Estimated burden of cardiovascular disease and value-based price range for evolocumab in a high-risk, secondary-prevention population in the US payer context

Figures & data

Figure 1. Design of study to estimate CV burden in high-risk patients. ACS: acute coronary syndrome; CPRD: Clinical Practice Research Datalink; CV: cardiovascular; HF: heart failure; IS: ischemic stroke; MI: myocardial infarction; UA: unstable angina.

Table 1. FOURIER eligibility criteria applied to study cohorts.

FOURIER inclusion criteria	CPRD translation of criteria
Major risk factors (1 required)	Major risk factors (1 required)
Diabetes (type 1 or type 2)	Diabetes (type 1 or type 2)
Age ≥65 and ≤85 years	Age ≥65 and ≤85 years
MI or non-hemorrhagic stroke within 6 months of screening	MI or IS diagnosis within last 6 months
Additional diagnosis of MI or non-hemorrhagic stroke	History of >1 MI or IS event
Current daily cigarette smoking	Current smoker
History of symptomatic PAD	PAD (for those qualifying with MI or IS)
Minor risk factors (2 required)	Minor risk factors (2 required)
History of non-MI-related coronary revascularization	Coronary revascularization without a history of MI
Residual coronary artery disease	History of unstable angina
HDL-C < 40 mg/dL for men or <50 mg/dL for women	Low HDL-C (<38.6 mg/dL for men or <50.3 mg/dL for women^a)
Highly sensitive CRP >2.0 mg/L Metabolic syndrome,^21 defined as the presence of at least 3 of the following 5 conditions:  • Elevated waist circumference  • Triglycerides ≥150 mg/dL  • Low HDL-C (as defined above)  • Fasting glucose ≥100 mg/dL  • Hypertension	CRP >2.0 mg/L  Metabolic syndrome, defined as the presence of at least 3 of the following 5 conditions:  • BMI ≥30 kg/m^2  • Triglycerides ≥150 mg/dL  • Low HDL-C (as defined above)  • Diabetes (type 1 or type 2)  • Hypertension

^a CPRD lipid values are in SI units; values converted to mg/dL.

BMI: body mass index; CAD: coronary artery disease; CPRD: Clinical Practice Research Datalink; CRP: C-reactive protein; HDL-C: high-density lipoprotein-cholesterol; IS: ischemic stroke; MI: myocardial infarction; PAD: peripheral arterial disease; SI: International System of Units.

Figure 2. Cost-effectiveness model structure for value-based pricing analysis.

Table 2. Cost-effectiveness model inputs: rate ratio of CV events per 1 mmol/L of LDL-C reduction, utility values, and direct costs.

Item	Rate ratio (CI)^a	Utility (CI)^b	Direct cost, US$(CI)^c
PAD	NA	0.824 (0.800–0.848)	8,096 (7,495–8,697)
ACS^d	0.71 (0.58–0.87)	0.672 (0.625–0.719)	49,604 (48,247–50,962)
IS	0.69 (0.50–0.95)	0.327 (0.264–0.390)	44,007 (41,965–46,049)
HF^e	0.71 (0.58–0.87)	0.602 (0.550–0.655)	45,514 (43,687–47,341)
Post-ACS^d	NA	0.824 (0.800, 0.848)	8,096 (7,495–8,697)
Post-IS	NA	0.524 (0.472–0.576)	8,396 (7,212–9,579)
Post-HF	NA	0.571 (0.526–0.616)	17,562 (16,126–18,997)
CHD death	0.80 (0.76–0.85)		72,892 (71,814–73,970)
IS death	1 (assumption)		72,892 (71,814–73,970)
Revascularization^f	0.66 (0.60–0.73)		56,556 (55,679–57,434)

Adapted and updated from “Cost-effectiveness of LDL-C lowering with evolocumab in patients with high cardiovascular risk in the United States”²³ under the terms of a Creative Commons BY-NC-ND 4.0 license. © 2016 The Authors.

^a CIs are 99% except for revascularization, which is 95%^8,24. The PAD health state was assumed to be equivalent to post-ACS in terms of costs and utilities. IS death was assumed to have a rate ratio of 1, because the rate ratio per 38.67 mg/dL LDL-C reduction was not statistically significant (1.04; 99% CI = 0.77–1.41).

^b In utilities, 0 represents death, and 1 represents perfect health.

^c Source: US Claims Data from 2006–2012^5,25.

^d ACS was defined as UA or MI.

