1. Acute Coronary Syndrome
A Cost Analysis on Utilizing Ticagrelor in the 30-day Treatment of Patients with
Acute Coronary Syndrome  
1 Anchah L, 2 ,3, 4 Fong AYY.
 1Department of Pharmacy, Sarawak General Hospital Heart Centre, Kota Samarahan, Sarawak
2Department of Cardiology, Sarawak General Hospital Heart Centre, Kota Samarahan, Sarawak
3Clinical Research Centre, Sarawak General Hospital
4 Faculty of Medicine and Health Sciences, Universiti Malaysia Sarawak, Malaysia
A Cost Analysis on Utilizing Ticagrelor in the 30-Day Treatment of Patients with Acute Coronary Syndrome
1Department of Pharmacy, Sarawak General Hospital Heart Centre, Kota Samarahan, Sarawak
2Department of Cardiology, Sarawak General Hospital Heart Centre, Kota Samarahan, Sarawak
3Clinical Research Centre, Sarawak General Hospital
4Faculty of Medicine and Health Sciences, Universiti Malaysia Sarawak, Malaysia
Lunch symposium for NCCR 2014 Conference, 1230pm -1300pm 2nd October 2014

2. A Cost Analysis on Utilizing Ticagrelor in the 30-day Treatment of Patients with Acute Coronary Syndrome
NHAM 2012, 13th April 2012, KL
Acs Update And Basic Pharmacoeconomics Workshop 23rd Feb 2013, Four Point Hotel Kuching

3. INTRODUCTION

4. Figure 2 Ticagrelor: A Novel Reversible Oral Antiplatelet Agent
Nawarskas, James J.; Clark, Sara M.
Cardiology in Review. 19(2):95-100, March/April 2011.
doi: /CRD.0b013e d86
FIGURE 2. Adenosine diphosphate (ADP) binds to the P2Y12 receptor and stimulates platelet activation, which ultimately leads to a conformational shape change of the platelet, thrombin generation and platelet aggregation. Clopidogrel and prasugrel directly and irreversibly block ADP through antagonism of the P2Y12 receptor for the life of the platelet. Ticagrelor binds at a separate P2Y12 sub-receptor that non-competitively blocks ADP activation through inactivating the receptor. Ticagrelor has reversible binding and leaves the receptor intact. Antiplatelet agents working at P2Y12 can be used simultaneously with aspirin due to separate and complementary mechanisms of action. Adapted from Curr Pharm Des. 2006;12:1255–
TxA2, thromboxane A2; GP, glycoprotein; COX, cyclooxygenase; TPα, thromboxane A2
Copyright © 2012 Cardiology in Review. Published by Lippincott Williams & Wilkins.

5. Hierarchical testing of major efficacy endpoints (adapted from PLATO Study)

6. Reversible, more intense P2Y12 receptor inhibition for one year with ticagrelor in comparison with clopidogrel in patients with STEMI intended for reperfusion with primary PCI provides
Reduction in composite of CV death, MI or stroke
Reduction in MI and stent thrombosis
Reduction in total mortality
No increase in the risk of major bleeding

7. Figure 3
Ticagrelor: A Novel Reversible Oral Antiplatelet Agent
Nawarskas, James J.; Clark, Sara M.
Cardiology in Review. 19(2):95-100, March/April 2011.
doi: /CRD.0b013e d86
FIGURE 3. Event rates for the primary efficacy outcome (cardiovascular death, myocardial infarction, and stroke) in the PLATO trial. Ticagrelor was superior to clopidogrel in the total population and in the patients outside of the United States (non-US), but not in the United States participants in whom a numerical benefit was seen in favor of clopidogrel. Data from .32
Copyright © 2012 Cardiology in Review. Published by Lippincott Williams & Wilkins.

