Cost-effectiveness of ticagrelor versus clopidogrel in patients with acute coronary syndromes in Canada

Figures & data

Figure 1 Model diagram of the 1-year decision tree.

Abbreviation: MI, myocardial infarction.

Table 1 One-year decision tree event probabilities

Clinical Pathway	Clopidogrel n=9,291		Ticagrelor n=9,333
	N	Proportion	N	Proportion
1. No Events	8,226	0.8854	8,432	0.9035
2. MI	485	0.0522	421	0.0451
3. Stroke	74	0.0080	81	0.0087
4. Dead any cause	506	0.0545	399	0.0428

Note: Copyright © 2013. Oxford University Press. Reproduced from Nikolic E, Janzon M, Hauch O, Wallentin L, Henriksson M. Cost-effectiveness of treating acute coronary syndrome patients with ticagrelor for 12 months: results from the PLATO study. Eur Heart J. 2013;34(3):220–228 by permission of Oxford University Press.¹²

Abbreviation: MI, myocardial infarction.

Figure 2 Diagram of the Markov model for post-1-year.

Note: *This state includes patients who had no events within the year after the incident hospitalization for ACS and patients who had an MI in the first year after the ACS event.
Abbreviations: MI, myocardial infarction; ACS, acute coronary syndrome.

Table 2 Health-related utility values used in the model

State	1-year decision tree*	Markov model**
No further event	0.875	0.854
New MI (nonfatal)	0.812	0.812
New stroke (nonfatal)	0.736	0.736
Post-MI	–	0.854
Post-stroke	–	0.736
All-cause death	0.249	0.0

Notes:

* Utilities for 1-year decision represent the average utility values reported in the PLATO trial for ticagrelor and clopidogrel. The utility value for “dead any cause” represents the utility value accrued by the patient before they died.

** Data from Banerjee et al.¹⁸ No further event state utilities were assumed to be the same as the post-MI state utilities. New stroke and post-stroke utility values were assumed to be the same as there is no evidence health-related quality of life improves over time.

Abbreviations: MI, myocardial infarction; PLATO, Platelet Inhibition and Patient Outcomes.

Table 3 Resource costs used in the 1-year decision tree and post-1-year Markov model

State	1-year decision tree	Markov model*
No further event	$21,781	$3,151
New MI (nonfatal)	$45,515	$10,961
New stroke (nonfatal)	$55,445	$21,087
Post-MI	–	$3,151
Post-stroke	–	$4,391
All-cause death	$39,630	N/A

Notes: Values inflated to 2011 (Canadian dollars) and rounded for display.

* Data from Banerjee et al.¹⁸ No further event state costs were assumed to be the same as the post-MI state costs.

Abbreviations: MI, myocardial infarction; N/A, not applicable.

Table 4 Summary of discounted cost-effectiveness results for different time horizons

Time horizon	Ticagrelor	Clopidogrel	Incremental	ICER
40 years
Costs	$52,490	$51,669	$821
Life-years	8.308	8.211	0.097	$8,438
QALYs	7.016	6.932	0.084	$9,745
20 years
Costs	$51,393	$50,586	$807
Life-years	8.041	7.947	0.094	$8,598
QALYs	6.801	6.720	0.081	$9,900
10 years
Costs	$44,801	$44,079	$722
Life-years	6.342	6.269	0.072	$9,983
QALYs	5.386	5.322	0.064	$11,329
5 years
Costs	$36,195	$35,582	$613
Life-years	4.040	3.996	0.044	$14,046
QALYs	3.442	3.402	0.040	$15,441

Note: All values are in Canadian dollars.

Abbreviations: ICER, incremental cost-effectiveness ratio; QALYs, quality-adjusted life years.

Figure 3 Cost-effectiveness acceptability curve for ticagrelor versus generic clopidogrel.

Note: All values are in Canadian dollars.
Abbreviations: CEAC, cost-effectiveness acceptability curve; QALY, quality-adjusted life year.

Figure 4 Scatterplot of incremental costs and QALYs for ticagrelor compared to clopidogrel.

Note: All values are in Canadian dollars.
Abbreviations: QALY, quality-adjusted life year.

