Cost effectiveness of AF

monitoring strategies in a

post-stroke population

LAUREN E. CIPRIANO

JEFF HEALEY

OMAR AKHTAR

KAREN LEE

LUCIANO A. SPOSATO

APRIL 12, 2016

Disclosures

Funding: CADTH

Conflicts: None to report

Atrial fibrillation in patients with a

history of stroke or TIA

• ~ 20% of stroke patients have a known history of AF

• ~ 20 - 25% of stroke patients without a prior AF diagnosis,

have AF

• History of stroke & AF 10-15% risk of recurrent

stroke in year 1

2

Oral anticoagulation treatment

• Reduce the risk of recurrent stroke (HR = 0.3-0.65)

• Increase the risk of bleeding (HR = 1.5-3.0)

• NOAC lower the risk of ICH but increase the risk of non-

brain bleeding compared to warfarin

• Warfarin is inexpensive, but has many contraindications and

requires regular visits for patients

• NOACs are expensive, similarly effective to warfarin, and

require less follow-up visits to ensure safety /efficacy

3

Post discharge AF monitoring

4

Patient with stroke or TIA

ECG

Hospital discharge

Age 70 CHADS-VASC ~4

24+ hr monitoring

(sometimes)

Focus of our analysis

24 hr – 7 days monitoring?

30 days monitoring?

2-3 years monitoring?

(implantable device)

Objective

To evaluate the cost effectiveness of outpatient cardiac

monitoring devices for the evaluation of atrial fibrillation in

discharged patients with a recent history of stroke or TIA

Variation in clinical evaluations of monitoring strategies

made many desired comparisons difficult to evaluate.

5

Research Question

Three separate cost effectiveness analyses

6

Study Higgins et al. (2013) Gladstone et al. (2014) Sanna et al. (2014)

Cohort: Ischemic stroke or TIA

within 7 days

Cryptogenic stroke or

TIA within 6 months

Cryptogenic stroke or

TIA within 90 days

Prior AF

monitoring: 12-lead ECG

12-lead ECG and

≥ 24-hour Holter

12-lead ECG and

≥ 24-hour Holter

Intervention: 7 day cardiac event

monitoring (ELR)

30-day event triggered

recorder (ELR)

3-yr insertable cardiac

monitor (ILR )

Comparator:

Standard practice

(60% received

24-hour Holter)

24-hour Holter

Standard practice

(30% ≥ 1 ECG and

8% 24-hour Holter)

Hx of Stroke/TIANo Hx ICHNo Hx MI

Hx of Stroke/TIANo Hx ICH

Hx MI

Hx of Stroke/TIAHx ICH

+/- Hx MI

Hx of Stroke/TIARecurrent major stroke

+/- Hx ICH+/- Hx MI

True Negative AF Diagnosis

Not on OAC treatment

Markov Model

7

• Undiagnosed AF / No AF

• Diagnosed AF

• May initiate OAC

• May discontinue OAC

+ GI bleed

(any cycle)

Model assumptions

• Monthly cycles & Lifetime horizon

• Perspective: Public payer and Soceital

• Input parameters

• Medical literature

• Expert opinion

• Validated to Oxford Vascular Study

• Life-expectancy, QALYs, and 5-year recurrent strokes

8

OAC assumptions

• 61% of patients initiate OAC after diagnosis

• 16% of patients on OACs quit each year

• OACs reduce the risk of recurrent stroke

• Warfarin: 36% reduction compared to aspirin

• Apixiban: 45% reduction compared to aspirin

Annual Cost Disutility Patient time*

Warfarin $396 - 0.013 2 hours every 3 weeks

Dabigatran $1288 - 0.006 -

Rivaroxaban $1157 - 0.006 -

Apixaban $1288 - 0.006 -

* Assume a caregiver attends all visits; patient and caregiver time @ $25/hr

Model-based outcomes

10

Outcomes AF without

diagnosis

AF with diagnosis

Warfarin Apixaban

Within 2 years (per 10,000)

