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PCSK9 inhibitors may improve cardiovascular outcomes—Can we afford them?
International Journal of Cardiology 220 (2016) 242–245
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
PCSK9 inhibitors may improve cardiovascular outcomes—Can we afford them? Ronen Arbel a,b,⁎, Ariel Hammerman c, Noa Triki d, Dan Greenberg a a
Department of Health Systems Management, Faculty of Health Sciences and The Guilford-Glazer Faculty of Business and Management, Ben-Gurion University of the Negev, Beer-Sheva, Israel Department of Technology Marketing, Sapir College, D.N. Hof Ashkelon 79165, Israel Department of Pharmaceutical Technology Assessment, Chief Physician's Office, Clalit Health Services Headquarters, Tel-Aviv, Israel d Department of Health Technology Policy, Maccabi Healthcare Services, Tel-Aviv, Israel b c
a r t i c l e
i n f o
Article history: Received 27 April 2016 Received in revised form 12 June 2016 Accepted 22 June 2016 Available online 23 June 2016 Keywords: Evolocumab Alirocumab LDL cholesterol Affordability Budget-impact
a b s t r a c t Background/Objectives: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) can significantly lower low-density lipoprotein (LDL) cholesterol levels. Early evidence suggests that use of PCSK9i also reduces the incidence of major adverse cardiovascular events (MACE). Our objective was to determine preliminary economic implications of PCSK9i use to avoid MACE, based on the current data from major phase III clinical trials. Methods: Outcome data of the 4529 patients treated with PCSK9i in the OSLER and ODYSSEY LONG TERM trials were collected from the published reports. Cost of preventing MACE was evaluated based on the existing outcome data and current US prices of PCSK9i. The pooled results were compared to the cost of curing Hepatitis C Virus (HCV) patients with novel HCV drugs. Results: PCSK9i treatment in the OSLER and ODYSSEY LONG TERM trials resulted in prevention of 35 MACE in a total of 4903 patient-years: 8 cardiovascular deaths, 22 myocardial infarctions, 0 strokes and 5 unstable anginas. The cost of PCSK9i drugs consumed during the trial's current follow-up period, could have reached $70,172,141. Therefore, the cost of preventing any MACE would be $2,004,918 and the cost of preventing one death would be $8,777,518. These figures are one hundred fold higher than the cost of curing one HCV patient (~$84,000). Conclusions: According to the current published data, using PCSK9i to prevent MACE seems to be a very expensive strategy. If upcoming outcome trials will demonstrate similar results, it seems that at current prices, using these drugs would not be affordable for most healthcare systems. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) Evolocumab and Alirocumab have shown a significant benefit in reducing low-density lipoprotein cholesterol (LDL) levels in several short-term studies [1]. The OSLER and ODYSSEY LONG TERM studies published in 2015 demonstrated early evidence of improving patient outcomes by reducing the rate of major adverse cardiovascular events (MACE) compared to standard statin therapy [2,3]. Based on these trials, the Food and Drug Administration (FDA) approved Evolocumab and
Abbreviation: CV, cardiovascular; FDA, Food and Drug Administration; HCV, hepatitis C virus; ICER, Institute for Clinical and Economic Review; LDL, low-density lipoprotein; MACE, major adverse cardiovascular events; MI, myocardial infarction; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitors; SOC, standard of care; UA, unstable angina. ⁎ Corresponding author at: Maximizing Health Outcomes under Constrained Budgets Research Lab, Department of Technology Marketing, Sapir College, D.N. Hof Ashkelon 79165, Israel. E-mail address: [email protected] (R. Arbel).
http://dx.doi.org/10.1016/j.ijcard.2016.06.126 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
Alirocumab for the treatment of hyperlipidemia, adjunct to diet and maximally tolerated statin therapy, in adult patients with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL levels [4,5]. Evolocumab is also indicated for the rare condition of homozygous familial hypercholesterolemia. Based on these two trials and the FDA approval, the National Lipid Association and the 2016 ACC Expert Consensus have already published updated guidelines to consider treatment with PCSK9i according to the approved FDA indications [6]. PCSK9i present an extraordinary challenge for healthcare payers. This is the first major case in which a specialty biologic drug is approved for a relatively common condition [7]. The entire intended population for PCSK9i treatment, according to the approved FDA indications, is estimated at more than 9.3 million patients in the US [8]. Based on the average US list price of $14,300 per year of treatment, the annual budget needed to treat this population could reach more than $130 billion. However, not all patients who meet the indication in the PCSK9i FDA label, would actually be treated with a PCSK9i. The recent published “2016 ACC Expert Consensus 2016 ACC Expert Consensus Decision Pathway
R. Arbel et al. / International Journal of Cardiology 220 (2016) 242–245
243
Table 1 Prevented MACE in ODYSSEY LONG TERM and OSLER trials and combined data. Trial
ODYSSEY LONG TERM
OSLER 1 + 2
Combined data
Treated patients
1553
2976
4529
Treated patient years
2091
2812
4903
Drug/MACE
Alirocumab + SOC
SOC
Prevented MACE
Evolucumab + SOC
SOC
Prevented MACE
Evolucumab or Alirocumab
Total SOC
Total Prevented MACE
CV or unknown death Nonfatal MI Nonfatal stroke UA requiring hospitalization Total MACE
8 14 5 0 27
14 35 4 2 55
6 21 −1 2 28
4 9 3 3 19
6 10 4 6 26
2 1 1 3 7
12 23 8 3 46
20 45 8 8 81
8 22 0 5 35
SOC = Standard of Care; CV = Cardiovascular; MI = Myocardial Infarction; MACE = Major Adverse Cardiovascular Events; UA = Unstable Angina; all MACE estimates rounded to whole numbers.
