Results

Over 10 yrs, patients treated with atorvastatin experienced fewer CV events, gained 0.07 QALYs/patient, and had 2% fewer deaths compared with placebo, at an additional cost of Can$922/patient.

Incremental costs decreased considerably over time despite the increase in drug costs, most likely as a result of decreased medical costs associated with fewer cardiac events.

The incremental cost-effectiveness of atorvastatin was Can$12,687/QALY [95% CI dominant–$66,048] at 10 yrs, Can$1,362 [dominant–$49,432] at 25 yrs (lifetime analysis), and Can$70,773/QALY [33,981–195,914] at 5 yrs.

The model was most sensitive to variations in age at baseline ($66,964 to -$1,896/QALY), followed by HRs for CHD and stroke

Systolic blood pressure, adherence rate, cholesterol levels, and cost of atorvastatin for subsequent years also had intermediate impact on incremental ratios.

The model was robust to variations in other risk factors such as gender, atrial fibrillation, and smoking status.

ObjectiveTo assess the clinical and economic benefits of atorvastatin 10 mg daily in Canadian patients with type 2 diabetes without established CHD and with at least one other CVD risk factor, from a Ministry of Health perspective, using the CARDS Health Economic Model.

Background In Canada, the prevalence of cardiovascular disease (CVD) is five-fold higher in individuals

with diabetes than those without.1

To reduce the risk of cardiovascular (CV) events, the Canadian Diabetes Association recommends aggressive lipid management involving statin therapy for high-risk patients to reach and maintain low density lipoprotein cholesterol (LDL-C) level below 2.5 mmol/l, and total cholesterol to high density lipoprotein cholesterol ratio (TC:HDL-C) below 4.0.2

The Collaborative Atorvastatin Diabetes Study (CARDS), a double-blind randomized controlled trial conducted in the UK and Ireland, explored primary prevention of CV events with atorvastatin 10 mg daily in 2,838 patients with type 2 diabetes and no previous history of coronary heart disease (CHD), with at least one other CVD risk factor, and baseline LDL-C levels ≤ 4.14 mmol/l.3

Over a 3.9-year follow-up period, CARDS demonstrated that atorvastatin 10 mg daily achieved significant reduction of primary CV events (relative risk [RRR] vs placebo: 0.37; 95% CI: 0.52 to 0.17; P=.001), and also reduced all-cause mortality (RRR:0.27; 95% CI: 0.48–1.0; P=.059).3

The CARDS Health Economic Model—a Markov-type decision analytic model of primary prevention designed to predict long-term outcomes—demonstrated that atorvastatin was cost-effective and improved clinical outcomes in US patients with type 2 diabetes and at least one other CVD risk factor.4

Conclusions Primary prevention of CV events with atorvastatin 10 mg/day resulted in incremental cost-

effectiveness ratios well below many other commonly used healthcare interventions15 (10-yr: $12,687/QALY; 25-yr: $1,362/QALY).

Atorvastatin is cost-effective for the primary prevention of major CV events and associated death among Canadians with type 2 diabetes without established CVD. Univariate and multuivariate SA indicate that the results are robust to variations in input parameters.

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2006;6:96-105.2 Harris SB, Lank CN. Recommendations from the Canadian Diabetes Association. 2003 guidelines for prevention and management of diabetes and related cardiovascular risk

factors. Can Fam Physician. 2004;50:425-33.3 Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the

Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364(9435):685-96.4 Ramsey SD, Clarke LD, Roberts CS, Sullivan SD, Johnson SJ, Liu LZ. An economic evaluation of atorvastatin for primary prevention of cardiovascular events in type 2

diabetes. Pharmacoeconomics. 2008;26(4):329-39.5 Kothari V, Stevens RJ, Adler AI, Stratton IM, Manley SE, Neil HA, et al. UKPDS 60: risk of stroke in type 2 diabetes estimated by the UK Prospective Diabetes Study risk

engine. Stroke. 2002;33(7):1776-81.6 Stevens RJ, Kothari V, Adler AI, Stratton IM. The UKPDS risk engine: a model for the risk of coronary heart disease in Type II diabetes (UKPDS 56). Clin Sci (Lond).

2001;101(6):671-9.7 D'Agostino RB, Sr., Grundy S, Sullivan LM, Wilson P. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation.