Figure 5 Tornado diagram of one-way sensitivity analyses for ticagrelor versus generic clopidogrel. The light shading represents the higher value for the input and dark shading represents the lower value for the input.

Note: All values are in Canadian dollars.
Abbreviations: MI, myocardial infarction; QALY, quality-adjusted life year; vs, versus.

Table 5 Probabilistic base case results (40 years) – cost per QALY and LY (5,000 simulations)

	Ticagrelor (95% CI)	Clopidogrel (95% CI)	Incremental (95% CI)	ICER (95% CI)
Costs	$57,697 ($57,055–$58,338)	$56,807 ($56,175–$57,438)	$890 ($879–$901)	–
LYs	8.92 (8.85–8.98)	8.81 (8.75–8.87)	0.105 (0.104–0.106)	$8,482 ($8,302–$8,663)
QALYs	7.43 (7.38–7.48)	7.34 ($56,175–$57,438)	0.090 (0.089–0.090)	$9,942 ($9,764–$10,120)

Note: All values are in Canadian dollars.

Abbreviations: CI, confidence interval; ICER, incremental cost-effectiveness ratio; LY, life year; QALY, quality-adjusted life year.

Table S1 Health state costs used in the first year of the model (2011 costs)

State	Clopidogrel	Ticagrelor	Average for both treatment groups
No further event	$21,735	$21,828	$21,781
New MI (nonfatal)	$45,205	$45,824	$45,515
New stroke (nonfatal)	$59,133	$51,758	$55,445
Dead any cause	$44,663	$34,597	$39,630

Notes: Values rounded for display, inflated to 2011 costs. All values are in Canadian dollars.

Abbreviation: MI, myocardial infarction.

Table S2 Unit costs (2011 Canadian$)