on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk ” [9] mentions “cost” as one of the major considerations in prescribing PCSK9 inhibitors and in the clinician-patient discussion regarding these drugs. As the ultimate goal of treating patients with PCSK9i is to reduce the rate of MACE, our objective was to determine the preliminary economic implications of achieving this goal, using the currently available outcome and follow-up data from the major published clinical trials. Although there have been at least 24 trials evaluating PCSK9i [1], most were conducted for a few weeks or months, too short follow up to evaluate definitive clinical outcomes. Our analysis focuses on the two longer term trials published to date: The Evolocumab “Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER)” phase III trial [2], with a mean follow-up of 50 weeks, and the Alirocumab “Longterm Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Drugs (ODYSSEY LONG TERM)” trial [3], with a mean follow-up of 78 weeks.
2. Methods Outcome data of patients enrolled in the OSLER and ODYSSEY LONG TERM trials were collected from the published trial reports. MACE was defined as termed and positively adjudicated in the ODYSSEY LONG TERM trial [2]: cardiovascular or unknown death; non-fatal myocardial infarction (MI), stroke and unstable angina (UA) requiring hospitalization. Cost of preventing MACE was approximated based on the existing published outcome data and current US prices of the PCSK9i. The results were compared to the cost of curing Hepatitis C Virus (HCV) patients with novel Hepatitis C drugs. We performed a one-way sensitivity analysis to examine the impact of PCSK9i hazard ratio of preventing any MACE on the cost of MACE prevention. Since the ODYSSEY LONG TERM trial reported a hazard ratio of adjudicated MACE of 0.53, with 95% confidence interval of 0.31 to 0.90 and the OSLER trial reported a comparable hazard ratio of 0.47 (including revascularization as MACE), with 95% confidence interval of
0.28 to 0.78, we used these 95% confidence intervals as a reference to the sensitivity analysis. A separate sensitivity analysis of the cost of preventing one CV death was also performed. This sensitivity analysis considered the following parameters: the annual cost of PCSK9i (since using the US list price may overestimate the actual price), the risk of CV death in the population treated with standard of care (SOC), and the relative risk reduction with the use of PCSK9i. 3. Results The combined results of the OSLER and ODYSSEY LONG TERM reveal that using PCSK9i by the 4529 patients enrolled in both trials led to the prevention of 35 MACE: 8 cardiovascular deaths, 22 myocardial infarctions, 0 strokes and 5 unstable angina requiring hospitalizations (Table 1). The estimated cost of using PCSK9i during the 4903 patientyears of follow-up would have been $70,172,141 at current US prices. The average cost for one prevented MACE would therefore be $2,004,098 and the average cost for each prevented death would be $8,771,558. The cost of preventing one death with PCSK9i was found to be one hundred fold higher than the cost of curing one HCV patient with novel Hepatitis C drugs (at $84,000 for an average protocol [11]). In a one-way sensitivity analysis, the cost per prevented MACE ranged from $1,238,259 to $6,254,202 (Table 2) and the cost per prevented death ranged from $4,385,758 to $35,086,070 (Table 3). 3.1. Revascularization as an additional MACE endpoint Coronary revascularization was not included as an endpoint in this analysis as there was some concern that the decision of revascularization may have been affected by the open label design of the trials and since in many trials revascularization is not considered as MACE. Moreover, the endpoints examined in this analysis were the same outcomes that were pre-specified in the ODYSSEY OUTCOMES trial [10]. However, since the OSLER trials had included revascularization as a MACE, we performed a separate sensitivity analysis to include the prevention of revascularizations as an additional endpoint (Table 4). The costs for
Table 2 Sensitivity analysis of costs for MACE prevention. Trial
ODYSSEY LONG TERM
Drug
Alirocumab + SOC
SOC
Prevented MACE
HR
Evolucumab + SOC
OSLER 1 + 2 SOC
Prevented MACE
HR
Combined data Evolocumab or Alirocumab
Total SOC
Total prevented MACE
Cost per prevented MACE
Base case HR 95% CI (low) HR 95% CI (high)
27 17 50
55 55 55
28 38 5
0.49 0.31 0.9
19 7 20
26 26 26
7 19 6
0.73 0.28 0.78
46 24 70
81 81 81
35 57 11
$2,004,918 $1,238,259 $6,254,202
SOC = Standard of Care; MACE = Major Adverse Cardiovascular Events; HR = Hazard Ratio; all MACE estimates rounded to whole numbers.
