Use of insertable cardiac monitors for the detection of atrial fibrillation in patients with cryptogenic stroke in the United States is cost-effective

Figures & data

Table 1. Overview of the key features of the model.

Attribute	Description
Type of economic study	Cost-effectiveness analysis
Patient population	Hypothetical cohort of patients that have suffered cryptogenic stroke, with suspected paroxysmal, silent AF
Proposed intervention	BioMonitor 2 (BM 2)
Standard of care (SoC) monitoring	Mix, including ECG, 24-h, 48-h, and 7-day Holter monitoring, as for CRYSTAL-AF^27
Model approach	Markov chain model developed in MS Excel 2013
Cycle length	3 month cycle length, with half-cycle correction
Perspective	US payer perspective (Medicare)
Costs	Direct medical costs (acute and long-term) in 2014
Time horizon	40 years, which is considered a lifetime horizon for these patients
Discounting	3% for both costs and benefits
Results (outputs)	Number needed to treat (NNT) Strokes avoided Life-years gained Quality-adjusted life years (QALYs) gained Costs
Sensitivity analysis	One way (point estimates) and probabilistic Programmed using Visual Basic for Applications
Validation of model assumptions	By a local (US) clinician expert

Figure 1. Markov model structure for cost-effectiveness of ICM use in patients with a history of cryptogenic stroke and suspected AF. *These additional adverse events can cause treatment switches, but no transitions between shown health states. AF: atrial fibrillation; CRNM: clinically relevant non-major; ECH: extracranial hemorrhage; FN: false negative; FP: false positive; GI: gastrointestinal; HS: hemorrhagic stroke; ICH: intracranial hemorrhage; TIA: transient ischemic attack; SE: systemic embolism; TN: true negative; TP: true positive.

Figure 2. AF detection rates over 36 months of monitoring.

Table 2. Estimated annual ischemic stroke risk by CHADS₂ score.

Group	FN aspirin	TP aspirin	TN aspirin	TP warfarin	TP NOAC	FP warfarin	FP NOAC	FP aspirin
HR/OR versus	Reference^46	1.00 FN aspirin	0.66 FN aspirin^45	0.38 FN aspirin^3^,^4	1.03 TP warfarin^47	0.66 TP warfarin	0.66 TP NOAC	0.66 TP aspirin
CHADS2 0	0.008	0.008	0.005	0.003	0.003	0.002	0.002	0.005
CHADS2 1	0.022	0.022	0.015	0.008	0.009	0.006	0.006	0.015
CHADS2 2	0.045	0.045	0.030	0.017	0.018	0.012	0.012	0.030
CHADS2 3	0.086	0.086	0.058	0.034	0.035	0.022	0.023	0.058
CHADS2 4	0.109	0.109	0.074	0.043	0.044	0.029	0.029	0.074
CHADS2 5	0.123	0.123	0.083	0.049	0.050	0.032	0.033	0.083
CHADS2 6	0.137	0.137	0.093	0.054	0.056	0.036	0.037	0.093
Cohort (weighted average)	0.078	0.078	0.053	0.031	0.031	0.020	0.021	0.053

HR=hazard ratio; OR=odds ratio.

Table 3. Annual risks of adverse events in patients with prior stroke or TIA.

Adverse event	Warfarin (Reference)	Annual risk on NOAC		Annual risk on aspirin
		OR NOAC vs. warfarin	Annual risk	HR apixaban vs. warfarin/	HR apixaban vs. aspirin	= HR aspirin vs. warfarin	HR aspirin vs. NOAC	Annual risk
Ischemic stroke (IS) **	0.0225	1.03 (0.87–1.21)*	0.0232	0.86 (0.60–1.22)*	0.33 (0.15–0.69)	2.61		0.0586
Transient Ischemic attack (TIA)	0.0080	1.06*	0.0084			1.56*		0.0124
Systemic embolism (SE)	0.0015	0.69 (0.39–1.20)*	0.0010			1.77*		0.0027
ICH (including HS)**	0.0048	0.47 (0.36–0.62)		0.37 (0.21–0.67)	0.80 (0.22–2.99)	0.46		0.0055
ICH (excluding HS)	0.0048	0.47 (0.36–0.62)	0.0023	0.37 (0.21–0.67)	0.80 (0.22–2.99)*	0.46		0.0022
Hemorrhagic stroke (HS)	0.0074	0.44 (0.32–0.62)	0.0033	0.40 (0.21–0.78)	0.25 (0.03–2.25)*	1.60		0.0119
GI bleed (as reported)	0.0111	1.22 (0.92–1.62)*	0.0134	0.83 (0.44–1.54)*	0.80 (0.20–3.02)*	1.04		0.0115
Other ECH	0.0154	0.86 (0.75–0.99)	0.0134	0.73 (0.55–0.98)	1.67 (0.61–4.59)*	0.44		0.0068
CRNM bleed	0.1013	0.85 (0.81–0.88)	0.0865				0.87 (0.65–1.16)*	0.0757
Source(s)	^4^,^30^,^31 TIA^29 ICH-HS and Other ECH^27	^47 TIA^28 CRNM^24		^3^,^4 (ARISTOTLE)	^3^,^3 (AVERROES)	^3^,^4 TIA, SE^28	^60

