A Delphi Consensus Approach for Difficult-to-Treat Patients with Severe Hemophilia A without Inhibitors

Figures & data

Figure 1 Modified Delphi process.

Table 1 Characteristics of Delphi Participants, Their Professional Background, and Hemophilia Patients They Treat

Characteristic	n	%
Total	13
Demographic characteristics
Age group
31–50 years	6	46.2%
51–70 years	6	46.2%
71–90 years	1	7.7%
Sex
Female	3	23.1%
Male	9	69.2%
Other	1	7.7%
Race
White	10	76.9%
Asian	2	15.4%
Other	1	7.7%
Professional background
Year when medical license was obtained
1950–1990	4	30.8%
1991–2000	4	30.8%
Later than 2000	5	38.4%
Number of years working in the field of hemophilia A
10–19 years	7	53.8%
20–29 years	5	38.5%
≥ 30 years	1	7.7%
Principal practice location^a
Hemophilia treatment center	10	76.9%
University hospital or university affiliated clinic	3	23.1%
Number of hemophilia A patients treated at the principal practice location
≤125	5	38.5%
126–150	2	15.4%
151–175	1	7.7%
>175	5	38.5%
Characteristics of hemophilia patients treated at clinical practice location
Hemophilia A patient population typically treated
Pediatric	5	38.5%
Both pediatric and adult	8	61.5%
SPwHA managed during past three months
≤40%	4	30.8%
41–50%	3	23.1%
>50%	6	46.1%
SPwHA prescribed emicizumab
6–10%	3	23.1%
11–20%	5	38.4%
21–30%	1	7.7%
More than 30%	4	30.8%

Note: ^aPrincipal practice location is the practice location where hematologist spends the most hours per week.

Abbreviation: SPwHA, severe patient with hemophilia A.

Table 2 Results of Round 3 of the Delphi Panel Survey of 13 Hemophilia Experts About Their Preferences Toward Therapeutic Options for Challenging Clinical Scenarios

Clinical Scenario	Therapeutic Options	Likelihood Estimate		Proportion of Panelists		Consensus^c
		Median^a	IQR^b	Rated Treatment as Not Appropriate (Likelihood Estimate ≤50%)	Rated Treatment as Appropriate (Likelihood Estimate >50%)
SPwHA without inhibitors with cardiovascular comorbidities
Scenario 1: PwHA diagnosed with MI and on DAP	Continue with FVIII prophylaxis with dual antiplatelet therapy	75.0	59.0	38.5%	61.5%	No
	FVIII prophylaxis to achieve desired FVIII levels and then episodic FVIII therapy along with dual antiplatelet therapy	20.0	24.0	84.6%	15.4%	Yes
	Emicizumab prophylaxis along with dual antiplatelet therapy	30.0	66.0	61.5%	38.5%	No
Scenario 2: PwHA diagnosed with stroke and on DOACs	Regular FVIII prophylaxis along with episodic FVIII and DOAC	74.0	47.5	46.2%	53.8%	No
	Episodic FVIII replacement therapy only with DOAC	3.0	17.5	100.0%	0.0%	Yes
	Emicizumab prophylaxis along with episodic FVIII and DOAC	50.0	72.5	53.8%	46.2%	No
SPwHA without inhibitors with physical activity and related musculoskeletal disorders
Scenario 1: PwHA with increasing demand for physical activity (soccer/high activity sports)	Continue current FVIII prophylaxis	3.0	14.5	92.3%	7.7%	Yes
	Episodic regimen prior to activity along with FVIII prophylaxis	80.0	59.5	46.2%	53.8%	No
	FVIII prophylaxis with on-demand FVIII treatment post-bleeds	7.0	8.5	100.0%	0.0%	Yes
	Prophylaxis with emicizumab once a week	30.0	50.5	69.2%	30.8%	No
	Prophylaxis with emicizumab once a week along with episodic regimen prior to activity	55	70.5	46.2%	53.8%	No
Scenario 2: PwHA with arthroscopic surgery	As needed FVIII replacement factor during and immediately post-surgery in addition to patient’s stable emicizumab prophylaxis	100.0	8.5	0.0%	100.0%	Yes
	Continue prophylaxis with emicizumab before and after surgery without breakthrough FVIII treatment	2.0	4.0	92.3%	7.7%	Yes
Scenario 3: PwHA with osteoporosis	Continue on emicizumab prophylaxis	87.0	88.5	30.8%	69.2%	No
	Switch to FVIII prophylaxis	5.0	48.5	76.9%	23.1%	Yes
	Switch to FVIII prophylaxis and episodic FVIII regimen	9.0	43.5	76.9%	23.1%	Yes
	Continue emicizumab prophylaxis along with episodic FVIII regimen	82.0	82.5	46.2%	53.8%	No
Newborn PwHA
Scenario 1: Newborn child with congenital hemophilia with family history of intracranial hemorrhage	Start FVIII prophylaxis immediately	5.0	9.0	92.3%	7.7%	Yes
	Start emicizumab prophylaxis immediately	52.0	76.5	46.2%	53.8%	No
	Wait until 6 months and start FVIII prophylaxis	26.0	44.0	84.6%	15.4%	Yes
	Wait until 6 months and start emicizumab prophylaxis	30.0	60.5	76.9%	23.1%	Yes
Scenario 2: An infant with post-circumcision bleeding	FVIII prophylaxis	5.0	16.5	92.3%	7.7%	Yes
	Emicizumab prophylaxis	15.0	43.0	84.6%	15.4%	Yes
	Episodic FVIII followed by FVIII prophylaxis	30.0	49.0	69.2%	30.8%	No
	Episodic FVIII followed by emicizumab prophylaxis	77.0	27.0	23.1%	76.9%	Yes