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R. Arbel et al. / International Journal of Cardiology 220 (2016) 242–245
Table 3 Sensitivity analysis of the costs of preventing one CV death. CV deaths prevented
Cost per prevented CV death
Parameter analyzed
Value Min
Base case
Max.
Min
Base case
Max
Min.
Base case
Max.
Annual cost of PCSK9i Relative risk of CV death in population treated with PCSK9i Relative risk of CV death of patients treated by SOC, compared to study data
$7150 30% 50%
$14,300 60% 100%
$17,160 90% 200%
8 14 4
8 8 8
8 2 16
$4,385,758 $5,012,295 $17,543,035
$8,771,517 $8,771,517 $8,771,517
$10,525,821 $35,086,070 $4,385,758
SOC = Standard of Care; PCSK9i = Proprotein Convertase Subtilisin/Kexin type 9 inhibitors; CV = cardiovascular; all MACE estimates rounded to whole numbers.
preventing MACE including revascularization were between $617,881 and $2,999,809, compared to the base case of $1,324,003 per MACE prevented.
effectiveness ratios compared to PCSK9i, ranging from $9700 to $284,000 per QALY gained [15]. 4.2. Budget impact
4. Discussion Both Alirocumab and Evolocumab have a proven and significant efficacy in lowering LDL levels; however, current published studies were too short and underpowered to assess the clinical endpoints of avoiding MACE including cardiovascular death. The number of outcome events on which to base such efficacy is small, with a large margin of error in the effect size. Performing a traditional cost-effectiveness analysis using the current limited data is challenging and requires modeling and many assumptions. We therefore have focused our analysis on straightforward economic implications, based on the limited available data at present. Recently, the Institute for Clinical and Economic Review (ICER) has attempted to perform an initial cost-effectiveness analysis of PCSK9i [8]. The Incremental cost-effectiveness ratios were estimated by ICER at $681,000 for a quality-adjusted-life-year gained (QALY) in familial hyperlipidemia patients, $557,000 for patients with history of coronary artery disease on statin therapy and $506,000 for statin-intolerant patients with history of coronary artery disease. These ratios are beyond any acceptable threshold value to determine good value for money. Although one of the PCSK9i manufacturers has pointed to many potential flaws in the ICER draft paper [11], they did not provide an alternative economic assessment. As of so, the ICER cost-effectiveness analysis could be used as some reference and an external validation to our findings. Consequently, in the UK, the National Institute for Health and Care Excellence (NICE) has issued a preliminary report [12] stating that Evolocumab, alone or in combination with lipid-lowering therapies, is not recommended within its marketing authorization for treating primary hypercholesterolemia, even though the price of the drugs in the UK is about half of the US price. Similarly, the Israel 2016 “Health Basket” committee rejected the drugs for the wider indications and approved Evolocumab only for the rare condition of homozygous familial hypercholesterolemia, which includes 14 patients in Israel [13]. 4.1. Comparison to HCV In our analysis, we chose to compare the cost of preventing death with PCSK9i to the cost of the novel drugs for treating HCV. The HCV drugs have been scrutinized extensively recently for their high costs and budget impact [10,14] despite having substantially better cost-
Regarding the budget-impact issue, the $70,172,141 assumed cost of PCSK9i consumed in the clinical trials could have provided the healthcare system 23,884 patient-years of therapy with high potency statins in high risk patients, as were enrolled in the JUPITER trial [16] (based on the US average online cost of branded Rosuvastatin; $2938). Allocating these funds for Rosuvastatin would have resulted in the prevention of 110 MACE compared to 35 avoided MACE using PCSK9i for its indications (Fig. 1). 4.3. Limitations Our analysis and presentation has several limitations. The primary limitation is the limited outcome data in current published trials. These studies recruited mainly low-risk populations and were not designed to test clinical endpoints. The ongoing phase III outcomes trials are enrolling higher risk patient population and event rates are projected to be substantially higher. The Evolocumab Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) [3], and the Alirocumab ODYSSEY OUTCOMES [10] trial are designed to evaluate the long term outcomes of these drugs and should provide more definitive data. Nevertheless, as the FDA already approved the two drugs for regular use and since they are already being utilized, it is not too early to explore the economic implications of these therapies. The second limitation of this analysis is that we assumed that the rate of MACE under SOC therapy and with PCSK9i will remain similar during a longer follow-up [17–19]. However, if the rate of MACE with SOC will grow higher in longer follow-up and rate of MACE under PCSK9i therapy will remain low, these therapies will provide higher value and the costs of each prevented MACE or death could decrease substantially. Our sensitivity analysis examines and presents various scenarios that cover the spectrum of possible outcome results from the FOURIER and ODYSSEY OUTCOMES trials and with a longer follow-up of the current published trials. A third limitation is our reliance on only two studies, each of which has its own limitations. One of the concerns with the ODYSSEY trial was that only 47% of its SOC patients were receiving high-dose statin therapy, which may have affected the MACE rate at the control group [20], and may have overestimated the effect of Alirocumab.