Recurrent IS, severe or fatal 1,087 709 636

Recurrent stroke, any 1,724 1,223 1,093

ICH 47 99 42

GI bleed 171 276 264

AF diagnosis:

Non-fatal strokes Fatal strokes

Bleeds

Model-based outcomes

11

Outcomes AF without

diagnosis

AF with diagnosis

Warfarin Apixaban

LE 4.31 4.53 4.60

Discounted LY 3.59 3.75 3.80

Discounted QALYs 2.30 2.39 2.45

Costs

Baseline 229,025 238,458 241,473

OAC 0 843 2,870

Acute events 19,876 17,223 15,952

Total 248,901 256,525 260,294

Life expectancy Quality-adjusted life expectancy

AF diagnosis:

Costs

Minimum diagnostic yield

to be cost effective

12

61% of AF patients initiate OAC 100% of AF patients initiate OAC

Minimum diagnostic yield

to be cost effective

13

61% of AF patients initiate OAC 100% of AF patients initiate OAC

7d 7d 30d 30d

Evaluation 1: 7-day monitoring vs standard practice

Patients: Stroke and TIA patients within 7 days of discharge

Previous evaluation: ECG

Comparison: 7-day ELR vs Standard practice

(60% 24-hr Holter)

diagnostic yield (sustained AF) = 16% (4.7% - 27.3%)

Results: ICER $50,000 - $80,000 per QALY gained

14

Base case analysis

15

Health economic outcomes OAC treatment

Warfarin Apixaban

Lifetime Costs

Cost of FN diagnosis $151,148 $151,435

Cost of TP diagnosis $153,490 $155,140

Incr. cost of correct diagnosis $2,342 $3,705

Incr. cost of monitoring $139 $139

Lifetime benefits

QALYs of FN diagnosis 2.30 2.31

QALYs of TP diagnosis 2.36 2.40

Incr. QALYs of correct diagnosis 0.055 0.088

Incr. cost effectiveness ratio

(ICERs) ($/QALY gained) $58,800 $52,200

Sensitivity analysis

7-day monitoring ICER <$100,000 / QALY gained with

incremental diagnostic yield as low as 5%

Patient characteristics that increase cost effectiveness

• Higher risk of recurrent stroke (>10% py)

• Lower baseline risk of bleeding

• Healthier / Fewer comorbidities (lower baseline mortality risk; lower

baseline health care costs; higher baseline utility)

• Higher likelihood of OAC uptake if diagnosed

Societal perspective (apixaban)

• ICER $75,000 – 85,000 / QALY gained

• ICER <$70,000 if OAC if patient is above average baseline health

16

Cost effectiveness improves with

connection to OAC treatment

17

Cost of monitoring is critical factor

influencing cost effectiveness

18

Summary: 7-day monitoring vs standard practice

ICER likely between $40,000-$80,000 per QALY gained

• Patient population

• Unselected stroke and TIA patients within 7 days

• Prior monitoring: only ECG

• Targeted patient populations ICER <$50,000 per QALY gained

• > 20% incremental diagnostic yield

• high rate of connection to OAC treatment

• low OAC discontinuation rate

• selection of relatively healthy patients

• Unable to evaluate 7-day monitoring vs. universal 24-hour monitoring

• Optimal duration of monitoring is unknown

19

Evaluation 2:

30-day ELR vs 24-hour Holter

Patients: Cryptogenic stroke patients within 6 months

Previous evaluation: ECG and at least 24-hrs of Holter

Comparison: 30-day ELR vs 24-hr Holter

Incremental diagnostic yield = 12.9% (8.0% - 17.6%)

Results: ICER $90,000 - $120,000 per QALY gained

20

Sensitivity analysis

30-day monitoring followed by treatment with warfarin and

apixaban has an ICER < 100,000 per QALY gained

• Incremental diagnostic yield > 20%

• Incremental cost of monitoring < $300

• OAC uptake > 85%

• Patients with above average baseline health

• Patient and system factors alone insufficient to make 30-day

monitoring cost effective compared to 24-hour Holter without

greater diagnostic yield and/or lower incremental cost

• Societal perspective: base case >$110,000 per QALY gained

22

Summary

30-day ELR vs 24-hour Holter

Unlikely to be cost effective (ICER > $100,000/QALY gained)

