an NNT per year of twelve and CNT per year of $2377.4 (Rs. 169,981) which is much lower than the values to prevent CV mortality. This makes valsartan beneficial in reducing hospital admissions than in preventing mortality in heart failure.
The study of the effects of Nebivolol Intervention on Outcomes and re-hospitalization in seniors with Heart Failure (SENIORS) was a 1 year 9 month study which showed that Nebivolol, a beta-blocker with vasodilating properties, was an effective and well-tolerated treatment for heart failure in the elderly. Nebivolol had an NNT per year of 27 to prevent CV mortality with CNT per year of $1950 (Rs. 139,836). To prevent one heart failure hospitalization, twenty eight patients had to be on Nebivolol at a CNT value of $2064.6 (Rs. 147,616). Nebivolol hence had lower CNT per year for preventing mortality.
Systolic Heart Failure Treatment with the If inhibitor Ivabradine Trial was a 1.9 years trial published in 2010 and it showed the importance of heart rate reduction with ivabradine for improvement of clinical outcome in patients with heart failure. Ivabradine, when used in heart failure treatment turned out to have an NNT per year value of 44 and CNT per year of $7524.2 (Rs. 537,972) to prevent CV mortality. To have a reduction in heart failure hospitalization, NNT per year and CNT per year values of ivabradine were eleven and $1892.1 (Rs. 135,682), respectively. This shows that Ivabradine has a better potential to reduce re-admissions than to bring about a reduction in mortality.
The prospective comparison of ARNi with ACEi to determine the impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF) published in 2014 was a 2 year 3 month year trial which compared Enalapril and ARNi, among which ARNi was found to be superior to Enalapril in reducing the risk of death and of hospitalization for heart failure. ARNi had NNT per year of fourteen and a CNT per year of $12,378 (Rs. 885,014) to prevent CV mortality. At the same time, to prevent heart failure hospitalization, NNT per year of ARNi was sixteen and CNT per year calculated was $13,836.5 (Rs. 989,295). The CNT of ARNi will definitely reduce once the drug is out of its patency period, thereby improving its pharmaco-economic profile.
The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG Outcome Trial) published in 2015 was a 3 years 1 month trial that showed the beneficial effect of this oral hypoglycemic agents in lowering the rate of CV death in type 2 Diabetes mellitus patients, which was a very surprising finding. The NNT per year and CNT per year to prevent CV mortality as per EMPA-REG trial data were fifteen, $3881.3(Rs. 27,487), respectively. For a reduction of one heart failure hospitalization NNT per year was higher at 23, whereas CNT per year was $6177.7(Rs. 441,699).
As heart failure worsens, patients are likely to receive a higher dose of these disease-modifying drugs, the costs involved per patient per year ($) using these medications at maximum therapeutic dose were also analysed [Figure 1].
|Figure 1: Log prices (in US$) of various heart failure drugs at minimum to maximum dose range in India. ACEi: Angiotensin-converting enzyme inhibitor, NEBI: Nebivolol, BISO: Bisoprolol, CARV: Carvedilol, ARB: Angiotensin receptor blocker, MRA: mineralocorticoid receptor antagonist, IFI: If inhibitor, ARNi: Angiotensin neprilysin inhibitor, SGLT-2 I: Sodium-glucose co-transporter inhibitor.|
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As our analysis depended only on a limited number of outcomes, we depended on NNT analysis to recommend the cost-effectiveness of the treatment methods. [Figure 2] thus summarizes the Incremental Cost-effectiveness ratio (ICER) of various trials and found three of them crossing the upper limit of cost-effectiveness.
|Figure 2: Log number needed to treat per year versus log cost needed to treat per year (based on different trials) to prevent cardiovascular mortality-1.|
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With the understanding that NNTs satisfy the premises of being equivalent to other measures such as quality-adjusted life-year (QALYs), the ICER of the interventions on heart failure hospitalization revealed that only one trial exceeded the level of cost-effectiveness [Figure 3]. Quality, size, and validity are fundamental in using NNTs in place of QALYs, but the randomized trials assessed in the article to some extent, fulfill those criteria.