Table 4 Sensitivity analysis of costs for MACE prevention including revascularization events. Trial
ODYSSEY LONG TERM
Drug
Alirocumab + SOC
SOC
Prevented MACE
HR
OSLER 1 + 2 Evolucumab + SOC
SOC
Prevented MACE
HR
Evolucumab or Alirocumab
Combined data Total SOC
Total prevented MACE
Cost per prevented MACE
Base case HR 95% CI (low) HR 95% CI (high)
75 32 92
102 102 102
27 70 10
0.73 0.31 0.9
34 17 47
60 60 60
26 43 13
0.57 0.28 0.78
109 48 139
162 162 162
53 114 23
$1,324,003 $617,881 $2,999,809
SOC = Standard of Care; MACE = Major Adverse Cardiovascular Events; HR = Hazard Ratio; all MACE estimates rounded to whole numbers.
R. Arbel et al. / International Journal of Cardiology 220 (2016) 242–245
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References
Fig. 1. Comparison of prevented MACE using the $70,172,141 budget.
Another important limitation is that we combined the data of two different drugs, which although have a similar mechanism of action and present similar effects on lowering of LDL, may have different effects on preventing MACE. The inclusion criteria of the two trials and within the OSLER trials were not identical as OSLER recruited patients from previous trials with varied inclusion criteria. Due to limited outcome data we only analyzed the merged MACE data – while in practice, each endpoint has different economic and quality of life implications. Finally, we did not include in our analysis the short or the long-term savings associated with preventing MACE. Given the modest number of MACE prevented, these savings are unlikely to have a major impact on our study findings. 5. Conclusions According to the current published data of the major trials that were the base of PCSK9i approval, using PCSK9i to prevent MACE seems to be a very expensive strategy. If upcoming outcome trials will demonstrate similar results, it seems that at the current prices, using these drugs to improve cardiovascular outcomes might not be affordable. Healthcare decision-makers will need to explore for reasonable cost-effective strategies for adopting these promising therapies, targeting them to the most unmet need patients, while searching for novel ways to significantly lower the cost of these drugs. Statement of authorship All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Sources of funding None. Conflict of interest/Disclosures The authors report no relationships that could be construed as a conflict of interest.
[1] E.P. Navarese, M. Kolodziejczak, V. Schulze, et al., Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia, Ann. Intern. Med. 163 (2015) 40. [2] J.G. Robinson, M. Farnier, M. Krempf, et al., Efficacy and safety of Alirocumab in reducing lipids and cardiovascular events, N. Engl. J. Med. 372 (2015) 1489–1499. [3] M.S. Sabatine, R.P. Giugliano, S.D. Wiviott, et al., Efficacy and safety of Evolocumab in reducing lipids and cardiovascular events, N. Engl. J. Med. 372 (2015) 1500–1509. [4] United States Food and Drug Administration, FDA approves Repatha to treat certain patients with high cholesterol, http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm460082.htm; (Accessed March 14, 2016). [5] United States Food and Drug Administration, FDA approves Praluent to treat certain patients with high cholesterol, http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm455883.htm; (Accessed March 14, 2016). [6] T.A. Jacobson, K.C. Maki, C. Orringer, et al., National Lipid Association recommendations for patient-centered management of dyslipidemia: part 2, J. Clin. Lipidol. 9 (2015) 1–127. [7] W.H. Shrank, J.F. Barlow, T.A. Brennan, New therapies in the treatment of high cholesterol an argument to return to goal-based lipid guidelines, JAMA 314 (2015) 1443–1444. [8] Institute for Clinical and Economic Review, PCSK9 inhibitors for treatment of high cholesterol: effectiveness, value, and value based price benchmarks draft report, 2015 Available from: www.icer-review.org (Accessed March 14, 2016). [9] D.M. Lloyd-jones, W. Committee, P.B. Morris, W. Committee, C.M. Ballantyne, W. Committee, et al., ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk, J. Am. Coll. Cardiol. (2016), http://dx.doi.org/10.1016/j. jacc.2016.03.519 (E-pub ahead of print; 2016). [10] G.G. Schwartz, L. Bessac, L.G. Berdan, et al., Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial, Am. Heart J. 168 (2014) 682–689. [11] J.J. Ofman, AMGEN response to the CEPAC/ICER request for public comments on the PCSK9 inhibitor (PSCK9i) report, 2015 available at https://www.amgen.com/~/ media/amgen/full/www-amgen-com/downloads/amgen_response_to_icer_pcsk9i_ report.ashx?la=en (Accessed March 14, 2016). [12] The National Institute for Health and Care Excellence, Appraisal consultation document Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia, https://www.nice.org.uk/guidance/GID-TAG498/documents/appraisal-consultation-document, 2015 (Accesed Jan 10,2016). [13] Israel Basket Committee