Systematic literature review of economics analysis on treatment of mild-to-moderate bleeds with aPCC versus rFVIIa

Abstract

Objective:

Two bypassing agents, activated prothrombin complex concentrates (aPCC) and recombinant factor VIIa (rFVIIa), have shown similar efficacy and safety in the treatment of bleeding episodes in patients with hemophilia and inhibitors as demonstrated through the only two head-to-head clinical trials. Given the economic burden of bypassing treatment, it is crucial to have a valid estimate of cost effectiveness of alternative treatments. The aims of this study were to conduct a systematic review of published pharmacoeconomic literature on the cost-effectiveness of aPCC versus rFVIIa to treat mild-to-moderate bleeds in patients with hemophilia and inhibitors, with a focus on the model assumptions and their impact on results.

Methods:

An English language search was conducted for original economic studies comparing aPCC and rFVIIa published between 1995 and July 2010. Detailed information on sponsorship, study design, assumptions and their impact on results was collected for each study.

Results:

A total of 11 economic studies were included in the review. Nine studies assessed cost per bleeding episode (eight cost-minimization analysis (CMA) and one cost-effectiveness analysis (CEA)). Two studies were from longitudinal perspective. Studies on cost per bleeding episode were evaluated and systematically compared. All studies were from a third-party payer perspective. Most analyses, except one study, used a similar decision-tree model. The assumptions for all CMA studies were obtained from non-comparable single-armed trials or observational data. All studies were sponsored by the two competing manufacturers of rFVIIa (seven studies) and aPCC (two studies). The crucial parameter assumptions on treatment efficacy and dosing drove their reported findings. Eight of these nine studies favored their sponsor’s product.

Conclusion:

With one exception, published economic studies tend to favor their sponsor’s product primarily by assuming a higher efficacy and lower dosing for the sponsored agent, even though the two existing head-to-head clinical studies do not support superior efficacy for either product.

Keywords::

• aPCC
• Cost minimization analysis
• Economic evaluation
• Hemophilia
• Inhibitor
• rFVIIa
• Systematic review

Introduction

Hemophilia is a rare chronic inherited bleeding disorder that occurs among one in 5,000 male births and affects approximately 20,000 persons in the United States, based on the expected births and deaths since 19941,2. Patients with hemophilia either are deficient in or are missing clotting factor VIII (hemophilia A) or factor IX (hemophilia B), which places them at high risk for internal, muscular and joint bleeding as well as prolonged bleeding following trauma or surgery. Repeated hemorrhages, especially in persons with severe hemophilia (having less than 1% of normal coagulation factor activity), can lead to the development of chronic arthropathy and disability.

Because there is no cure for hemophilia, most patients require intravenously injecting the missing clotting factor episodically or prophylactically. However, the development of persistent inhibitors to foreign factor proteins is an ongoing challenge in hemophilia care. Approximately 20–35% of patients with severe hemophilia A and 4–6% of patients with severe hemophilia B develop factor inhibitors3–5. Bleed episodes in patients with low titer inhibitors (≤5 Bethesda units [BU]/mL) can be treated with escalating doses of factor, while patients with high-titer inhibitors (>5 BU/mL) require the use of bypassing agents to achieve hemostasis6. Two bypassing agents are currently available in the market, activated prothrombin complex concentrates (aPCC, brand name FEIBA, manufacturer Baxter Healthcare) and recombinant factor VIIa (rFVIIa, brand name NovoSeven, manufacturer Novo Nordisk A/S). Both aPCC and rFVIIa demonstrate similar efficacy (∼80–90%) and safety to treat bleeding episodes in clinical trials7–9. An objective summary of head-to-head comparative studies for aPCC and rFVIIa conducted by the Cochrane Collaboration indicates that there is no conclusive evidence that one product has superior efficacy to the other10. In fact, discordance has been suggested for inhibitor patients where some patients respond better to one agent over another11. Some bleeding episodes are refractory to either agent alone and require the use of sequential therapy with both aPCC and rFVIIa.

Despite the benefits, treatment with bypassing agents is costly and time-consuming. Given the ever-rising healthcare costs and pressure to contain costs across the healthcare system, it is vital to have a valid estimate of the cost effectiveness of alternative treatments among hemophilia patients with inhibitors. To date, a number of cost-effectiveness analyses have been conducted comparing aPCC versus rFVIIa in various countries. Several comprehensive pharmacoeconomic reviews have also been published on most of these analyses12–14. To summarize the research to date and to add to our current understanding of the cost effectiveness of aPCC versus rFVIIa in the treatment of bleeding episodes in hemophilia patients with inhibitors, a systematic and critical review of published literature was conducted with a focus on the detailed parameter assumptions in each model and their impact on the results.