|Figure 3: Log number needed to treat per year versus log cost needed to treat per year (based on different trials) to prevent heart failure hospitalization in India.|
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| Discussion|| |
Heart failure in India has neither been studied extensively nor does a specific treatment protocol exist in India, using the costs of various drugs used in the treatment of heart failure. Most of the studies, including major landmark trials in the field of heart failure, resulted in management guidelines being revised by the addition of newer drugs that are more effective and also improves the quality of life of these patients. However, all these newer drugs are costlier and beyond the reach of the common man. This prompted us to undertake our study in pharmaco-economics of heart failure in the Indian scenario.
In our study, we analyzed the cost-effectiveness of drugs for treating chronic heart failure based on treatment recommendations as per consensus for the treatment of chronic heart failure published in the Indian Heart Journal of Cardiac Society of India January 2018 issue. This is the only available consensus for treating heart failure in the Indian scenario. As per this document, the medications (BB, ACEi, ARB, MRA, diuretics, ARNi, Sodium-Glucose Co-Transporter-2 inhibitors) that were labeled as Class I were included in our analysis. We derived the various parameters like CNT, NNT from various international landmark trials of these drugs. Hence, we have calculated the cost of treatment individually for each drug for reducing morbidity and mortality. However, no studies are available till date for the combination of these drugs, which is the actual scenario when it comes to the treatment of heart failure.
Data extracted from the SOLVD trial (1991) when applied in the Indian health sector, the government needs to spend US$ 108.6 (Rs. 7800) per year per patient (which falls well within three times per capita GDP cutoff of India) for preventing premature mortality due to heart failure. Enalapril is now available in most of the government hospital run pharmacies and is available free of cost to patients and hence has been a pivotal drug for improving the mortality of Indians with heart failure at a satisfying pharmaco-economic value.
Bisoprolol from the CIBIS II trial had better pharmaco-economic value in preventing hospitalization than reducing mortality. Carvedilol (COPERNICUS trial) closely followed suit but with a better value in preventing cardiovascular mortality than re-hospitalization reduction. These two drugs had CNT value within three times of Indian per capita GDP hence can be considered to be given free of cost or at subsidized rates. In India, nebivolol is the preferred BB in patients with obstructive airway disease. Its CNT showed that it is more economical in preventing mortality than reducing hospitalizations due to heart failure.
Along with diuretics (frusemide), aldosterone receptor blocker (Spironolactone) has shown significant improvement in Indian patients as per various heart failure registries. CNT and NNT of spironolactone are so low for reducing morbidity and mortality that it is already in the list of drugs given free of cost by the government.
The role of Ivabradine is in preventing heart failure hospitalization and not in preventing mortality, as evidenced by the wide difference in the respective CNTs. CNT per year to prevent CV mortality is approximately four times the per capita GDP of India, but the CNT per year to prevent heart failure hospitalization was well within the proposed WHO cutoff.
Valsartan has gained importance in the treatment of heart failure both alone as well as in the most acclaimed combination with Sacubitril (ARNi). It is surprising that Valsartan has a very high NNT per year of 273.1 and CNT per year of $54620.5which is twenty-six times the per capita GDP of India to prevent CV mortality. Every practicing physician and the health care sector professional should be aware of the fact that prescribing valsartan for heart failure may reduce cardiac mortality (high NNT) and morbidity, but the same is not economically viable in India when compared to lower-cost drugs like Enalapril.
The approval of sacubitril-valsartan marked the first new medication with a demonstrated mortality benefit in HFrEF in >10 years. Great interest and awe have been reciprocated by the Indian physicians and cardiologists for ARNi. PARADIGM-HF catapulted ARNi to the helm of treatment protocols endorsed by all the international and national associations of cardiology alike. The cost-effectiveness of ARNi when analyzed on the basis of PARADIGM-HF revealed that the CNT per year to prevent CV mortality and the same to prevent heart failure hospitalization was approximately six times the per capita GDP of India. Currently, the cost of sacubitril-valsartan is decided by the patency holding company; once the patency period is over the cost will considerably come down and will influence favorably its clinical utility in India.