8. Table 1 Ticagrelor: A Novel Reversible Oral Antiplatelet Agent
Nawarskas, James J.; Clark, Sara M.
Cardiology in Review. 19(2):95-100, March/April 2011.
doi: /CRD.0b013e d86
TABLE 1. Comparison of Antiplatelet P2Y12 Inhibitors7,11,12,17,18,22–24
Copyright © 2012 Cardiology in Review. Published by Lippincott Williams & Wilkins.

9. Ticagrelor: Does Not Require Hepatic Metabolism for Activation
Does NOT require metabolic activation to become active drug
Ticagrelor
Binding
Platelet
Clopidogrel
P2Y12
CYP-dependent
oxidation
CYP1A2
CYP2B6
CYP2C19
CYP-dependent
oxidation
CYP2C19
CYP3A4/5
CYP2B6
BRILIQUE: Does Not Require Hepatic Metabolism For Activation
Reference
Schomig A. Ticagrelor — is there need for a new player in the antiplatelet-therapy field? N Engl J Med. 2009;361:1108–1111.
Active compound
Intermediate metabolite
Prodrug
Clopidogrel:
A prodrug; requires metabolism to become active drug
Adapted from Schomig A. N Engl J Med. 2009;361:1108–1111.

10. Pharmacoeconomics
Pharmacoeconomics is the scientific discipline that evaluates the clinical, economic and humanistic aspects of :
pharmaceutical products,
services,
programs,
other health care interventions
To provide valuable information (health care decision makers, providers and patients)
To opt optimal outcomes and resources.
Pharmacoeconomics incorporates health economics, clinical evaluations, risk analysis, technology assessment, and health-related quality of life, epidemiology, decision sciences and health services research in the examination of drugs, medical devices, diagnostics, biotechnology, surgery, disease-prevention services.
Brief Definition Pharmacoeconomics is the scientific discipline that evaluates the clinical, economic and humanistic aspects of pharmaceutical products, services, and programs, as well as other health care interventions to provide health care decision makers, providers and patients with valuable information for optimal outcomes and the allocation of health care resources. Pharmacoeconomics incorporates health economics, clinical evaluations, risk analysis, technology assessment, and health-related quality of life, epidemiology, decision sciences and health services research in the examination of drugs, medical devices, diagnostics, biotechnology, surgery, disease-prevention services.

11. Pharmacoeconomics
Health economics evaluation using “cost effectiveness concept” and broad range of techniques.
Perspective, direct cost from …..societal (working days lost, opportunity costs, etc), healthcare providers (resources lost, operational costs, procedure costs)

12. Objectives
To perform a cost saving analysis of treating Malaysian patient with acute coronary syndromes with Ticagrelor
To supplement expert opinion with empirical data regarding the next potential alternative antiplatelet for Adenosine Diphosphate (ADP) antagonist for acute coronary syndrome (ACS).

13. METHODOLOGY

14. Cost-Effectiveness
This data-driven exploration of actual costing practices
Relative cost of one intervention vs. another
Costing Protocol
Supply costs included costs of all medical and nonmedical supplies.
Cost incur from Healthcare provider perspective.

15. PLATO : Primary Endpoint Over Time
EZ BRILIQ
EZ001301
PLATO : Primary Endpoint Over Time
Time to first primary efficacy event (composite of CV death, MI or stroke) 8 8
6.60
5.43
Clopidogrel 6 6
Clopidogrel
5.28
Cumulative incidence (%) 4
Cumulative incidence (%) 4
Ticagrelor
4.77
Ticagrelor 2 2
HR 0.88 (95% CI 0.77–1.00), p=0.045
HR 0.80 (95% CI 0.70–0.91), p<0.001
10 days
20 days
30 days 31 90
150
210
270
330
Days after randomisation
Days after randomisation*
No. at risk
Ticagrelor
9,333
8,942
8,827
8,763
8,763
8,543
8,397
7,028
6,480
4,822
Clopidogrel
9,291
8,875
8,763
8,688
8,688
8,437
8,286
6,945
6,379
4,751
*Excludes patients with any primary event during the first 30 days
Wallentin et al. New Eng J Med 2009; 361(11):