^e For transitions from HF to HF and post-HF to HF, the clinical benefit was not applied, reflecting results of statin trials in which LDL-C reduction did not significantly reduce primary composite end-points in patients with recurrent HF²⁶.

^f Revascularization was defined as percutaneous coronary intervention or coronary artery bypass graft.

ACS: acute coronary syndrome; CHD: coronary heart disease; CI: confidence interval; CV: cardiovascular; HF: heart failure; IS: ischemic stroke; LDL-C: low-density lipoprotein-cholesterol; MI: myocardial infarction; NA: not applicable; PAD: peripheral artery disease; UA: unstable angina.

Table 3. Demographic and clinical characteristics of CPRD cohorts at baseline.

	High-risk ASCVD (n = 1,448)	ACS incident (n = 602)	IS incident (n = 151)	HF incident (n = 291)
Follow-up, years, mean (SD)	5.4 (2.2)	2.8 (1.7)	2.8 (1.9)	2.7 (1.7)
Age, years, mean (SD)	67.0 (9.7)	69.2 (10.0)	69.8 (9.5)	70.5 (9.7)
Sex, male, %	60	59	61	65
BMI, kg/m^2, mean (SD)	28.6 (5.2)	28.9 (4.8)	28.1 (4.8)	29.4 (5.5)
Smoker, %	26	22	19	19
High BP, %	93	92	94	97
Systolic BP, mmHg, mean (SD)	137.8 (16.1)	140.0 (15.8)	139.6 (16.5)	135.0 (15.5)
Diabetes, %	29	39	34	41
Atrial fibrillation, %	7	8	13	18
Using antithrombotic medication, %	93	82	87	94
Vascular beds, number, mean (SD)	1.3 (0.5)	1.3 (0.5)	1.7 (0.7)	1.3 (0.5)
LDL-C, mg/dL, mean (SD)	103.2 (32.1)	109.8 (36.3)	104.8 (33.6)	98.6 (30.5)
Non–HDL-C, mg/dL, mean (SD)	140.9 (32.1)	141.9 (38.7)	138.1 (38.6)	129.2 (34.4)
HDL-C, mg/dL, mean (SD)	50.2 (15.1)	53.0 (15.1)	51.8 (15.9)	4,848.7 (16.2)
Total cholesterol, mg/dL, mean (SD)	193.0 (34.0)	193.0 (40.6)	190.6 (42.2)	177.5 (35.6)

ACS: acute coronary syndrome; ASCVD: atherosclerotic cardiovascular disease; BMI: body mass index; BP: blood pressure; CPRD: Clinical Practice Research Datalink; HDL-C: high-density lipoprotein-cholesterol; HF: heart failure; IS: ischemic stroke; LDL-C: low-density lipoprotein-cholesterol; SD: standard deviation.

Table 4. Cumulative incidence of CV events among the different cohorts in the observational study.

	High-risk ASCVD (n = 1,448)	ACS incident (n = 602)	IS incident (n = 151)	HF incident (n = 291)
Primary composite outcome, n (%)
≥1 event	482 (33)	241 (40)	41 (27)	96 (33)
≥2 events	203 (14)	111 (18)	15 (10)	27 (9)
≥3 events	89 (6)	50 (8)	2 (1)	9 (3)
≥4 events	42 (3)	19 (3)
≥5 events	20 (1)	12 (2)
Sensitivity analysis composite outcome excluding revascularization, n (%)
≥1 event	417 (29)	189 (31)	37 (25)	81 (28)
≥2 events	142 (10)	66 (11)	12 (8)	17 (6)
≥3 events	58 (4)	34 (6)	2 (1)	6 (2)
≥4 events	26 (2)	11 (2)
≥5 events	14 (1)	6 (1)

ACS: acute coronary syndrome; ASCVD: atherosclerotic cardiovascular disease; IS: ischemic stroke; HF: heart failure.

Table 5. CV event incidence rates per 100 patient-years.

	High-risk ASCVD (n = 1,448)	ACS incident (n = 602)	IS incident (n = 151)	HF incident (n = 291)
Primary composite outcome
Incidence rate per 100 patient-years	7.5	21.1	11.9	16.3
Multiple-event rate per 100 patient-years	12.3	25.7	13.3	23.3
Sensitivity analysis excluding revascularization
Incidence rate per 100 patient-years	6.4	14.8	11.2	13.1
Multiple-event rate per 100 patient-years	10.0	18.3	12.1	19.1

ACS: acute coronary syndrome; ASCVD: atherosclerotic cardiovascular disease; IS: ischemic stroke; HF: heart failure.