Methods

Literature search

The studies in this review were identified based on a systematic search of published literature on the economic studies comparing aPCC and rFVIIa in the treatment of bleeding episodes in hemophilia A and B patients with inhibitors.

To include all relevant studies, an initial search was conducted in Medline, the Cochrane Library, and the ISI Web of Science citation database to identify original papers published between 1995 and July 2010. Search terms included combination of the following: [‘hemophilia’ or ‘haemophilia’] and [‘inhibitor’ or ‘antibody’] or [‘recombinant factor viia’ or ‘fviia’ or ‘novoseven’ or ‘novo seven’] or [‘prothrombin complex concentrate’ or ‘apcc’ or ‘feiba’] and [‘cost’ or ‘economic’]. The search strategy and the specific algorithm varied based on the characteristics of each database. The language was limited to English only. The bibliographic references of each selected study were reviewed for additional reports of similar analyses. For the initial screening, papers were excluded if they were irrelevant to the economics studies of bypassing agents based on title and abstract. Full texts were obtained and reviewed if the relevance could not be sufficiently determined by title and abstract. Further review was conducted to exclude studies on using aPCC and rFVIIa for prophylaxis or immune tolerance induction, or treating bleeds in surgical patients or non-hemophiliac patients.

Syntheses of literature

Detailed information on sponsorship, study country, model type, data source, perspective, assumptions on efficacy, number of infusions needed to achieve hemostasis, unit cost of each agent, body weight, rebleed rate, total cost and sensitivity analyses was collected for each study. Data were abstracted by two reviewers, J.W.H. and Z.Y.Z. Discrepancies were resolved by consensus.

There were substantial variations among studies in terms of analysis type (cost-minimization or cost-effectiveness analysis), model design (hypothetical decision model, or analysis based on clinical trial), length of follow-up (per bleeding episode, or from longitudinal perspective), data resource (observational data, published literature, or expert opinion), body weight, and the year and currency chosen for cost reporting. To facilitate the comparisons among studies, cost per bleeding episode was chosen to synthesize our findings. Because studies were conducted in different time periods and in various countries, all costs were converted into US dollars using the purchasing power parity conversion rate and inflated to 2010 prices using the medical component of the consumer price index from the Bureau of Labor Statistics18.

Results

The search identified 129 studies in Medline, 40 in the Cochrane Library, 164 in ISI Web of Science, and two additional studies from article bibliographic references. Of the 335 studies, 107 were excluded as kinship studies. After excluding 159 studies by screening title and abstract, 69 studies were retrieved for full text review and ten original articles and two conference abstracts met the inclusion criteria (Figure 1). One conference abstract was further excluded after consensus, since no detailed information was provided regarding the assumptions of efficacy and dosing, which are crucial to the economic analysis15. Hence, a total of 11 articles were finally identified and formed the basis of this review.

Figure 1.  Flow diagram of the results of the search strategy.

Nine of these 11 studies are comparative economic studies (eight published literature and one conference abstract) based on the cost of treating one mild-to-moderate bleeding episode19–27. Eight of the nine studies were cost-minimization analyses comparing the treatment costs of two bypassing agents, assuming outcomes to be equivalent. Only one study was a cost-effectiveness analysis, in which both costs and outcomes (effects) of the two bypassing agents were compared and expressed as an incremental cost-effectiveness ratio. The model details for each study are summarized in Table 1. All studies were sponsored by the two competing manufacturers of rFVIIa (seven studies) and aPCC (two studies). Eight of these nine studies favored their sponsor’s product. All studies were from a third-party payer perspective, considering direct medical cost only. Most analyses used a similar decision-tree model comparing treatment cost of rFVIIa versus aPCC as first-line bypassing agent, except the study by Steen Carlsson et al.26, which was based on data collected alongside a head-to-head clinical comparative trial13. The flow charts of these decision models were adapted from Odeyemi’s and Knight’s studies16,19,20. In summary, the authors assumed patients were initially treated at home with one of the two bypassing agents as first-line therapy (initial stage) when a bleed occurred. If bleed was not controlled, patients continued on subsequent treatments. In the subsequent stages, patients could either switch to another bypassing agent or augment current treatment (increase the frequency of infusion). Depending on the clinical practice in various countries, some models assumed patients were admitted into the hospital and others assumed patients to continue being treated at home. According to the general treatment guideline28, switching bypassing products is the optimal choice if augmentation is not successful. However in most models, patients using rFVIIa were not allowed to switch to aPCC in subsequent treatments. Rebleed might occur in each stage and were managed in the same manner as original bleed within that stage. A 15% rebleed rate was assumed in most models19,20,23–25.