Notes: ^aMedian likelihood estimate: smaller value indicates less preferred while larger value indicates more preferred therapeutic option by panelists; ^bIQR indicates strength of agreement, where 0=perfect agreement, <20% = strongest agreement, 21–40% = strong agreement, 41–60% = better agreement and >60% = weak agreement; ^cconsensus reached if ≥75% panelists reported therapeutic option as “not appropriate” or “appropriate”.

Abbreviations: DAP, dual antiplatelet therapy; DOAC, direct oral anticoagulant; IQR, interquartile range; SPwHA, severe patient with hemophilia A.

Table 3 Results of Round 3 of the Delphi Panel Survey of 13 Hemophilia Experts About Their Opinions About Switching Treatment from Factor to Non-Factor Replacement Therapy

Question	Options	Likelihood Estimate		Proportion of Panelists		Consensus^c
		Median^a	IQR^b	With Likelihood Estimate ≤50%	With Likelihood Estimate >50%
Given the current evidence on efficacy and safety for emicizumab, the likelihood that hematologist will switch treatment from a FVIII therapy to emicizumab prophylaxis for different number of bleeds during previous year for SPwHA without inhibitors	0–1 bleeds during previous year	25.0	48.5	69.2%	30.8%	No
	2–3 bleeds during previous year	66.0	61.0	46.2%	53.8%	No
	4–5 bleeds during previous year	88.0	23.0	7.7%	92.3%	Yes
	>5 bleeds during previous year	95.0	18.5	0.0%	100.0%	Yes
Among SPwHA without inhibitors who had ~5 bleeding events while on FVIII prophylaxis during the past 6 months, the likelihood of the reduction in bleeding events if treatment is switched to emicizumab prophylaxis	<10% reduction in bleeding events	5.0	9.0	92.3%	7.7%	Yes
	10–40% reduction in bleeding events	30.0	38.5	76.9%	23.1%	Yes
	41–80% reduction in bleeding events	80.0	13.5	0.0%	100.0%	Yes
	> 80% reduction in bleeding events	69.0	37.5	30.8%	69.2%	No
Among SPwHA without inhibitors who have switched from FVIII prophylaxis to emicizumab prophylaxis, the likelihood of the change in medication adherence (given that other factors associated with adherence such as age, frequency of bleeding, medication beliefs, etc. remain constant)	No change in medication adherence	11.0	67.5	61.5%	38.5%	No
	10–20% increase in doses/medication administered	36.0	62.5	61.5%	38.5%	No
	21–50% increase in doses/medication administered	50.0	54.0	61.5%	38.5%	No
	51–75% increase in doses/medication administered	50.0	50.0	53.8%	46.2%	No
	>75–80% increase in doses/medication administered	30.0	51.5	69.2%	30.8%	No