Cost item	Unit	2011 Cost*	Source
Drugs
Daily ticagrelor	90 mg twice daily	$2.96	AstraZeneca Canada
Loading dose ticagrelor	180 mg	$2.96	AstraZeneca Canada
Loading dose clopidogrel	300 mg	$10.31 (generic $2.58)	Ontario Drug Benefit Program^Citation3
Daily clopidogrel	75 mg once daily	$2.58	Ontario Drug Benefit Program^Citation3
Daily clopidogrel (generic)	75 mg once daily	$0.645	Calculated (25% of brand name)
Daily ASA	75–150 mg	$0	Equivalent between two groups
Hospitalizations
General ward, cardiac care unit, and coronary care ward	Per day	$1,612	Ontario Case Costing Initiative^Citation1 Based on average cost per day for CCU for UA and MI (I200, I201, I2080, I2088, I209, and I219)
Intensive care unit	Per day	$3,932	Ministry of Health and Long-Term Care^Citation4
Interventions (physician fees)
CABG with valve replacement	Per operation	$7,396	Ontario Schedule of Benefits^Citation5
CABG without valve replacement	Per operation	$6,001	Ontario Schedule of Benefits^Citation5
Implantable cardiac defibrillator	Per procedure	$1,096	Ontario Schedule of Benefits^Citation5
Intra-aortic balloon pump	Per procedure	$312	Ontario Schedule of Benefits^Citation5
Left ventricular assist device	Per procedure	$2,817	Ontario Schedule of Benefits^Citation5
Pacemaker
Implantation of single chamber rate-responsive pacemaker	Per procedure	$487	Ontario Schedule of Benefits^Citation5
PCI without stent	Per procedure	$567	Ontario Schedule of Benefits^Citation5
PCI with stent	Per procedure	$647	Ontario Schedule of Benefits^Citation5
Bare metal stent	Per unit	$600	Goeree et al^Citation6
Drug-eluting stent	Per unit	$1,899	Goeree et al^Citation6
Investigations (physician fees)
Coronary angiography	Per procedure	$212	Ontario Schedule of Benefits^Citation5
CT abdomen	Per procedure	$115	Ontario Schedule of Benefits^Citation5
CT chest	Per procedure	$92	Ontario Schedule of Benefits^Citation5
CT extremity
CT, arm	Per procedure	Assumed all were leg	Ontario Schedule of Benefits^Citation5
CT, leg	Per procedure	$81	Ontario Schedule of Benefits^Citation5
CT head/brain
CT, head	Per procedure	$81	Ontario Schedule of Benefits^Citation5
CT, brain	Per procedure	Assumed all were head	Ontario Schedule of Benefits^Citation5
CT helical	Per procedure	Assumed the same as spine	Ontario Schedule of Benefits^Citation5
CT spine	Per procedure	$115	Ontario Schedule of Benefits^Citation5
Echocardiography	Per procedure	$140	Ontario Schedule of Benefits^Citation5
Electrophysiology study	Per procedure	$1,608	Ontario Schedule of Benefits^Citation5
Holter study	Per procedure	$273	Ontario Schedule of Benefits^Citation5
MRI abdomen	Per procedure	$78	Ontario Schedule of Benefits^Citation5
MRI chest	Per procedure	$78	Ontario Schedule of Benefits^Citation5
MRI extremity	Per procedure	$67	Ontario Schedule of Benefits^Citation5
MRI, arm	Per procedure	Assumed same as CT extremity	Ontario Schedule of Benefits^Citation5
MRI, leg	Per procedure	Assumed same as CT extremity	Ontario Schedule of Benefits^Citation5
MRI head/brain	Per procedure	$74	Ontario Schedule of Benefits^Citation5
MRI, head	Per procedure	Assumed same as CT head/brain	Ontario Schedule of Benefits^Citation5
MRI, brain	Per procedure	Assumed same as CT head/brain	Ontario Schedule of Benefits^Citation5
MRI spine	Per procedure	$108	Ontario Schedule of Benefits^Citation5
Myocardial scintigraphy	Per procedure	$166	Ontario Schedule of Benefits^Citation5
Pulmonary angiography	Per procedure	$120	Ontario Schedule of Benefits^Citation5
Stress test	Per procedure	$98	Ontario Schedule of Benefits^Citation5
Ventilation/perfusion scan	Per procedure	$301	Ontario Schedule of Benefits^Citation5
Bleeds
Reoperation due to bleeding	Per operation	$694	Ontario Schedule of Benefits^Citation5
Unit of fresh frozen plasma	Per unit	$249	Callum and Pinkerton^Citation7
Unit of packed red blood cells	Per unit	$453	Callum and Pinkerton^Citation7
Unit of platelets	Per unit	$566	Callum and Pinkerton^Citation7
Unit of whole blood	Per unit	$453	Callum and Pinkerton^Citation7
Significant adverse events
Dyspnea	Physician visits	$35.40 * 2 = $70.80	Ontario Schedule of Benefits^Citation5

Notes:

* In some instances costs were inflated to 2011. All values are in Canadian dollars.

Abbreviations: ASA, acetylsalicylic acid; CABG, coronary artery bypass surgery; CCU, coronary care unit; CT, computed tomography; MI, myocardial infarction; MRI, magnetic resonance imaging; PCI, percutaneous coronary intervention; UA, unstable angina.

Table S3 Values used in one-way sensitivity analysis

Variable	Parameter	Range		Source
		Low	High
Event rates for clopidogrel (1-year decision tree)
Dead any cause	0.0545	0.0500	0.0590	95% confidence intervals based on PLATO data
Nonfatal MI	0.0522	0.0477	0.0567
Nonfatal stroke	0.0080	0.0062	0.0097
Hazard ratios for ticagrelor versus clopidogrel (1-year decision tree)
Dead any cause	0.78	0.69	0.89	95% confidence intervals based on PLATO data
Nonfatal MI	0.86	0.76	0.98
Nonfatal stroke	1.09	0.80	1.49
Utilities from PLATO study
No further event	0.875	0.871	0.879	95% confidence intervals based on PLATO HECON substudy
New MI	0.812	0.792	0.832
New stroke	0.736	0.662	0.810
Dead any cause	0.249	0.222	0.276
New MI (mm)	0.812	0.792	0.832
Post-MI/no event (mm)	0.854	0.834	0.873
New stroke (mm)	0.736	0.662	0.810
Post-stroke (mm)	0.736	0.662	0.810
Resource cost for the Markov model
New MI	$10,824	$8,659	$12,989	Costs were varied by ±20%
Post-MI/no event	$3,112	$2,490	$3,734
New stroke	$20,823	$16,658	$24,988
Post-stroke	$4,336	$3,469	$5,203

Note: All values are in Canadian dollars.