Table 1.  Comparative economic studies of aPCC and rFVIIa in the treatment of a mild-to-moderate bleeding episode in patients with hemophilia and inhibitors.

	Odeyemi et al.19	Odeyemi et al.20	Chung et al.21	Putnam et al.22	Dundar et al.23	Joshi et al.24	Ozelo et al.25	Carlsson et al.26	You et al.27
Study type	CMA	CMA	CMA	CMA	CMA	CMA	CMA	CEA	CMA
Sponsorship	Novo Nordisk	Novo Nordisk	Baxter	Novo Nordisk	Novo Nordisk	Novo Nordisk	Novo Nordisk	Baxter	Novo Nordisk
Study design
Country	UK	UK	USA	USA	Turkey	USA	Brazil	USA	South Korea
Model	Decision tree	Decision tree	Decision tree	Decision tree	Decision tree	Decision tree	Decision tree	NA	Decision tree
Perspective	National Health Service	National Health Service	Third-party payer	Third-party payer	Reimbursement institutions	Third-party payer	National Health Service	Third-party payer	Reimbursement authorities
Data source	Literature and panelists’ evaluation	Literature and panelists’ evaluation	Literature	Literature and panelists’ evaluation	Retrospective study, literature and panelists’ evaluation	Literature	Observational (rFVIIa) and retrospective (aPCC) study	Prospective study (Base on FENOC11)	Observational (rFVIIa) and retrospective (aPCC) study
Study setting	Home	HCC	Home	Home	Home or HCC	Home	Home or HCC	Home	Home or HCC
Assumptions
Efficacy
aPCC	79%	79% (2nd line: 62%)	78%	75% (1st line)	79.0%	78%	56.7%	NA	63.6%
rFVIIa	92%	92%	87.5%	90% (1st line)	89.3%	92%	100%	NA	92.3%
1st-line dose
aPCC (IU/kg)	75 × 3 = 225	75 × 3 = 225	75 × 3 = 225	75	167*	75 × 2.4 = 180	260*	85	168*
rFVIIa (μg/kg)	90 × 2.3 = 207	90 × 2.3 = 207	90 × 4 = 360	270	204*	90 × 2.3 = 207	190*	105 × 2 = 210	136*
2^nd -ine dose
aPCC
(a) Cont’ or aug’	228–287	480	NA	120 (91%)	NR	180	NR	NA	NR
(b) Switch	NA	NA	NA	NA	NR	NA	NA	NA	NR
rFVIIa
(a) Cont’ or aug’	235–844	567	NA	270 (73%)	NR	207	NR	NA	NR
(b) Switch	844	NA	NA	NA	NR	207	NA	NA	NR
3rd-line dose	Vary	Vary	NA	NA	NR	vary	NR	NA	NR
Drug cost†
aPCC (per IU)	NR	NR	$2.02	$1.93	$1.31	$2.01	$0.73	$2.01	$1.67
rFVIIa (per μg)	NR	NR	$1.91	$2.08	$1.08	$1.84	$0.83	$1.77	$1.63
Body weight (kg)	NR	NR	70	NR	49	70	52.6	NR	49.8
Rebleed rate	15%	15%	NA	NA	15%	15%	15%	NA	rFVIIa: 16.1% aPCC: 12%
Results
Total direct cost†
aPCC	$35,068	$49,010	$25,078	$31,127	$16,319	$36,938–38,453	$16,147	$11,485	$21,631
rFVIIa	$30,995	$28,241	$49,391	$49,507	$11,857	$33,581	$9,078	$25,490	$14,725
Sensitivity analysis	aPCC is cost-saving if aPCC efficacy is 90% or rFVIIa efficacy is lower than 90%	aPCC is cost-saving if the rFVIIa efficacy is below 50% or rFVIIa is given 5 doses of 90 µg/kg	aPCC is the less expensive 99% of the time	Insensitive to changes in drug cost, dosing, and efficacy	rFVIIa is cost-saving if rFVIIa efficacy is >89%	aPCC is cost-saving if rFVIIa efficacy is lower than 82% or rFVIIa unit price is increased by 16%	aPCC is cost-saving if aPCC efficacy is 80% or rFVIIa efficacy is lower than 66%	Sensitive to unit price	Insensitive to changes in efficacy, dose and rebleed rate
Major limitation	Efficacy and dosing assumptions are based non-controlled single armed studies	Efficacy and dosing assumptions are based non-controlled single armed studies	Efficacy and dosing assumptions are based non-controlled single armed studies; Only first line of treatment was considered	Efficacy and dosing assumptions are based non-controlled single armed studies; Dosing for rFVIIa is higher than what reported in other studies; aPCC unit price was not discounted	Data were obtained from a retrospective study with small sample size	Efficacy and dosing assumptions are based non-controlled single armed studies	Data were obtained prospectively for rFVIIa and retrospectively for aPCC in two different time periods	Only first line of treatment was considered; The dosing of rFVIIa is different from what reported in other studies.	Data were obtained prospectively for rFVIIa and retrospectively for aPCC in two different time periods