Notes: ^aMedian likelihood estimate: smaller value indicates less preferred while larger value indicates more preferred therapeutic option by panelists; ^bIQR indicates strength of agreement, where 0=perfect agreement, <20% = strongest agreement, 21–40% = strong agreement, 41–60% = better agreement and >60% = weak agreement; ^cconsensus reached if ≥75% panelists reported therapeutic option as “not appropriate” or “appropriate”.

Abbreviations: IQR, interquartile range; SPwHA, severe patient with hemophilia A.

Figure 2 Factors considered by hematologists while switching SPwHA without inhibitors from FVIII prophylaxis to emicizumab prophylaxis.

Note: ^*Panelists provided their likelihood estimates ranging from 1–100, where 1 means highly unlikely and 100 means extremely likely.

Figure 3 Hemophilia treatment characteristics considered by hematologists while switching treatment for SPwHA without inhibitors.

Figure 4 Health system related factors considered by hematologists while switching treatment for SPwHA without inhibitors.

Table 4 Results of Round 1 of the Delphi Panel Survey of 13 Hemophilia Experts About Their Preferences Toward Therapeutic Options for Challenging Clinical Scenarios

Clinical Scenario	Therapeutic Options	Likelihood Estimate			Proportion of Panelists
		Median^a	IQR^b		Rated Treatment as Not Appropriate (Likelihood Estimate ≤50%)		Rated Treatment as Appropriate (Likelihood Estimate >50%)
SPwHA without inhibitors with cardiovascular comorbidities
Scenario 1: PwHA diagnosed with MI and on dual antiplatelet therapy (DAP)	Continue with FVIII prophylaxis with dual antiplatelet therapy	75.0	47.5		23.1%		76.9%
	FVIII prophylaxis to achieve desired FVIII levels and then episodic FVIII therapy along with dual antiplatelet therapy	16.0	40.0		76.9%		23.1%
	Emicizumab prophylaxis along with dual antiplatelet therapy	20.0	57.5		69.2%		30.8%
Scenario 2: PwHA diagnosed with stroke and on direct oral anticoagulants (DOACs)	Regular FVIII prophylaxis along with episodic FVIII and DOAC	75.0	37.0		30.8%		69.2%
	Episodic FVIII replacement therapy only with DOAC	5.0	40.0		84.6%		15.4%
	Emicizumab prophylaxis along with episodic FVIII and DOAC	50.0	59.0		53.8%		46.2%
SPwHA without inhibitors with physical activity and related musculoskeletal disorders
Scenario 1: PwHA with increasing demand for physical activity (soccer/high activity sports)	Continue current FVIII prophylaxis	3.0	24.0		92.3%		7.7%
	Episodic regimen prior to activity along with FVIII prophylaxis	75.0	69.5		38.5%		61.5%
	FVIII prophylaxis with on-demand FVIII treatment post-bleeds	7.0	20.5		92.3%		7.7%
	Prophylaxis with emicizumab once a week	37.0	63.5		61.5%		38.5%
	Prophylaxis with emicizumab once a week along with episodic regimen prior to activity	24.0	67.5		61.5%		38.5%
Scenario 2: PwHA with arthroscopic surgery	As needed FVIII replacement factor during and immediately post-surgery in addition to patient’s stable emicizumab prophylaxis	97.0	10.0		0.0%		100.0%
	Continue prophylaxis with emicizumab before and after surgery without breakthrough FVIII treatment	5.0	10.0		84.6%		15.4%
Scenario 3: PwHA with osteoporosis	Continue on emicizumab prophylaxis	90.0	59.5		23.1%		76.9%
	Switch to FVIII prophylaxis	10.0	53.5		76.9%		23.1%
	Switch to FVIII prophylaxis and episodic FVIII regimen	7.0	32.0		84.6%		15.4%
	Continue emicizumab prophylaxis along with episodic FVIII regimen	15.0	76.5		53.8%		46.2%
Newborn PwHA
Scenario 1: Newborn child with congenital hemophilia with family history of intracranial hemorrhage	Start FVIII prophylaxis immediately	5.0	7.0		92.3%		7.7%
	Start emicizumab prophylaxis immediately	53.0	83.5		46.2%		53.8%
	Wait until 6 months and start FVIII prophylaxis	32.0	62.0		69.2%		30.8%
	Wait until 6 months and start emicizumab prophylaxis	52.0	70.5		46.2%		53.8%
Scenario 2: An infant with post-circumcision bleeding	FVIII prophylaxis	5.0	14.0		92.3%		7.7%
	Emicizumab prophylaxis	10.0	50.0		76.9%		23.1%
	Episodic FVIII followed by FVIII prophylaxis	30.0	77.0		61.5%		38.5%
	Episodic FVIII followed by emicizumab prophylaxis	66.0	57.0		46.2%		53.8%