Abbreviations: MI, myocardial infarction; PLATO, Platelet Inhibition and Patient Outcomes.

Table S4 Summary of probabilistic sensitivity analysis inputs and distributions

Variable	Value (95% CI)	Distribution	Source
Event rates for clopidogrel (1-year decision tree)
Dead any cause	0.0545 (0.05–0.059)	Lognormal	Based on the raw data from the PLATO study
Nonfatal MI	0.0522 (0.0477–0.0567)	Lognormal
Nonfatal stroke	0.008 (0.0062–0.0097)	Lognormal
Hazard ratios for ticagrelor versus clopidogrel (1-year decision tree)
Dead any cause	0.78 (0.69–0.89)	Lognormal	Based on the PLATO study
Nonfatal MI	0.86 (0.76–0.98)	Lognormal
Nonfatal stroke	1.09 (0.80–1.49)	Lognormal
Event rates (Markov model)
Subsequent events (MI, stroke, and vascular death)	Various	Normal	Coefficients for the risk equations from Karnon et al^Citation8 were varied around their respective SE
Utility values (decision tree and Markov model)
No further event	0.875 (0.871–0.879)	Beta	95% confidence intervals based on PLATO study
New MI	0.8120 (0.792–0.832)	Beta
New stroke	0.7360 (0.662–0.810)	Beta
Dead any cause	0.2490 (0.222–0.726)	Beta
Resource costs (decision tree)
No further event (ticagrelor)	$21,911	Gamma	Based on 95% confidence intervals of individual resource use from the PLATO study
New MI (ticagrelor)	$46,024	Gamma
New stroke (ticagrelor)	$51,351	Gamma
Dead any cause (ticagrelor)	$34,387	Gamma
No further event (clopidogrel)	$21,849	Gamma
New MI (clopidogrel)	$45,298	Gamma
New stroke (clopidogrel)	$58,769	Gamma
Dead any cause (clopidogrel)	$44,391	Gamma
Resource costs (Markov model)
New MI	$10,824	Gamma	As no standard error was reported in the original study, we assumed an SE equal to the mean
Post-MI/no event	$3,112	Gamma
New stroke	$20,823	Gamma
Post-stroke	$4,336	Gamma

Note: All values are in Canadian dollars.

Abbreviations: CI, confidence interval; MI, myocardial infarction; SE, standard error; PLATO, Platelet Inhibition and Patient Outcomes.

Table S5 Output of one-way sensitivity analyses: incremental cost per QALY for ticagrelor versus clopidogrel

Parameters	Low value	High value
Hazard ratio for ticagrelor versus clopidogrel for death from any cause within trial	$7,391	$17,685
Hazard ratio for ticagrelor versus clopidogrel for nonfatal MI within trial	$8,209	$11,618
Hazard ratio for ticagrelor versus clopidogrel for nonfatal stroke within trial	$8,465	$11,479
Probability of death from any cause within trial for clopidogrel	$10,467	$9,120
Probability of nonfatal MI within trial for clopidogrel	$9,927	$9,564
Probability of nonfatal stroke within trial for clopidogrel	$9,657	$9,830
Probability of dyspnea whilst on ticagrelor	$9,739	$9,750
Probability of dyspnea whilst on clopidogrel	$9,749	$9,740
Cost associated with no event state in Markov model	$9,090	$10,398
Cost associated with post-MI state in Markov model	$9,865	$9,624
Cost associated with post-stroke state in Markov model	$9,628	$9,861
Cost associated with nonfatal MI state in Markov model	$9,632	$9,857
Cost associated with nonfatal stroke state in Markov model	$9,688	$9,801
Cost of dyspnea in primary care	$9,719	$9,770
Cost of brand clopidogrel	–	$1,523
Cost of generic clopidogrel (20% brand price)	–	$10,293
Utility accrued in no event in decision tree	$9,753	$9,736
Utility accrued in death any cause in decision tree	$9,708	$9,782
Utility accrued in nonfatal MI in decision tree	$9,728	$9,761
Utility accrued in nonfatal stroke in decision tree	$9,751	$9,738
Utility associated with no event state in Markov model	$9,962	$9,536
Utility associated with nonfatal MI state in Markov model	$9,746	$9,743
Utility associated with nonfatal stroke state in Markov model	$9,757	$9,732
Utility associated with post-MI state in Markov model	$9,709	$9,780
Utility associated with post-stroke state in Markov model	$9,839	$9,651
Utility associated with dyspnea (utility reduced by 7% for 7 days^Citation9)	–	$9,849