16. Risk Difference
Straightforward method in looking two groups in RCT relates to number needed to treat
Therefore the Risk Difference is the difference of Hazard Ratio within 30 days is calculated by:
HR 5.43 (Clopidogrel) HR 4.77 (Ticagrelor) = 0.66
Those in clopidogrel may have more risk of 0.66 event as compared to Ticagrelor group.
Note: In Cox proportional hazards models, the “hazard ratio” presented is interpreted as “relative risk” of an event (CV death, MI or stroke)

17. Relative Risk Reduction (RRR)
RRR is the reduction in risk (risk difference) with new therapy (Ticagrelor) relative to the risk without the new therapy.
‘Difference event rate’ devided by the ‘control event rate’
Risk diff /CER
Relative Risk Reduction of 0.66/5.43 = 0.12
The Ticagrelor treatment group reduced the risk of death from vascular causes, MI, or stroke by 12% relative to that occurring in the Clopidogrel treatment group.
Note: CER=control event rate (clopidogrel)
Beth Dawson & Robert G. Trapp. Basic & Clinical Biostatistics 2004

18. A well-designed pharmacoeconomic analysis involves 10 steps:
(1) defining the problem, (2) determining the study's perspective, (3) determining the alternatives and outcomes, (4) selecting the appropriate pharmacoeconomic method, (5) placing monetary values on the outcomes, (6) identifying study resources, (7) establishing the probabilities of the outcomes, (8) applying decision analysis, (9) discounting costs or performing a sensitivity or incremental cost analysis, and (10) presenting the results, along with any limitations of the study.
LM Jolicoeur, AJ Jones-Grizzle, and JG Boyer. Guidelines For Performing A Pharmacoeconomic Analysis

19. Measuring Costs by weighing up the costs of services/interventions
Direct costs
Medical cost of drugs, laboratory test, consumables, acquisition costs, staff costs
Fixed costs such as overhead costs
Indirect costs
Loss of earning (morbidity & mortality costs)
Loss of productivity
Difficult to measures from society perspective

20. RESULTS

21. We noted that there was a 12
We noted that there was a 12.3% PEV at 30 days (4 deaths, and 3 admissions with UA) in patients admitted with ACS in a 2-month study involving a single tertiary cardiology centre in the Malaysian state of Sarawak
In the National Cardiovascular Disease – Acute Coronary Syndrome Registry in 2007, involving 14 public funded healthcare canters located in 12 Malaysian states, the all-cause mortality at 30-days was 20%.

22. In patient admitted with ACS and all-cause mortality at 30-days
A 2-month Study from a Single Tertiary Cardiology Centre of Sarawak
12.3% primary event at 30 days
4 deaths, and 3 admissions with UA
The National Cardiovascular Disease – Acute Coronary Syndrome Registry in 2007
In the National Cardiovascular Disease – Acute Coronary Syndrome Registry in 2007, involving 14 public funded healthcare canters located in 12 Malaysian states, the all-cause mortality at 30-days was 20% and 10% die from CV cause..
3646 pts were registered

23. NCVD-ACS 2007 Based on our experience 3/7 of MACCE was due to UA.
More than 97% with Aspirin
Approximately 65% with Clopidogrel
10% die from CV cause.
10% X 3/7 can be suffering UA
MACCE is 14.3% (10% + 4.3%)

24. NCVD 2007 3646 pts were registered
20% die of all cause (10% die from CV cause).
Based on our experience 3/7 of MACCE was due to UA.
More than 97% with Aspirin
Approximately 60% with Clopidogrel
Patients with clopidogrel can contribute to 10% (die) + 10%X3/7 (UA)
Therefore contribute to 14.3% MACCE
“This study provided information on the occurrence rate of major adverse coronary events (MACE) during the first 30 days post-ACS. Among the 57 patients recruited, 7 had a MACE, of which 4 were cardiovascular deaths and 3 were UA (Table 2). This fraction 4 over 7 (4/7 MACE) can be related to a similar approach presented in NCVD ACS where cardiovascular death rate was 10%. Similarly, unstable angina was seen in a fraction of 3 over 7 MACE or corresponding rate 7.5% MACE in ACS patients post admission in 30 days. Thus, the prevalence rate of total MACE as estimated from NCVD ACS 2007 was 17.6%.12”
Fong AYY, Tiong LL, Wong JL, et al. Impact of an onsite cardiac catheter laboratory and pharmacotherapy on clinical outcomes of Acute Coronary Syndrome: A comparison of a Tertiary Referral Centre with a District General Hospital.