Notes: ^aMedian likelihood estimate: smaller value indicates less preferred while larger value indicates more preferred therapeutic option by panelists; ^bIQR indicates strength of agreement, where 0=perfect agreement, <20% = strongest agreement, 21–40% = strong agreement, 41–60% = better agreement and >60% = weak agreement.

Abbreviations: DAP, dual antiplatelet therapy; DOAC, direct oral anticoagulant; IQR, interquartile range; SPwHA, severe patient with hemophilia A.

Table 5 Results of Round 1 of the Delphi Panel Survey of 13 Hemophilia Experts About Their Opinions About Switching Treatment from Factor to Non-Factor Replacement Therapy

Question	Options	Likelihood Estimate		Proportion of Panelists
		Median^a	IQR^b	With Likelihood Estimate ≤50%	With Likelihood Estimate >50%
Given the current evidence on efficacy and safety for emicizumab, the likelihood that hematologist will switch treatment from a FVIII therapy to emicizumab prophylaxis for different number of bleeds during previous year for SPwHA without inhibitors	0–1 bleeds during previous year	15.0	66.0	61.5%	38.5%
	2–3 bleeds during previous year	66.0	78.0	46.2%	53.8%
	4–5 bleeds during previous year	84.0	36.5	23.1%	76.9%
	>5 bleeds during previous year	93.0	24.0	15.4%	84.6%
Among SPwHA without inhibitors who had ~5 bleeding events while on FVIII prophylaxis during the past 6 months, the likelihood of the reduction in bleeding events if treatment is switched to emicizumab prophylaxis	<10% reduction in bleeding events	7.0	35.5	76.9%	23.1%
	10–40% reduction in bleeding events	30.0	61.0	61.5%	38.5%
	41–80% reduction in bleeding events	81.0	18.5	7.7%	92.3%
	> 80% reduction in bleeding events	69.0	33.5	30.8%	69.2%
Among SPwHA without inhibitors who have switched from FVIII prophylaxis to emicizumab prophylaxis, the likelihood of the change in medication adherence (given that other factors associated with adherence such as age, frequency of bleeding, medication beliefs, etc. remain constant)	No change in medication adherence	10.0	74.0	61.5%	38.5%
	10–20% increase in doses/medication administered	38.0	72.5	61.5%	38.5%
	21–50% increase in doses/medication administered	50.0	52.5	53.8%	46.2%
	51–75% increase in doses/medication administered	48.0	51.0	61.5%	38.5%
	>75–80% increase in doses/medication administered	20.0	52.0	76.9%	23.1%

Notes: ^aMedian likelihood estimate: smaller value indicates less preferred while larger value indicates more preferred therapeutic option by panelists^{; b}IQR indicates strength of agreement, where 0=perfect agreement, <20% = strongest agreement, 21–40% = strong agreement, 41–60% = better agreement and >60% = weak agreement.

Abbreviations: IQR, interquartile range; SPwHA, severe patient with hemophilia A.