Note: All values are in Canadian dollars.

Abbreviations: MI, myocardial infarction; QALY, quality-adjusted life year.

Table S6 Summary of subgroup analysis (40-year time horizon)

Subgroup	Incremental cost per QALY gained
12-month cohort	$10,020
STEMI	$10,596
NSTEMI	$7,959
Unstable angina	$11,499
Diabetes	$7,950
No diabetes	$10,285
Low dose ASA	$6,573
Invasive	$11,043
Medically managed	$7,042

Note: All values are in Canadian dollars.

Abbreviations: ASA, acetylsalicylic acid; NSTEMI, non-ST segment myocardial infarction; QALY, quality-adjusted life year; STEMI, ST segment elevation myocardial infarction.

NikolicEJanzonMHauchOWallentinLHenrikssonMCost-effectiveness of treating acute coronary syndrome patients with ticagrelor for 12 months: results from the PLATO studyEur Heart J201334322022822719022

 PubMed Web of Science ®Google Scholar

Canadian Agency for Drugs and Technologies in Health Adapted from: Banerjee S, Brown A, McGahan L, et alClopidogrel versus other antiplatelet agents for secondary prevention of vascular events in adults with acute coronary syndrome or peripheral vascular disease: clinical and cost-effectiveness analysesTechnology Report, No 133Ottawa, CanadaCanadian Agency for Drugs and Technologies in Health2010 Available from: http://www.cadth.ca/media/pdf/cadth-2-1-02.pdfAccessed October 11, 2013

 Google Scholar

Ontario Drug Benefits ProgramDrugs Funded by Ontario Drug Benefit (ODB) Program2011 Available from: https://www.healthinfo.moh.gov.on.ca/formulary/index.jspAccessed October 11, 2013

 Google Scholar

Ontario Case Costing Initiative (OCCI)2010 Available from: http://www.occp.com/Accessed October 11, 2013

 Google Scholar

Ontario Ministry of Health and Long-Term CareChronic Ventilation Strategy Task Force2006 Available from: http://www.stmichaelshospital.com/pdf/crich/sru-cvs-task-force.pdfAccessed October 11, 2013

 Google Scholar

Ontario Ministry of Health and Long-Term CareOntario Health Insurance (OHIP) Schedule of Benefits and Fees (Physicians)2010 Available from: http://www.health.gov.on.ca/english/providers/program/ohip/sob/physserv/physserv_mn.htmlAccessed October 11, 2013

 Google Scholar

GoereeRBowenJMBlackhouseGEconomic evaluation of drug-eluting stents compared to bare metal stents using a large prospective study in OntarioInt J Technol Assess Health Care200925219620719331710

 PubMed Web of Science ®Google Scholar

CallumJLPinkertonPHSunnybrook and Women’s College Health Sciences CentreBloody Easy 2: Blood Transfusions, Blood Alternatives and Transfusion Reactions: A Guide to Transfusion Medicine2nd edToronto, CanadaSunnybrook and Women’s College Health Sciences Centre2005

 Google Scholar

KarnonJBrennanAPandorAModelling the long term cost effectiveness of clopidogrel for the secondary prevention of occlusive vascular events in the UKCurr Med Res Opin200521110111215881481

 PubMed Web of Science ®Google Scholar

CrespinDJFederspielJJBiddleAKJonasDERossiJSTicagrelor versus genotype-driven antiplatelet therapy for secondary prevention after acute coronary syndrome: a cost-effectiveness analysisValue Health201114448349121669373

 PubMed Web of Science ®Google Scholar