• Patient population

• Cryptogenic stroke and TIA patients within 6 months

• Prior monitoring: ECG and 24-hour Holter

• Unable to compare 24-hour Holter to no monitoring

• Unclear if any monitoring after ECG and 24-hour Holter is cost effective

• Unable to evaluate whether evaluating patients sooner (within 30 or

90 days of stroke) would improve cost effectiveness

24

Evaluation 3:

3-years of ILR vs standard practice

Patients: Cryptogenic stroke patients within 90 days

Previous evaluation: ECG and at least 24-hrs of Holter

Comparison: 3-years of ILR vs. standard practice

(38% ECG or 24-hour Holter within 6 months)

30% of patients in ILR group diagnosed with AF

vs. 3% in the standard practice group

Incremental cost: EV ~$3400 ($2800 implantation + monitoring)

Results: ICER > $250,000 per QALY gained

25

Post discharge AF monitoring Evaluation 1: 7-day ELR vs. standard care

28

Patient with stroke or TIA

ECG in Hospital

Hospital discharge

Age 70 CHADS-VASC ~4

7-day ELR

Standard care

Conclusion: Likely cost effective • $40,000-80,000/QALY gained • ∆ diagnostic yield > 10-20% • Patient factors

• ↑risk of stroke; ↓risk of bleeding • Relatively healthy • ↑ connection to OAC

∆ diagnostic yield = 16% ∆ cost = $140

Post discharge AF monitoring Evaluation 2: 30-day ELR vs. 24-hr Holter

29

Patient with cryptogenic stroke or TIA

ECG in Hospital

Hospital discharge

Age 70 CHADS-VASC ~4

30-day ELR

24-hour Holter

Conclusion: Not cost effective • $90,000-120,000 / QALY gained • <$100,000 if ∆ diagnostic yield > 20% • <$100,000 if ∆ cost < $300 • Patient or system factors alone are unlikely to be sufficient

∆ diagnostic yield = 13% ∆ cost = $476

24-hr Holter

Post discharge AF monitoring Evaluation 3: ILR vs. standard care

30

Patient with cryptogenic stroke or TIA

ECG in Hospital

Hospital discharge

Age 70 CHADS-VASC ~4

3-year ILR

Standard care

Conclusion: Not cost effective • ICER > $250,000 / QALY gained

∆ diagnostic yield = 27% ∆ cost = $3400

24-hr Holter

Summary

In a stroke or TIA patient who received ECG in hospital

• 7-days of monitoring is likely cost effective compared to standard care

• Unclear if cost effective vs. universal 24-hour monitoring

• Unclear if 7-days is the optimal duration of monitoring

• Unlikely to be cost effective in a patient who has received in-patient

Holter/CICT/cECG monitoring (needs large incremental diagnostic yield)

In a cryptogenic stroke or TIA patient who received ECG and 24-hr Holter

• 30-day monitoring is unlikely cost effective compared to 24-hr Holter

• ILR is not cost effective compared to standard care

• Unclear 24-hour Holter is cost effective compared to no further monitoring

• Unclear if 30-days of monitoring is cost effective compared to 7-days in a

patient cohort without prior 24-hr Holter

31

Limitations

• Many comparisons of interest were not evaluated • Optimal sequence of monitoring technologies remains unknown

• Many simplifying structural assumptions • Assume a constant rate of recurrent stroke

• AF diagnosis after subsequent event

• OAC adherence, quitting after a bleeding event, and re-starting after a

clotting event

• Model considers patients at average risk • Explored the influence of patient factors on cost effectiveness of monitoring

• Do not consider correlation between patient factors

• Do not consider the incidence of AF after stroke • Incident AF will be captured by longer-monitoring technologies (ILR)

32

33

Evaluation 1: 7-day ELR vs. standard care

OAC Adherence

34

Evaluation 2: 30-day ELR vs. 24-hr Holter

OAC Adherence

35

Comparisons to other models

Kamel et al.