*As the confidence interval for these parameters is unknown or indicates a difference that is not statistically significant, these estimates were set at 1.00 in a separate scenario analysis. **Included in table to allow comparison, but not directly used in the model.

Table 4. Case fatality rates.

Adverse event	Case fatality rate (source)
Ischemic stroke (IS)	22.17%^27
Transient ischemic attack (TIA)	0.00%
Systemic embolism (SE)	9.40%^49^,^50
Haemorrhagic stroke (HS)	37.17%^27
Other intracranial bleed (ICH)	13.00%^27^,^49^,^50
Gastro-intestinal bleed (GI)	2.00%^27^,^49^,^50
Other extracranial bleed (ECH)	2.00%^27^,^49^,^50
CRNM bleed	0.00%*

*Assumption as the event is non-major.

Table 5. Baseline health state utility estimates used in the model by diagnosis and health state.

Health state	Utility without AF	Utility with AF
Post-index event	0.757	0.702
Post-mild stroke	0.712	0.657
Post-moderate stroke	0.570	0.515
Post-severe stroke	0.389	0.334
Death	0.000	0.000

Table 6. Health state disutilities from adverse events.

Adverse event	Disutility (annual)	Duration	One-off HRQL Impact	Reference
IS or HS - Mild	−0.044	3 months	−0.011	^49^,^50
IS or HS - Moderate	−0.274	3 months	−0.069	^49^,^50
IS or HS - Severe	−0.644	3 months	−0.161	^49^,^50
Other ICH	−0.074	3 months	−0.019	^49^,^50
TIA	−0.103	3 months	−0.003	^28^,^54
SE	−0.120	3 months	−0.027	^28
GI bleed	−0.151	2 weeks	−0.006	^49^,^50
Other ECH	−0.151	2 weeks	−0.006	^49^,^50
CRNM bleed	−0.058	2 days	−0.0003	^49^,^50

Table 7. Costs US$ included in the analysis.

	Cost*
Intervention^40
ICM device acquisition and insertion	$6,223.00
ICM removal	$826.00
ICM monitoring costs – per cycle	$58.00
ECG	$17.19
Holter	$92.02
Treatment costs (per cycle)^41
Aspirin (plus dipyridamole)	$1.80 ($39.42)
Warfarin plus INR monitoring	$117.00
NOAC (average)	$684.68
Apixaban 10mg	$702.84
Rivaroxaban 20mg	$714.33
Dabigatran 300mg	$704.61
Edoxaban	$616.92
Acute adverse events^28
IS - mild	$18,836
IS - moderate	$21,943
IS - severe	$28,192
IS - fatal	$0 ($28,192)
HS - mild	$20,631
HS - moderate	$29,178
HS - severe	$37,725
HS - fatal	$0 ($37,725)
Other ICH	$21,964
TIA	$3,788
SE	$21,184
GI bleed	$7,979
Other ECH	$12,064
CRNM bleed	$1,016
Stroke management (per cycle)^28
Post-mild stroke	$2,829
Post-moderate stroke	$7,725
Post-severe stroke	$16,779
Post-MI	$939

*Based on 2014 estimates.

Table 8. Key model outputs based on discounted values for a cohort of one patient.