CMA, cost minimization analysis; CEA, cost effectiveness analysis; NA, not applicable; NR, not reported; cont’, Continue; aug’, augmentation; HCC, hemophilia comprehensive center.

†Costs are adjusted to 2010 US dollar using Purchasing Power Parity (PPP) conversion rate and Consumer Price Index (CPI).The original costs are available upon request from the authors.

*The units are the mean treatment units per body weight by averaging all bleeding episodes treated with each agent.

The treatment cost of aPCC and rFVIIa was calculated based on the efficacy rate, dosing, unit price, and body weight each study assumed. Because most studies modeled the treatment in the home setting, the major portion of expense was the bypassing agent cost. Two studies included costs associated with bypassing agents only21,22. Another two studies modeled the medication costs alone in the base case, but included hospitalization cost in the sensitivity analysis24,26. The rest of the studies included both medication costs and costs associated with hospitalization, emergency room visit or other healthcare utilization19,20,23,25,27.

Two of the eleven studies were longitudinal cost-effectiveness studies over a lifetime or 1-year time horizon16,17. It is difficult to convert the cost of certain periods of time into cost per bleeding episode, so that we evaluated them separately.

Cost-minimization analysis: per bleeding episode

The first two economic analyses comparing rFVIIa and aPCC were conducted by Odeyemi et al. from the United Kingdom National Health Service (NHS) perspective19,20. Based on the same framework and assumptions, the authors estimated the cost and consequences of using rFVIIa versus aPCC to treat a mild-to-moderate bleeding episode in both home and hemophilia comprehensive care center (CCC) settings. In the initial treatment, 3 doses of 75 IU/kg aPCC were assumed to achieve 79% hemostasis, whereas the dosing of rFVIIa was 2.3 doses at 90 μg/kg to resolve 92% of bleeds. Different dose and efficacy rate were assumed for the subsequent treatment in the home setting versus CCC setting. 100% efficacy was assumed after three stages of treatment. The efficacy and corresponding dosing of aPCC or rFVIIa as first-line bypassing agent were based on two single-arm open-label clinical studies by Hilgartner et al. and Key et al., respectively9,29. The rebleed rate was assumed to be 15%. Efficacy and dosing assumptions for subsequent treatments were obtained from expert panelists’ opinion. No detailed information was provided regarding the base-case patient body weight and unit price of each bypassing agent.

The total cost consisted of the cost of bypassing agents and other medications, outpatient and inpatient visit, lab tests and ambulance transport. In the home setting, the estimated total cost to manage a minor bleed was $30,995 in 2010 US dollars for rFVIIa as first-line agent and US$35,068 for aPCC. In the clinic, the total cost of using rFVIIa was US$28,241, which was relatively lower than that seen in the home setting. However, the cost of using aPCC was US$49,010 – much higher than that in home setting. Thus, the authors concluded that rFVIIa was a cost-effective strategy in both home and clinical settings. However, both studies were quite sensitive to efficacy and dosing assumptions. For example, in the home setting, aPCC would be cost saving if the efficacy of aPCC is above 90% or the frequency of infusion was less than 2.5 doses. Similarly, if the probability of rFVIIa of resolving a bleeding episode was less than 90% or the infusion frequency was increased to 2.5 doses, aPCC became the cost minimizing option.

