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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

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Cost effectiveness of AF monitoring strategies in a post-stroke population

LAUREN E. CIPRIANOJEFF HEALEY OMAR AKHTAR KAREN LEE LUCIANO A. SPOSATO

APRIL 12, 2016

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Disclosures

Funding: CADTH

Conflicts: None to report

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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

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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

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Post discharge AF monitoring

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Patient with stroke or TIA

ECG

Hospitaldischarge

Age 70 CHADS-VASC ~4

24+ hrmonitoring

(sometimes)

Focus of our analysis

24 hr – 7 daysmonitoring?

30 daysmonitoring?

2-3 yearsmonitoring?

(implantable device)

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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.

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Research QuestionThree separate cost effectiveness analysesStudy 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 Holter12-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 HolterStandard practice (30% ≥ 1 ECG and 8% 24-hour Holter)

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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 treatmentMarkov Model

• Undiagnosed AF / No AF• Diagnosed AF

• May initiate OAC• May discontinue OAC

+ GI bleed (any cycle)

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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

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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

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Model-based outcomesOutcomes AF without

diagnosisAF with diagnosis

Warfarin ApixabanWithin 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 strokesFatal strokes Bleeds

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Model-based outcomesOutcomes AF without

diagnosisAF 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 expectancyQuality-adjusted life expectancy

AF diagnosis:

Costs

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Minimum diagnostic yield to be cost effective

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

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Minimum diagnostic yield to be cost effective

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

7d 7d30d 30d

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Evaluation 1: 7-day monitoring vs standard practicePatients: 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

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Base case analysisHealth economic outcomes OAC treatment

Warfarin Apixaban

Lifetime Costs

Cost of FN diagnosis $151,148 $151,435Cost of TP diagnosis $153,490 $155,140Incr. cost of correct diagnosis $2,342 $3,705Incr. cost of monitoring $139 $139

Lifetime benefits QALYs of FN diagnosis 2.30 2.31QALYs of TP diagnosis 2.36 2.40Incr. QALYs of correct diagnosis 0.055 0.088

Incr. cost effectiveness ratio (ICERs) ($/QALY gained) $58,800 $52,200

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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

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Cost effectiveness improves with connection to OAC treatment

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Cost of monitoring is critical factor influencing cost effectiveness

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Summary: 7-day monitoring vs standard practiceICER 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

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Evaluation 2: 30-day ELR vs 24-hour HolterPatients: 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

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Sensitivity analysis30-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

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Summary30-day ELR vs 24-hour HolterUnlikely 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

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Evaluation 3: 3-years of ILR vs standard practicePatients: 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 AFvs. 3% in the standard practice group

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

Results: ICER > $250,000 per QALY gained

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

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Patient with stroke or TIA

ECG in Hospital

Hospitaldischarge

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

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

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Patient with cryptogenic stroke or TIA

ECG in Hospital

Hospitaldischarge

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

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Post discharge AF monitoringEvaluation 3: ILR vs. standard care

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Patient with cryptogenic stroke or TIA

ECG in Hospital

Hospitaldischarge

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

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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

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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)

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Evaluation 1: 7-day ELR vs. standard careOAC Adherence

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Evaluation 2: 30-day ELR vs. 24-hr HolterOAC Adherence

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Comparisons to other modelsKamel et al.Cost effectiveness of dabigatran, apixaban vs. warfarin in

post-stroke patients with AF

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 4.12Apixaban 4.19 2.63 4.08 2.74 4.24Warfarin 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

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Comparisons to other modelsCoyle 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)

* 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

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Model-based outcomesOutcomes AF without

diagnosisAF with diagnosis

Warfarin ApixabanWithin 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

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Model-based outcomes

Outcomes AF without diagnosis

AF with diagnosisWarfarin 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

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Model Validation

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Comparison to Oxford Vascular StudyOxford 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

Life years QALYsTIA 4.3 3.3Stroke 3.6 2.5Mild 4.1 2.9Moderate 2.8 1.7Severe 1.4 0.7Overall 3.8 2.7Adjusted (12%) 4.4 3.1

Life years QALYsNo AF 7.2 4.73AF without diagnosis 4.3 2.75AF with diagnosis

Warfarin 4.5 2.88Apixaban 4.6 2.95

Our model Oxford Vascular Study

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Comparison to Oxford Vascular StudyOxford 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

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

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Inputs: Natural history

Recurrent stroke MI ICH GI bleed

Annual risk of eventNo 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

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Inputs: Costs and Utilities Recurrent stroke

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

Month ofMortality (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 ofAnnual 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

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Comparison to Yong et al.

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

* 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. CADTH30-day ELR LE = 8.158 years LE = 6.8 years24-hr Holter LE = 8.138 years LE = 6.2 yearsICER Cost saving $151,208 / QALY gained

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AF diagnosis occurs over timeAssumed

• 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)

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Cohort with 30% AF prevalence

Outcomes WarfarinStandard practice ILR

ApixabanStandard 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

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Cohort with 30% AF prevalence

Outcomes WarfarinStandard practice ILR

ApixabanStandard 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

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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

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Comparison to Diamantopoulos et al.

Cost effectiveness of ILR vs standard care

* 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