Health state	BIOMONITOR ICM				Standard of care
			Costs	QALYs			Costs	QALYs
Index event			$10,007	5.2004			$1,258	4.9327
Post mild stroke			$15,512	0.8681			$16,011	0.9065
Post moderate stroke			$28,295	0.4696			$30,043	0.4996
Post severe stroke			$14,997	0.0783			$16,207	0.0843
Death			$11	0.0000			$11	0.0000
Subtotal			$68,822	6.6163			$63,530	6.4230
Events	Events	AE deaths	Costs	QALYs	Events	AE deaths	Costs	QALYs
Ischemic stroke	0.9319	0.2066	$11,803	−0.0273	0.9693	0.2149	$12,467	−0.0288
Transient ischemic attack	0.1433	0.0027	$440	−0.0030	0.1449	0.0028	$451	−0.0030
Systemic embolism	0.0302	0.0028	$516	−0.0007	0.0311	0.0029	$538	−0.0008
Hemorrhagic stroke	0.2442	0.0908	$3,092	−0.0069	0.2534	0.0942	$3,256	−0.0073
Other intracranial bleed	0.0535	0.0070	$893	−0.0008	0.0511	0.0063	$801	−0.0007
Gastro-intestinal bleed	0.2587	0.0052	$1,558	−0.0011	0.2469	0.0049	$1,493	−0.0011
Other extracranial bleed	0.1698	0.0034	$1,564	−0.0008	0.1500	0.0029	$1,346	−0.0006
CRNM bleed	1.7709	0.0000	$1,363	−0.0004	1.6563	0.0000	$1,278	−0.0004
Adverse Events			$21,229	−0.0410			$21,627	−0.0428
Total	3.6024	0.3184	$90,052	6.5753	3.4972	0.3289	$85,157	6.3803

Table 9. Events, total costs, life-years and QALYs per patient.

Intervention	ICM	SoC	Difference
Ischemic strokes	0.932	0.969	−0.037
Transient ischemic attack	0.143	0.145	−0.002
Systemic embolism	0.030	0.031	−0.001
Hemorrhagic strokes	0.244	0.253	−0.009
Other ICH bleeds	0.053	0.048	0.005
GI bleeds	0.259	0.247	0.012
Other ECH bleeds	0.170	0.147	0.023
CRNM bleeds	1.771	1.656	0.115
Total QALYs	6.575	6.380	0.195
Total Life years	9.742	9.478	0.265*
Total (post-stroke) costs	$90,052	$85,157	$4,895
Incremental cost per QALY gained			$25,098
Incremental cost per life year gained			$18,487
Incremental cost per stroke avoided			$104,941

*Non-rounded.

Figure 3. Tornado graph of parameters shown in the one-way sensitivity analysis to have the greatest impact on the cost-effectiveness of ICM use (cost in US$per QALY gained). The vertical line represents the base-case ICER for ICMs versus SoC. The horizontal bars indicate the ICER range between their low and high values.

Figure 4. Cost-effectiveness plane illustrating the lifetime differences in costs and outcomes (QALYs) between the two management strategies: ICM versus SoC.

Figure 5. Cost-acceptability curve summarizing the impact of uncertainty on the cost-effectiveness or willingness-to-pay threshold.

Table 10. Parameters having the greatest impact in terms of cost-effectiveness outcomes on the one-way sensitivity analysis.

Parameter	Base case	Low value	High value	ICER low	ICER high
Hazard ratio of apixaban vs. aspirin on the risk of having an ischemic stroke	0.33	0.15	0.69	$12,191	$95,534
Specificity of SoC intervention	1.00	0.75	1.00	$61,031	$25,098
True AF prevalence in this population	0.31	0.17	0.31	$56,077	$25,098
Hazard ratio of apixaban vs. warfarin on the risk of having an ischemic stroke	0.86	0.60	1.22	$41,458	$17,392
Hazard ratio of apixaban vs. aspirin on the risk of having an HS	0.25	0.03	2.25	$11,001	$32,296
Time horizon of the analysis	40.00	10.00	50.00	$42,426	$25,098
Percent of patients using NOACs	0.38	0.00	1.00	$18,553	$35,642
Acquisition and implantation cost of ICM	$6,223	$5,063	$7,500	$19,175	$31,622
Specificity of ICM	1.00	0.75	1.00	$12,962	$25,098
Discount rate for health outcomes	0.03	0.00	0.05	$18,576	$30,109
Sensitivity of ICM	1.00	0.90	1.00	$33,696	$25,098
Hazard ratio of apixaban vs. warfarin on the risk of having an HS	0.40	0.21	0.78	$28,439	$20,522
Age of population entering the model	65.00	60.00	70.00	$19,111	$25,405
Increase in ischemic stroke risk per decade	1.46	0.80	2.16	$21,944	$28,169
Case fatality of an ischemic stroke event (% fatal)	0.22	0.14	0.32	$22,512	$27,519

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