JAMA. 2001;286(2):180-7.8 Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without

prior myocardial infarction. N Engl J Med. 1998;339(4):229-34.9 World Health Organization. Life tables for WHO member states: Canada- 2005. On World Health Organization website [updated 2007; cited 2007 Nov 14]. Available from:

http://www.who.int/whosis/database/life_tables/life_tables.cfm.10 Schultz SE, Kopec JA. Impact of chronic conditions. Health Rep. 2003;14(4):41-53.11 Ontario Ministry of Health and Long-Term Care. Ontario Drug Benefit Formulary/Comparative Drug Index. On Ontario Ministry of Health and Long-Term Care website [updated

2007 May 31; cited 2007 Jun 7]. Available from: http://www.health.gov.on.ca/english/providers/program/drugs/odbf_mn.html.12 Ontario Ministry of Health and Long-Term Care. Ontario Case Costing Initiative. On Ontario Case Costing Initiative website [updated 2004; cited 2006 Jul 5]. Available from:

http://www.occp.com/.13 O'Brien JA, Patrick AR, Caro JJ. Cost of managing complications resulting from type 2 diabetes mellitus in Canada. BMC Health Serv Res. 2003;3(1):7.14 Canadian Agency for Drugs and Technologies in Health. Guidelines for the economic evaluation of health technologies: Canada. On Canadian Agency for Drugs and

Technologies in Health website [updated 2006 Apr; Available from: http://www.cadth.ca.15 Eichler HG, Kong SX, Gerth WC, Mavros P, Jonsson B. Use of cost-effectiveness analysis in health-care resource allocation decision-making: how are cost-effectiveness

thresholds expected to emerge? Value Health. 2004;7(5):518-28.16 Yan AT, Yan RT, Tan M, Hackam DG, Leblanc KL, Kertland H, et al. Contemporary management of dyslipidemia in high-risk patients: targets still not met. Am J Med.

2006;119(8):676-83.17 Wackers FJ, Young LH, Inzucchi SE, Chyun DA, Davey JA, Barrett EJ, et al. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study.

Diabetes Care. 2004;27(8):1954-61.18 Lipscombe LL, Hux JE. Trends in diabetes prevalence, incidence, and mortality in Ontario, Canada 1995-2005: a population-based study. Lancet. 2007;369(9563):750-6.19 Pilote L, Dasgupta K, Guru V, Humphries KH, McGrath J, Norris C, et al. A comprehensive view of sex-specific issues related to cardiovascular disease. CMAJ.

2007;176(6):S1-44.20 Statistics Canada. Visible minority population, by age group (2001 Census). On Statistics Canada website [updated 2005 Jan 25; Available from:

http://www40.statcan.ca/l01/cst01/demo50a.htm.21 Shah BR, Hux JE, Laupacis A, Mdcm BZ, Austin PC, van Walraven C. Diabetic patients with prior specialist care have better glycaemic control than those with prior primary

care. J Eval Clin Pract. 2005;11(6):568-75.22 Rucker D, Johnson JA, Lee TK, Eurich DT, Lewanczuk RZ, Simpson SH, et al. The natural history of LDL control in type 2 diabetes: a prospective study of adherence to lipid

guidelines. Diabetes Care. 2006;29(11):2506-8.23 Rabi DM, Edwards AL, Svenson LW, Sargious PM, Norton P, Larsen ET, et al. Clinical and medication profiles stratified by household income in patients referred for diabetes

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Cost-effectiveness of atorvastatin 10 mg daily in the primary prevention of major cardiovascular events in patients with type 2 diabetes in Canada

H. Khoury1, M. Wagner1, E. Merikle2, S.J. Johnson3, C. Roberts4

1BioMedCom Consultants inc, Montreal, QC, Canada; 2At the time of the study: Pfizer Canada Inc., Montreal, QC, Canada; Current affiliation: Center for Health Outcomes Research, United BioSource Corporation, Montreal, Canada;3Analysis Group Inc., New York, NY; 4Global Outcomes Research, Pfizer Inc., New York, NY

1 Base-case results

2 One-way deterministic SA – 10-year horizon

AcknowledgementsThis study was funded by Pfizer Canada Inc.

Methods The CARDS Health Economic Model predicts the incidence of CV events (CHD and

stroke), total costs, survival and quality-adjusted life years (QALYs) (Figure1). The model followed a hypothetical cohort of Canadians with type 2 diabetes and no

documented history of CVD, with at least one other CVD risk factor, over 5, 10, and 25-year time horizons.

Annual transition probabilities for primary events were derived from the United Kingdom Prospective Diabetes Study (UKPDS) risk equations,5,6 and the CARDS trial.7 The risk of having a second event was increased to reflect the increased CVD risk for patients with diabetes with a prior myocardial infarction (MI).8

Hazard ratios (HR) were taken from the CARDS trial.3

Adherence rate: 100% for the 1st yr, adjusted to reflect decreasing rates from the CARDS trial3 during the first 4 yrs, and kept constant after 4 yrs.