25. Ticagrelor With Ticagrelor Relative Risk Reduction (RRR) of 0.122
14.3% (MACCE) X (RRR) = 1.74%
Therefore we have can determine if all patients were on Ticagrelor, we may have reduced MACCE to 12.6% ( )
Considering that 62% of all patients received an ADP antagonist and assuming that 50% of patients died of cardiovascular causes, a calculated PEV total of would be 17.6%.
Using Ticagrelor, the corresponding PEV would be 15.4%.
NCVD-ACS 2007

26. NCVD-ACS 2007 Based on our experience 3/7 of MACCE was due to UA.
More than 97% with Aspirin
Approximately 65% with Clopidogrel
10% die from CV cause.
10% X 3/7 can be suffering UA
MACCE is 14.3% (10% + 4.3%)

27. Attribution of PLATO information
Relative Risk Reduction (RRR) = 0.12
14.3% (MACCE from NCVD-ACS) X 0.12 (RRR) = 1.74%
If all patients with Ticagrelor, we may have reduced MACCE to 12.6% ( )

28. (composite of CV death, MI or stroke)
EZ BRILIQ
EZ001301
Based on the NCVD
(composite of CV death, MI or stroke) 13
Clopidogrel
14.3 12 11 10
12.6 9
Ticagrelor 8 7
Incidence (%) 6 5 4 3 2 1
30 days
Days

29. Using ticagrelor, the corresponding PEV would be 15.4%.
The actual total with PEV (i.e.UA), requiring re-admission and treatment, and that 2072 of the 3646 fulfilled the PLATO inclusion criteria, would be 137 patients; compared to 158 patients if using clopidogrel.

30. From NCVD-ACS 2006-2008, 65% of all patients (STEMI, NSTEMI & UA) in 2007 received an ADP antagonist

31. What we know in NCVD-ACS 2007:
65% of all patients received an ADP antagonist or clopidogrel
50% of patients died of cardiovascular causes, a calculated PEV total of would be 17.6%.
If Ticagrelor:PEV would be 15.4%.

32. The actual total with PEV (i. e
The actual total with PEV (i.e.UA), requiring re-admission and treatment, and that 2072 of the 3646 fulfilled the PLATO inclusion criteria, would be 137 patients; compared to 158 patients if using clopidogrel.
Chapter 2 page 12

33. Decision three

34. COSTING direct costs (i.e. hospitalisation)

35. Measuring Costs by weighing up the costs of services/interventions
Direct costs
Medical cost of drugs, laboratory test, consumables, acquisition costs, staff costs

36. Master List for Surgical & Equipments

37. Costing for Angiogram:
Disposable items
Stents
Other equipments

38. Costing for CABG
** Presented by Dr Maggie Seldon at Cardiothoracic Conference 2008, Kelantan , Malaysia

39. Costing for lab test according to LOS

40. Medication costs during admission, discharge, follow-up.

41. Procedure costs for PCI (2007)

42. Annual Cost and Incremental Cost Ratio
Optimised Medical Therapy
TOTAL Cost Annually
QALY
Incremental Cost Ratio
(ICR)
MCRP
6,052.43
7,213.86
$51.31
CCRP *
6,009.38
7,162.55 -
Control
5,992.17
8,000.23
$837.68
PCI (Angiogram)
15,756.90
18,780.57
CCRP
15,713.85
18,729.26
15,696.64
20,956.79
$2,227.53
CABG (Bypass)
53,605.30
63,891.89
53,562.25
63,840.58
53,545.04
71,488.70
$7,648.12
Malaysian Pharmaceutical Society Pharmacy Scientific Conference, Hotel Istana, Kuala Lumpur, 2011