Patients with type 2 diabetes who are at high risk for cardiovascular events had significantly lower cardiovascular outcomes and death from any cause while on empagliflozin. In the course of the study, hospitalization for heart failure showed a 35% relative risk reduction. Cost-effectiveness of Empagliflozin showed favorable CNT per year to prevent CV mortality, which is two times the GDP and the same to prevent heart failure hospitalization, which is about three times the per capita GDP of India.
| Conclusion|| |
Although there were scarce availability of literature on treatment of heart failure in India and an absence of treatment guideline we could identify drugs that have cost-benefit and cost-effectiveness suited for the Indian health sector to cater economically deprived section of heart failure patients. Through this economic evaluation of drugs for the treatment of heart failure in India, we intend to guide the formulation of treatment policies in the country.
Our study had to make assumptions regarding hospitalization rates and CV mortality due to the absence of studies on clinical trials of heart failure drugs from India. Our study utilized data from landmark trials of each drug we studied. Moreover, no studies are available till date for the combination of these drugs, which is the actual scenario when it comes to the treatment of heart failure in the country. For future research compliance factors for these treatments need to be assessed along with Willingness to Pay to understand the real acceptance of these drugs on the ground in India.
Since the study did not involve the recruitment of human subjects, ethical committee clearance was not required as per our institution guidelines (IEC NO.: ECR/878/InsuKLI2016).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302.
Brunhuber LP, Hofmann KW, Kuhn R, Nesser P, Joachim H, Slany J, et al
. The cardiac insufficiency bisoprolol study II (CIBIS II): A randomized trial. Lancet 1999;353:9-13.
Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al.
The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-17.
Eichhorn EJ, Bristow MR. The carvedilol prospective randomized cumulative survival (COPERNICUS) trial. Curr Control Trials Cardiovasc Med 2001;2:20-3.
Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: The CAPRICORN randomised trial. Lancet 2001;357:1385-90.
Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-75.
Flather MD, Shibata MC, Coats AJ, Van Veldhuisen DJ, Parkhomenko A, Borbola J, et al.
SENIORS Investigators Randomised trial to determine the effect of nebivolol on mortality and hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26:215-25.
Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, et al
. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study. Lancet 2010;376:875-85.
McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al.
Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al
. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes”. N Engl J Med 2015;373:2117-28.
Sanjay G, Jeemon P, Agarwal A, Viswanathan S, Sreedharan M, Vijayaraghavan G, et al
. In-hospital and three-year outcomes of heart failure patients in South India: The trivandrum heart failure registry. J Card Fail 2018;24:842-8.
Chaturvedi V, Parakh N, Seth S, Bhargava B, Ramakrishnan S, Roy A, et al
. The INDUS (INDiaUkireri Study) study. J Pract Cardiovasc Sci 2016;2:28-35. [Full text]
Titler MG, Jensen GA, Dochterman JM, Xie XJ, Kanak M, Reed D, et al.
Cost of hospital care for older adults with heart failure: Medical, pharmaceutical, and nursing costs. Health Serv Res 2008;43:635-55.
Masri A, Althouse AD, McKibben J, Thoma F, Michael M, Ramani R, et al.
Outcomes of heart failure admissions under observation versus short inpatient stay. J Am Heart Assoc 2018;7:e007944.
Kuehn BM. High costs and caution yield slow start for new heart drugs. AHA J 2018;137:197-9.
Hutubessy R, Chisholm D, Edejer TT. Generalized cost-effectiveness analysis for national-level priority-setting in the health sector. Cost Eff Resour Alloc 2003;1:8.
Ahuja J, Gupta M, Gupta AK, Kohli K. Pharmaco-economics. Natl Med J India 2004;17:80-3.
McMurray JJ, Stewart S. The burden of heart failure. Eur Heart J Suppl 2002;4:D50-8.
[Figure 1], [Figure 2], [Figure 3]