Cost effectiveness of dabigatran, apixaban vs. warfarin in

post-stroke patients with AF

36

Kamel et al. QALY

CADTH Base case OAC discontinuation No OAC discontinuation QALY LY QALY LY

Dabigatran 4.27 2.57 4.01 2.64 4.12

Apixaban 4.19 2.63 4.08 2.74 4.24

Warfarin 3.91 2.56 4.02 2.63 4.14

* 3% annual discount rate

Utility weight for initial health state = 0.994-0.987 vs. 0.68

Comparisons to other models

Coyle et al.

Cost effectiveness of NOACs vs. warfarin in post-stroke

patients with AF

• Lifetime QALYs with warfarin

• Coyle et al. Mild stroke (utility = 0.75): 4.45 QALYs

• Coyle et al. Severe stroke (utility = 0.33): 2.2 QALYs

• Our model Mixed cohort (utility = 0.68): 2.4 QALYs (3.75 LY)

37

* 5% annual discount rate

Our rate of recurrent stroke on warfarin is greater. Coyle et al. = 0.035 (base rate of 0.016 x HR of 2.2) Our model = 10.2% annual rate on aspirin x HR of 0.63 = 0.068

Model-based outcomes

38

Outcomes AF without

diagnosis

AF with diagnosis

Warfarin Apixaban

Within 2 years (per 10,000)

Recurrent IS, severe or fatal 1,087 709 636

Recurrent stroke, any 1,724 1,223 1,093

ICH 47 99 42

GI bleed 171 276 264

Within 5 years (per 10,000)

Recurrent IS, severe or fatal 2,002 1,455 1,345

Recurrent stroke, any 3,189 2,459 2,266

ICH 87 170 80

GI bleed 316 487 471

LE 4.31 4.53 4.60

Model-based outcomes

39

Outcomes AF without

diagnosis

AF with diagnosis

Warfarin Apixaban

LE 4.31 4.53 4.60

Discounted LY 3.59 3.75 3.80

Discounted QALYs 2.30 2.39 2.45

Costs

Baseline 229,025 238,458 241,473

OAC 0 843 2,870

Acute events 19,876 17,223 15,952

Total 248,901 256,525 260,294

Model Validation

40

Comparison to Oxford Vascular Study

Oxford vascular study • 440 TIA and 748 stroke patients (2002-2007) followed up for 5-10 years

• 17% prior history of stroke

• 18% prior diagnosis of AF

41

Life years QALYs

TIA 4.3 3.3

Stroke 3.6 2.5

Mild 4.1 2.9

Moderate 2.8 1.7

Severe 1.4 0.7

Overall 3.8 2.7

Adjusted (12%) 4.4 3.1

Life years QALYs

No AF 7.2 4.73

AF without diagnosis 4.3 2.75

AF with diagnosis

Warfarin 4.5 2.88

Apixaban 4.6 2.95

Our model Oxford Vascular Study

Comparison to Oxford Vascular Study

Oxford vascular study • 440 TIA and 748 stroke patients (2002-2007) followed up for 5-10 years

• 17% prior history of stroke

• 18% prior diagnosis of AF

42

5-year risk of recurrent stroke

TIA 16%

Stroke 20%

5-year risk of recurrent stroke

No AF 8.1%

AF without diagnosis 31.9%

AF with diagnosis

Warfarin 24.6%

Apixaban 22.7%

Our model Oxford Vascular Study

Inputs: Natural history

Recurrent stroke

MI ICH GI bleed

Annual risk of event

No AF 2.2% 2.6% 0.3% 1.1%

AF no OAC 10.2% 5.1% 0.3% 1.1%

HR with OAC (compared to aspirin*)