44. 21 Patients Seeking Treatments
Annual health care resources used in
MCRP median RM 25,994 (6,110 to 75,509)
CCRP RM 21,471 ( 7,813 to 61,542) and
Usual care RM 16,620 ( 4,565 to 61,854).
However, the total direct cost of health care resources annually for bypass (CABG) is estimated with
Median RM 51,542 (RM 44,266 to RM 75,509)
similar to CABG with CCRP
Median RM 53,376 (RM 46,538 to RM 61,542).
Malaysian Pharmaceutical Society Pharmacy Scientific Conference, Hotel Istana, Kuala Lumpur, 2011

45. Assuming that an approximately equal number undergo medical therapy, percutaneous coronary intervention with drug eluting stent, and cardiac bypass surgery, the total direct cost of admission and treatment of these 21 unstable angina patients would be RM403,040.36
The total annual drug cost of treating Malaysian patients admitted with ACS with clopidogrel (RM5.55) for 30 days would be RM1,381,733.92
If ticagrelor was used (RM8.70), the corresponding amount would be RM1,555,471.12
Cost saving = RM229,302.24

46. Cost Saving
Assuming that an approximately equal number undergo medical therapy, percutaneous coronary intervention with drug eluting stent, and cardiac bypass surgery, the total cost of admission and treatment of these 21 unstable angina patients would be RM403, (A).
The total annual drug cost of treating Malaysian patients admitted with ACS with clopidogrel for 30 days would be RM1,381, (B).
If Ticagrelor was used, assuming the daily cost is RM8.70, the corresponding amount would be RM1,555, (C); deriving a cost saving of RM229, {(A)- ((C)-(B)}
Do the decision three

47. Decision Diagram of two groups of treatment with Clopidogrel or Ticagrelor in 30-days
MACCE
Treament on Clopidogrel 17.6%
Died (10% due to CVD)
UA (4/7 of MACCE based in SGHHC 2007)
N=158
Treatment on Ticagrelor 15.4%
RRR=0.12
N=137
saving
RM229,000
ACS Registry in 2007, All-cause mortality at 30-days was 20%.
Total of n=3646
Calculated Total Primary Event
RRR calculated based on Plato Study
COST
21 unstable angina patients would be RM403, (Mx, PCI and CABG)
ACS in Malaysia with clopidogrel for 30 days would be RM1,381,733.92
and Ticagrelor
RM1,555,471.12

48. CONCLUSION

49. CONCLUSION
In a cost analysis of treating Malaysian patients with ACS for 30 days, treatment with ticagrelor compared to clopidogrel be cost saving for the main public sector healthcare provider.

50. A cost-saving alternative to Ticagrelor
In a cost analysis of treating Malaysian patients with ACS for 30 days, treatment with ticagrelor compared to clopidogrel be cost saving for main public health provider.

51. LIMITATION

52. Some Types of Economic Analysis in Health Care Studies
Cost - efficiency Studies - What should it cost?
Cost-of-illness Studies (COI) - Economic burden of illness
Cost Evaluation Studies
Cost Benefit Analysis (CBA)
Cost Effectiveness Analysis (CEA)
Cost Utility Analysis (CUA)
Slide adopted from: Martin L. Brown, PhD., Introduction to the Principles and Practice of Clinical Research

53. Suggestion NCVD is invaluable database: Health Economics Modeling:
economic modeling combined with results of randomized clinical trials through modeling
Pharmacoeconomics incorporates health economics, clinical evaluations, risk analysis, technology assessment, and health-related quality of life, epidemiology, decision sciences and health services research in the examination of drugs, medical devices, diagnostics, biotechnology, surgery, disease-prevention services.

54. THANK YOU