Acute CVD-related mortality rates were based on the CARDS trial.3 Mortality due to causes other than CVD were taken from 2005 life tables for Canada.9

Utility scores were obtained from a cross-sectional sample of the National Population Health Survey in Canada.10

Resource utilization and costs: Canadian cost for atorvastatin was obtained from the Ontario Drug Benefit formulary (ODBF);11 drug cost was reduced by 50% after the 4th yr to account for genericization of atorvastatin. Acute care cost of stroke and aggregate acute care cost of CHD events (angina, MI, coronary artery bypass graft (CABG), percutaneous coronary interventions (PCI) with and without stent, and cardiac catheterization) were obtained from the Ontario Case Costing Initiative (OCCI) Acute Inpatient Cost 2003/04 database.12 Subsequent year costs for stroke and CHD (aggregate cost of MI and angina) were estimated based on O’Brien et al.13

Costs and benefits were discounted by 5%.14

One-way deterministic (tornado diagram) and probabilistic (acceptability curve) sensitivity analyses (SA) were conducted to assess model uncertainty.

Figure 1: Markov analytical model

Table 1: Base-case input parameters

CARDS Canadian cohort

Atorvastatin 10 mg

Placebo

Other Death

Event Death

Second Event History

Event History

Well

Remain Well

Primary CHD Event

Primary Stroke Event

Other Death

Remain Event History

Secondary CHD Event

Secondary Stroke Event

Other Death

Remain SecondEvent History

Other Death

Well

Event Survive

Event Death

Stroke Survive

Stroke Death

Other Death

Event History

Event Survive

Event Death

Stroke Survive

Stroke Death

Other Death

Second Event History

Other Death

Event History

Event Death

Event History

Event Death

Second Event History

Event Death

Second Event History

Event Death

Baseline characteristics of Canadians with type 2 diabetes and no previous CHD Age,16 yrs 61 Disease duration,17 yrs 8.1 Women,18 % 48 Atrial fibrillation,19 % 4.7 Afro-Caribbean,20 % 2.2 Current smoker,16 % 16.1 HbA1c,21 % 8.3 Systolic blood pressure,16 mm Hg 130 TC,22 mmol/l 4.9 HDL-C,23 mmol/l 1.1 Baseline incidence, events/year

CHD6 0.01120 Stroke5 0.00186

Event probabilities 1st yr baseline probability in placebo*

CHD 0.0154 Stroke 0.0055

HR associated with 10 mg atorvastatin† CHD 0.660 Stroke 0.590

Probability of death3 CHD event 0.273 Stroke event 0.107

Relative risk8 CHD secondary event 2.22 Stroke secondary event 1.89

Utilities, mean10 Well/baseline 0.76 CHD -0.03 Stroke -0.16

Costs 2007 Can$ First year costs

Atorvastatin 10 mg/day11 607 Stroke event12 17,106 CHD procedures and medical admission-based events‡

12,365

Subsequent (post-event) year costs Atorvastatin 10 mg/day, up to 4th year (pre-generic)11 607 Atorvastatin generic drug after 4th year§ 285 Stroke event (non-fatal) history 10,137 CHD event history** 1,444

CHD: coronary heart disease; HbA1c: glycated hemoglobin, HDL-C: high density lipoprotein-C; total cholesterol * Based on Canadian patient characteristics and patients of the UKPDS model 24 † Based on patient-level CARDS trial data3 ‡ Total average cost of any CHD intervention (angina, MI, CABG, PCI with or without stent, cardiac catherization) weighted by the frequency of

utilization of each intervention from the OCCI database12

Atorvastatin 10 mg daily Placebo Increment

Base case results: 10-year horizon

Clinical outcomes per patient* Number of CV events (CHD & stroke) 0.17 0.26 -0.08 Life years gained 7.40 7.32 0.07 QALYs 5.58 5.51 0.07

Death (all-cause), proportion of patients 0.17 0.19 -0.02 Costs*, 2007 Can$

Medical cost† 3,531 5,256 -1,725 Drug cost only 2,833 186 2,647 Total cost 6,364 5,442 922

Incremental cost, 2007 Can$ per event averted 11,083 per life-year gained 12,327 per QALY [95% CI] 12,687 [dominant–$66,048]

5-year horizon

QALYs* 3.26 3.24 0.02 Total costs*, 2007 Can$ 3,243 1,855 1,389

Incremental cost per QALY, 2007 Can$ [95% CI] 70,773 [33,981–195,914]

25-year horizon

QALYs* 8.47 8.22 0.25 Total costs*, 2007 Can$ 18,988 18,646 342

Incremental cost per QALY, 2007 Can$ [95% CI] 1,362 [dominant–$49,432] CI: confidence interval; LYG: life-year gained; QALY: quality-adjusted life year *Discounted at 5%; †Includes total cost of hospitalization (including overhead) due to stroke, CHD procedures and CHD medical admissions

95.7% and 98.3% of 1,000 simulations were below a Can$50,000/QALY in the 10-yr and 25-yr horizons, respectively, with almost half (46.3%) of the simulations indicating that atorvastatin is a dominant treatment strategy.

3 Probabilistic SA – acceptability curve