Table 6. Cost-effectiveness results for EvoMab added to SOC vs SOC alone.

Population by baseline LDL-C	Total cost, US$			Total QALY			ICER, US$	Value-based price, US$
	EvoMab + SOC	SOC alone	Incre	EvoMab + SOC	SOC alone	Incre		$100,000 per QALY	$150,000 per QALY	$200,000 per QALY
≥70 mg/dL
Medication	166,346	837	165,509
Fatal events^a	19,863	24,255	−4,392
Non-fatal events^b	34,145	53,206	−19,060	0.43	0.67	−0.24
Revascularization^c	37,922	60,797	−22,875
Long-term health states^d	104,516	96,768	7,748	9.48	8.56	0.91
Total (deterministic)	362,792	235,863	126,929	9.91	9.23	0.68	187,538	9,051	11,935	14,819
Total (probabilistic, CrI)	362,980 (349,750–378,632)	235,891 (224,953–246,904)	127,088 (112,827–141,830)	9.92 (9.50–10.32)	9.24 (8.80–9.66)	0.68 (0.51–0.87)	190,440 (138,943–262,158)	9,064 (6,869–11,254)	11,990 (9,341–14,833)	14,850 (11,371–18,395)
≥100 mg/dL
Medication	163,282	800	162,482
Fatal events^a	21,269	27,321	−6,052
Non-fatal events^b	34,731	61,806	−27,075	0.44	0.78	−0.34
Revascularization^c	35,370	65,021	−29,651
Long-term health states^d	102,397	91,102	11,296	9.29	8.00	1.29
Total (deterministic)	357,049	246,050	110,999	9.73	8.77	0.96	115,913	12,777	16,934	21,091
Total (probabilistic, CrI)	356,820 (339,461–375,591)	245,904 (233,878–257,578)	110,916 (91,632–129,449)	9.74 (9.31–10.18)	8.79 (8.35–9.25)	0.95 (0.73–1.19)	118,905 (83,491–167,391)	12,775 (10,029–15,497)	16,856 (12,903–20,678)	21,029 (16,366–25,936)

^a CV death and non-CV death health states.

^b ACS, IS, and HF health states.

^c Defined as coronary artery bypass graft or percutaneous coronary intervention.

^d PAD, Post-ACS, post-IS, and post-HF health states.

CrI: credible interval; EvoMab: evolocumab; ICER: incremental cost-effectiveness ratio; incre: incremental; LDL-C: low-density lipoprotein-cholesterol; QALY: quality-adjusted life-year; SOC: standard of care.

Figure 3. Tornado diagram for estimated value-based price range at a WTPT of $150,000 per QALY gained by baseline LDL-C (a) ≥ 70 mg/dL and (b) ≥100 mg/dL. Only factors that affected the ICER by ≥5% are displayed. ACS: acute coronary syndrome; CHD: coronary heart disease; CVD: cardiovascular disease; HF: heart failure; ICER: incremental cost-effectiveness ratio; IS: ischemic stroke; LDL-C: low-density lipoprotein-cholesterol; QALY: quality-adjusted life-year; SOC: standard of care; WTPT: willingness-to-pay threshold.

Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention. National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640-5

 PubMed Web of Science ®Google Scholar

Gandra SR, Villa G, Fonarow GC, et al. Cost-effectiveness of LDL-C lowering with evolocumab in patients with high cardiovascular risk in the United States. Clin Cardiol 2016;39:313-20

 PubMed Web of Science ®Google Scholar

Cholesterol Treatment Trialists (CTT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-81

 PubMed Web of Science ®Google Scholar

Cholesterol Treatment Trialists (CTT) Collaborators, Mihaylova B, Emberson J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90

 PubMed Web of Science ®Google Scholar

Bonafede MM, Johnson BH, Richhariya A, et al. Medical costs associated with cardiovascular events among high-risk patients with hyperlipidemia. Clinicoecon Outcomes Res 2015;7:337-45

 PubMed Web of Science ®Google Scholar

Fox KM, Wang L, Gandra SR, et al. Long-term economic burden associated with cardiovascular events among high-risk patients with hyperlipidemia. Value Health 2015;18:A139-40

 Google Scholar

Lipinski MJ, Cauthen CA, Biondi-Zoccai GG, et al. Meta-analysis of randomized controlled trials of statins versus placebo in patients with heart failure. Am J Cardiol 2009;104:1708-16

 PubMed Web of Science ®Google Scholar