Warfarin 0.38 0.89 2.60 2.50

Dabigatran 0.38 1.42 1.08 4.11

Rivaroxaban 0.36 0.72 1.74 3.65

Apixaban 0.35 0.78 1.09 2.23

43

Inputs: Costs and Utilities

Recurrent stroke

Death GI bleed MI ICH TIA/Mild* Mod-Sev

Month of

Mortality (no OAC/OAC) 0% 11% 31%/44% 39% / 29%

Cost $43,600 $9,975 $18,400 $36,000 $16,200 $55,000

QOL - 0.03 - 0.01 - 0.05 - 0.02 - 0.13

History of

Annual mortality (no AF/AF) 12 % / 16 % 16 % / 22 %

Direct health costs 18,400 18,400 18,400 30,900

Unpaid caregiver costs 15,000 15,000 15,000 25,000

QOL 0.65 0.62 0.68 0.31

Comparison to Yong et al.

Cost effectiveness of 30-day ELR vs 24-hr Holter

46 * 5% annual discount rate ** assumes 16.1% AF prevalence

Key differences • Yong et al. are modeling a healthier cohort

• Annual mortality rate = 5.4% per year vs. 12.1% per year • Baseline utility = 0.93 vs. 0.68 • Baseline costs associated with history of stroke = $9301 vs. $43,200

Yong et al. CADTH

30-day ELR LE = 8.158 years LE = 6.8 years

24-hr Holter LE = 8.138 years LE = 6.2 years

ICER Cost saving $151,208 / QALY gained

AF diagnosis

occurs over time

Assumed

• 30% AF prevalence

• While undiagnosed, patients

(with and without AF) may

die or have recurrent stroke

• Considered censored

• Calculated the rate of AF

identification in undiagnosed

patients to match KM curves in

Sanna (NEJM 2014)

47

Cohort with 30% AF prevalence

48

Outcomes Warfarin

Standard practice ILR

Apixaban

Standard practice ILR

Within 2 years (per 10,000)

Recurrent IS, severe or fatal 475 449 474 443

Recurrent stroke, any 780 746 777 735

ICH 51 54 50 49

GI bleed 183 190 183 189

LE 6.31 6.33 6.31 6.34

Discounted LY 4.82 4.83 4.82 4.84

Discounted QALY 3.18 3.19 3.18 3.19

Cohort with 30% AF prevalence

49

Outcomes Warfarin

Standard practice ILR

Apixaban

Standard practice ILR

Costs

Baseline $292,815 $293,792 $292,959 $294,14

Testing $40 $1,129 $40 $1,129

OAC $41 $118 $138 $402

Acute Events $11,651 $11,404 $11,591 $11,227

TOTAL $304,547 $306,443 $304,727 $306,971

Incr. cost of ILR monitoring $1,896 $2,244

Incr. QALYs 0.009 0.015

Incr. cost effectiveness ratio

(ICERs) ($/QALY gained)

$205,169 $151,208

Sensitivity analysis

ILR monitoring vs. standard care

• ICER > 100,000 per QALY gained is robust

• Doubling the diagnosis rate (diagnosing patients faster)

W: $175,400 per QALY gained A: $132,600 per QALY gained

• Immediate diagnosis in ILR arm

W: $154,300 per QALY gained A: $120,500 per QALY gained

• Cost of implantation = $0 ICER > $100,000 per QALY gained

• Cost of monitoring =$0 ICER > $100,000 per QALY gained

• ICER < 100,000 per QALY gained Cost of implantation and

monitoring 25% of base case

50

Comparison to Diamantopoulos et al.

Cost effectiveness of ILR vs standard care

51

* 3.5% annual discount rate ** 5% annual discount rate

Key differences • Baseline mortality rate in Diamantopoulos et al. is based on UK life tables (no increase in mortality rate for history of stroke) • Baseline utility = 0.76 vs. 0.68 • Low costs of long-term care

• e.g., £578 per year after a mild stroke (vs. $43,200) • e.g., £1,712 per year after a recurrent major stroke (vs. $65,000)

Diamantopoulos et al.* CADTH**

ILR 7.367 QALY 4.84 QALY

Standard care 7.216 QALY 4.82 QALY

ICER £ 17,175 / QALY gained $151,208 / QALY gained