Recommendations, line item 68- Evolucumab (Hebrew), http://www.health.gov.il/newsandevents/spokemanmesseges/documents/ 07012016hamlazot_sal.pdf, 2016 (Accessed March 14, 2016). [14] A. Hill, G. Cooke, Hepatitis C can be cured globally, but at what cost? Science 345 (2014) 141–142. [15] J. Chhatwal, F. Kanwal, M.S. Roberts, et al., Cost-effectiveness and budget impact of hepatitis C virus treatment with Sofosbuvir and Ledipasvir in the United States, Ann. Intern. Med. 162 (6) (2015) 397–406. [16] P.M. Ridker, E. Danielson, F.A.H. Fonseca, et al., Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein, N. Engl. J. Med. 359 (2008) 2195–2207. [17] I. Ford, H. Murray, C.J. Packard, et al., Long-term follow-up of the West of Scotland Coronary Prevention Study, N. Engl. J. Med. 357 (2007) 1477–1486. [18] K.L. Margolis, B.R. Davis, C. Baimbridge, et al., Long-term follow-up of moderately hypercholesterolemic hypertensive patients following randomization to Pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT), J. Clin. Hypertens. 15 (2013) 542–554. [19] J.R. Downs, M. Clearfield, S. Weis, et al., Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels, JAMA 279 (1998) 1615–1622. [20] J.G. Robinson, J.J.P. Kastelein, PCSK9 inhibitors and cardiovascular events, N. Engl. J. Med. 373 (2015) 774.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
PCSK9 inhibitors may improve cardiovascular outcomes—Can we afford them? Ronen Arbel a,b,⁎, Ariel Hammerman c, Noa Triki d, Dan Greenberg a a
Department of Health Systems Management, Faculty of Health Sciences and The Guilford-Glazer Faculty of Business and Management, Ben-Gurion University of the Negev, Beer-Sheva, Israel Department of Technology Marketing, Sapir College, D.N. Hof Ashkelon 79165, Israel Department of Pharmaceutical Technology Assessment, Chief Physician's Office, Clalit Health Services Headquarters, Tel-Aviv, Israel d Department of Health Technology Policy, Maccabi Healthcare Services, Tel-Aviv, Israel b c
a r t i c l e
i n f o
Article history: Received 27 April 2016 Received in revised form 12 June 2016 Accepted 22 June 2016 Available online 23 June 2016 Keywords: Evolocumab Alirocumab LDL cholesterol Affordability Budget-impact
a b s t r a c t Background/Objectives: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) can significantly lower low-density lipoprotein (LDL) cholesterol levels. Early evidence suggests that use of PCSK9i also reduces the incidence of major adverse cardiovascular events (MACE). Our objective was to determine preliminary economic implications of PCSK9i use to avoid MACE, based on the current data from major phase III clinical trials. Methods: Outcome data of the 4529 patients treated with PCSK9i in the OSLER and ODYSSEY LONG TERM trials were collected from the published reports. Cost of preventing MACE was evaluated based on the existing outcome data and current US prices of PCSK9i. The pooled results were compared to the cost of curing Hepatitis C Virus (HCV) patients with novel HCV drugs. Results: PCSK9i treatment in the OSLER and ODYSSEY LONG TERM trials resulted in prevention of 35 MACE in a total of 4903 patient-years: 8 cardiovascular deaths, 22 myocardial infarctions, 0 strokes and 5 unstable anginas. The cost of PCSK9i drugs consumed during the trial's current follow-up period, could have reached $70,172,141. Therefore, the cost of preventing any MACE would be $2,004,918 and the cost of preventing one death would be $8,777,518. These figures are one hundred fold higher than the cost of curing one HCV patient (~$84,000). Conclusions: According to the current published data, using PCSK9i to prevent MACE seems to be a very expensive strategy. If upcoming outcome trials will demonstrate similar results, it seems that at current prices, using these drugs would not be affordable for most healthcare systems. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) Evolocumab and Alirocumab have shown a significant benefit in reducing low-density lipoprotein cholesterol (LDL) levels in several short-term studies [1]. The OSLER and ODYSSEY LONG TERM studies published in 2015 demonstrated early evidence of improving patient outcomes by reducing the rate of major adverse cardiovascular events (MACE) compared to standard statin therapy [2,3]. Based on these trials, the Food and Drug Administration (FDA) approved Evolocumab and
Abbreviation: CV, cardiovascular; FDA, Food and Drug Administration; HCV, hepatitis C virus; ICER, Institute for Clinical and Economic Review; LDL, low-density lipoprotein; MACE, major adverse cardiovascular events; MI, myocardial infarction; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitors; SOC, standard of care; UA, unstable angina. ⁎ Corresponding author at: Maximizing Health Outcomes under Constrained Budgets Research Lab, Department of Technology Marketing, Sapir College, D.N. Hof Ashkelon 79165, Israel. E-mail address: [email protected] (R. Arbel).
http://dx.doi.org/10.1016/j.ijcard.2016.06.126 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
Alirocumab for the treatment of hyperlipidemia, adjunct to diet and maximally tolerated statin therapy, in adult patients with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL levels [4,5]. Evolocumab is also indicated for the rare condition of homozygous familial hypercholesterolemia. Based on these two trials and the FDA approval, the National Lipid Association and the 2016 ACC Expert Consensus have already published updated guidelines to consider treatment with PCSK9i according to the approved FDA indications [6]. PCSK9i present an extraordinary challenge for healthcare payers. This is the first major case in which a specialty biologic drug is approved for a relatively common condition [7]. The entire intended population for PCSK9i treatment, according to the approved FDA indications, is estimated at more than 9.3 million patients in the US [8]. Based on the average US list price of $14,300 per year of treatment, the annual budget needed to treat this population could reach more than $130 billion. However, not all patients who meet the indication in the PCSK9i FDA label, would actually be treated with a PCSK9i. The recent published “2016 ACC Expert Consensus 2016 ACC Expert Consensus Decision Pathway
R. Arbel et al. / International Journal of Cardiology 220 (2016) 242–245
243
Table 1 Prevented MACE in ODYSSEY LONG TERM and OSLER trials and combined data. Trial
ODYSSEY LONG TERM
OSLER 1 + 2
Combined data
Treated patients
1553
2976
4529
Treated patient years
2091
2812
4903
Drug/MACE
Alirocumab + SOC
SOC
Prevented MACE
Evolucumab + SOC
SOC
Prevented MACE
Evolucumab or Alirocumab
Total SOC
Total Prevented MACE
CV or unknown death Nonfatal MI Nonfatal stroke UA requiring hospitalization Total MACE
8 14 5 0 27
14 35 4 2 55
6 21 −1 2 28
4 9 3 3 19
6 10 4 6 26
2 1 1 3 7
12 23 8 3 46
20 45 8 8 81
8 22 0 5 35
SOC = Standard of Care; CV = Cardiovascular; MI = Myocardial Infarction; MACE = Major Adverse Cardiovascular Events; UA = Unstable Angina; all MACE estimates rounded to whole numbers.
on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk ” [9] mentions “cost” as one of the major considerations in prescribing PCSK9 inhibitors and in the clinician-patient discussion regarding these drugs. As the ultimate goal of treating patients with PCSK9i is to reduce the rate of MACE, our objective was to determine the preliminary economic implications of achieving this goal, using the currently available outcome and follow-up data from the major published clinical trials. Although there have been at least 24 trials evaluating PCSK9i [1], most were conducted for a few weeks or months, too short follow up to evaluate definitive clinical outcomes. Our analysis focuses on the two longer term trials published to date: The Evolocumab “Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER)” phase III trial [2], with a mean follow-up of 50 weeks, and the Alirocumab “Longterm Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Drugs (ODYSSEY LONG TERM)” trial [3], with a mean follow-up of 78 weeks.
2. Methods Outcome data of patients enrolled in the OSLER and ODYSSEY LONG TERM trials were collected from the published trial reports. MACE was defined as termed and positively adjudicated in the ODYSSEY LONG TERM trial [2]: cardiovascular or unknown death; non-fatal myocardial infarction (MI), stroke and unstable angina (UA) requiring hospitalization. Cost of preventing MACE was approximated based on the existing published outcome data and current US prices of the PCSK9i. The results were compared to the cost of curing Hepatitis C Virus (HCV) patients with novel Hepatitis C drugs. We performed a one-way sensitivity analysis to examine the impact of PCSK9i hazard ratio of preventing any MACE on the cost of MACE prevention. Since the ODYSSEY LONG TERM trial reported a hazard ratio of adjudicated MACE of 0.53, with 95% confidence interval of 0.31 to 0.90 and the OSLER trial reported a comparable hazard ratio of 0.47 (including revascularization as MACE), with 95% confidence interval of
0.28 to 0.78, we used these 95% confidence intervals as a reference to the sensitivity analysis. A separate sensitivity analysis of the cost of preventing one CV death was also performed. This sensitivity analysis considered the following parameters: the annual cost of PCSK9i (since using the US list price may overestimate the actual price), the risk of CV death in the population treated with standard of care (SOC), and the relative risk reduction with the use of PCSK9i. 3. Results The combined results of the OSLER and ODYSSEY LONG TERM reveal that using PCSK9i by the 4529 patients enrolled in both trials led to the prevention of 35 MACE: 8 cardiovascular deaths, 22 myocardial infarctions, 0 strokes and 5 unstable angina requiring hospitalizations (Table 1). The estimated cost of using PCSK9i during the 4903 patientyears of follow-up would have been $70,172,141 at current US prices. The average cost for one prevented MACE would therefore be $2,004,098 and the average cost for each prevented death would be $8,771,558. The cost of preventing one death with PCSK9i was found to be one hundred fold higher than the cost of curing one HCV patient with novel Hepatitis C drugs (at $84,000 for an average protocol [11]). In a one-way sensitivity analysis, the cost per prevented MACE ranged from $1,238,259 to $6,254,202 (Table 2) and the cost per prevented death ranged from $4,385,758 to $35,086,070 (Table 3). 3.1. Revascularization as an additional MACE endpoint Coronary revascularization was not included as an endpoint in this analysis as there was some concern that the decision of revascularization may have been affected by the open label design of the trials and since in many trials revascularization is not considered as MACE. Moreover, the endpoints examined in this analysis were the same outcomes that were pre-specified in the ODYSSEY OUTCOMES trial [10]. However, since the OSLER trials had included revascularization as a MACE, we performed a separate sensitivity analysis to include the prevention of revascularizations as an additional endpoint (Table 4). The costs for
Table 2 Sensitivity analysis of costs for MACE prevention. Trial
ODYSSEY LONG TERM
Drug
Alirocumab + SOC
SOC
Prevented MACE
HR
Evolucumab + SOC
OSLER 1 + 2 SOC
Prevented MACE
HR
Combined data Evolocumab or Alirocumab
Total SOC
Total prevented MACE
Cost per prevented MACE
Base case HR 95% CI (low) HR 95% CI (high)
27 17 50
55 55 55
28 38 5
0.49 0.31 0.9
19 7 20
26 26 26
7 19 6
0.73 0.28 0.78
46 24 70
81 81 81
35 57 11
$2,004,918 $1,238,259 $6,254,202
SOC = Standard of Care; MACE = Major Adverse Cardiovascular Events; HR = Hazard Ratio; all MACE estimates rounded to whole numbers.
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Table 3 Sensitivity analysis of the costs of preventing one CV death. CV deaths prevented
Cost per prevented CV death
Parameter analyzed
Value Min
Base case
Max.
Min
Base case
Max
Min.
Base case
Max.
Annual cost of PCSK9i Relative risk of CV death in population treated with PCSK9i Relative risk of CV death of patients treated by SOC, compared to study data
$7150 30% 50%
$14,300 60% 100%
$17,160 90% 200%
8 14 4
8 8 8
8 2 16
$4,385,758 $5,012,295 $17,543,035
$8,771,517 $8,771,517 $8,771,517
$10,525,821 $35,086,070 $4,385,758
SOC = Standard of Care; PCSK9i = Proprotein Convertase Subtilisin/Kexin type 9 inhibitors; CV = cardiovascular; all MACE estimates rounded to whole numbers.
preventing MACE including revascularization were between $617,881 and $2,999,809, compared to the base case of $1,324,003 per MACE prevented.
effectiveness ratios compared to PCSK9i, ranging from $9700 to $284,000 per QALY gained [15]. 4.2. Budget impact
4. Discussion Both Alirocumab and Evolocumab have a proven and significant efficacy in lowering LDL levels; however, current published studies were too short and underpowered to assess the clinical endpoints of avoiding MACE including cardiovascular death. The number of outcome events on which to base such efficacy is small, with a large margin of error in the effect size. Performing a traditional cost-effectiveness analysis using the current limited data is challenging and requires modeling and many assumptions. We therefore have focused our analysis on straightforward economic implications, based on the limited available data at present. Recently, the Institute for Clinical and Economic Review (ICER) has attempted to perform an initial cost-effectiveness analysis of PCSK9i [8]. The Incremental cost-effectiveness ratios were estimated by ICER at $681,000 for a quality-adjusted-life-year gained (QALY) in familial hyperlipidemia patients, $557,000 for patients with history of coronary artery disease on statin therapy and $506,000 for statin-intolerant patients with history of coronary artery disease. These ratios are beyond any acceptable threshold value to determine good value for money. Although one of the PCSK9i manufacturers has pointed to many potential flaws in the ICER draft paper [11], they did not provide an alternative economic assessment. As of so, the ICER cost-effectiveness analysis could be used as some reference and an external validation to our findings. Consequently, in the UK, the National Institute for Health and Care Excellence (NICE) has issued a preliminary report [12] stating that Evolocumab, alone or in combination with lipid-lowering therapies, is not recommended within its marketing authorization for treating primary hypercholesterolemia, even though the price of the drugs in the UK is about half of the US price. Similarly, the Israel 2016 “Health Basket” committee rejected the drugs for the wider indications and approved Evolocumab only for the rare condition of homozygous familial hypercholesterolemia, which includes 14 patients in Israel [13]. 4.1. Comparison to HCV In our analysis, we chose to compare the cost of preventing death with PCSK9i to the cost of the novel drugs for treating HCV. The HCV drugs have been scrutinized extensively recently for their high costs and budget impact [10,14] despite having substantially better cost-
Regarding the budget-impact issue, the $70,172,141 assumed cost of PCSK9i consumed in the clinical trials could have provided the healthcare system 23,884 patient-years of therapy with high potency statins in high risk patients, as were enrolled in the JUPITER trial [16] (based on the US average online cost of branded Rosuvastatin; $2938). Allocating these funds for Rosuvastatin would have resulted in the prevention of 110 MACE compared to 35 avoided MACE using PCSK9i for its indications (Fig. 1). 4.3. Limitations Our analysis and presentation has several limitations. The primary limitation is the limited outcome data in current published trials. These studies recruited mainly low-risk populations and were not designed to test clinical endpoints. The ongoing phase III outcomes trials are enrolling higher risk patient population and event rates are projected to be substantially higher. The Evolocumab Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) [3], and the Alirocumab ODYSSEY OUTCOMES [10] trial are designed to evaluate the long term outcomes of these drugs and should provide more definitive data. Nevertheless, as the FDA already approved the two drugs for regular use and since they are already being utilized, it is not too early to explore the economic implications of these therapies. The second limitation of this analysis is that we assumed that the rate of MACE under SOC therapy and with PCSK9i will remain similar during a longer follow-up [17–19]. However, if the rate of MACE with SOC will grow higher in longer follow-up and rate of MACE under PCSK9i therapy will remain low, these therapies will provide higher value and the costs of each prevented MACE or death could decrease substantially. Our sensitivity analysis examines and presents various scenarios that cover the spectrum of possible outcome results from the FOURIER and ODYSSEY OUTCOMES trials and with a longer follow-up of the current published trials. A third limitation is our reliance on only two studies, each of which has its own limitations. One of the concerns with the ODYSSEY trial was that only 47% of its SOC patients were receiving high-dose statin therapy, which may have affected the MACE rate at the control group [20], and may have overestimated the effect of Alirocumab.
Table 4 Sensitivity analysis of costs for MACE prevention including revascularization events. Trial
ODYSSEY LONG TERM
Drug
Alirocumab + SOC
SOC
Prevented MACE
HR
OSLER 1 + 2 Evolucumab + SOC
SOC
Prevented MACE
HR
Evolucumab or Alirocumab
Combined data Total SOC
Total prevented MACE
Cost per prevented MACE
Base case HR 95% CI (low) HR 95% CI (high)
75 32 92
102 102 102
27 70 10
0.73 0.31 0.9
34 17 47
60 60 60
26 43 13
0.57 0.28 0.78
109 48 139
162 162 162
53 114 23
$1,324,003 $617,881 $2,999,809
SOC = Standard of Care; MACE = Major Adverse Cardiovascular Events; HR = Hazard Ratio; all MACE estimates rounded to whole numbers.
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References
Fig. 1. Comparison of prevented MACE using the $70,172,141 budget.
Another important limitation is that we combined the data of two different drugs, which although have a similar mechanism of action and present similar effects on lowering of LDL, may have different effects on preventing MACE. The inclusion criteria of the two trials and within the OSLER trials were not identical as OSLER recruited patients from previous trials with varied inclusion criteria. Due to limited outcome data we only analyzed the merged MACE data – while in practice, each endpoint has different economic and quality of life implications. Finally, we did not include in our analysis the short or the long-term savings associated with preventing MACE. Given the modest number of MACE prevented, these savings are unlikely to have a major impact on our study findings. 5. Conclusions According to the current published data of the major trials that were the base of PCSK9i approval, using PCSK9i to prevent MACE seems to be a very expensive strategy. If upcoming outcome trials will demonstrate similar results, it seems that at the current prices, using these drugs to improve cardiovascular outcomes might not be affordable. Healthcare decision-makers will need to explore for reasonable cost-effective strategies for adopting these promising therapies, targeting them to the most unmet need patients, while searching for novel ways to significantly lower the cost of these drugs. Statement of authorship All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Sources of funding None. Conflict of interest/Disclosures The authors report no relationships that could be construed as a conflict of interest.
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