Chung et al. conducted a cost-minimization study from the US payer perspective21, but unlike Odeyemi et al.19,20, the study compared the outcomes and costs after each infusion of aPCC or rFVIIa until the bleed was controlled within 36 hours, rather than conducting the cost effectiveness of the whole treatment course involving initiation of therapy with one or the other agent. Up to three home infusions of aPCC or rFVIIa were considered. All bleeds failing to resolve following the third infusion were assumed to be not resolveable with the study therapy. The efficacy and dosing of aPCC and rFVIIa were also based on single-armed studies by Hilgartner et al. and Key et al., respectively9,29. The dosing was 75 IU/kg for aPCC and 90 μg/kg for rFVIIa. Since Hilgartner et al. only reported efficacy for aPCC after first infusion (52%) and third infusion (78%), it was assumed that following the initial infusion, an additional 13.0% of bleeds would be controlled following the second and third infusions, respectively. In a study by Key et al., 92.0% of bleeds resolved following three infusions of rFVIIa; however, 5.0% of all resolved bleeds failed to maintain hemostasis for at least 24 hours. Consequently, these authors discounted all efficacy rates by 5%, which resulted in efficacy rates of 25.6%, 21.2%, and 40.5% following the first, second, and third infusions, respectively and 87.3% for the efficacy at 36 hours. A ‘maintenance’ dose was also added to all bleed episodes treated and resolved with rFVIIa as reported by Key et al.9. Only costs of bypassing agents were considered in the model.

The results demonstrated that initiation of treatment with aPCC was expected to resolve 78.0% of bleeds at an average cost of US$19,560 per bleed resolved; the corresponding values for rFVIIa were 87.3% and US$42,970 respectively. Thus, the estimated medication cost per resolved bleed was US$25,078 for aPCC and US$49,391 for rFVIIa. The results were quite robust in the one-way sensitivity analysis showing aPCC to be less expensive 99% of the time in the probabilistic sensitivity analysis.

Another cost-minimization model from a US payer perspective was conducted by Putnam et al.22. Data were collected from literature review and panelists’ interview. Only the first 24 hours of bleeding episode were evaluated and patients were assumed to be hemostatic after two lines of treatment. No rebleed or hospitalization was considered in the model. The authors assumed that patients received 270 μg/kg rFVIIa at initiation of treatment. However, even when 90% efficacy was achieved, 73% patients were assumed to receive another 270 μg/kg rFVIIa in the next 12–16 hours. For aPCC treatment, the dosing was more consistent with previous literature – patients received the initial aPCC at 75 IU/kg and 91% received another dose in the next 12–16 hours. Only costs of bypassing agents were considered in the model.

The total medication cost for aPCC as first-line agent was US$31,127 versus US$49,507 for rFVIIa. Applying one-way and two-way sensitivity analyses, the authors found the base-case model was insensitive to the changes in efficacy, price and dosage for both products. rFVIIa would have been the preferred strategy if the unit price was decreased by half. However, as Seremtis et al. pointed out, the unit price for aPCC was 15.4% lower than the actual price30. Thus the actual cost-saving of aPCC versus rFVIIa could be much smaller if a lower dosage of rFVIIa and higher unit price for aPCC were used in the model.

The study done by Dundar et al. was a decision analysis from the Turkish third-party payer perspective23. The outcomes and resource utilization data were collected retrospectively from 105 bleeding episodes in 24 Turkish patients between1996 and 2002. Patients were able to receive any of the four treatment options (rFVIIa, aPCC, PCC, and high-dose factor VIII) during each bleeding episode. Thus, the sample size was quite small after breakdown: only 9 bleeds were evaluated for aPCC as the first-line agent and 28 bleeds for rFVIIa. Patients using rFVIIa as the first-line agent were allowed to switch to aPCC if rFVIIa did not work, and vice versa. Clinical outcomes showed that rFVIIa achieved 89.3% hemostasis with 3.6 infusions and the mean total dose was 204 μg/kg. aPCC achieved 66.7% hemostasis with 4.8 doses of infusion. The total dose for aPCC was 166.8 IU/kg, implying a very low dose per infusion, which may explain the lower bleeding episode resolve rate compared to other reports. In the analytical model, the authors decided to use a 79% efficacy rate for aPCC to take into account the poor observed outcomes. The costs included those for hemostatic agents, concomitant medication, outpatient visits, and hospital stay.

The total medical cost was US$11,857 for rFVIIa versus US$16,319 for aPCC. In the sensitivity analysis, rFVIIa as first-line therapy was cost saving compared to treatment with aPCC, when the efficacy was varied by 10% or the unit cost by 20%.

Joshi et al. conducted a third study from a US payer perspective24. The model structure and parameter value were based on Knight’s model and adapted to a short-term US perspective after consulting expert opinion. The efficacy and dosing assumptions were also based on the two single-armed open-labeled clinical trials used by Odeyemi et al. Three treatment regimens were assumed (first-, second- and third-line): aPCC–aPCC–rFVIIa, aPCC–rFVIIa–rFVIIa, or rFVIIa–rFVIIa–rFVIIa. Efficacy was assumed to be 100% after three lines of treatment. The assumed body weight was 70 kg. Only medication costs were included in the base-case model, because the model assumed all treatments were administered at home. Potential hospitalization costs for third-line treatment were adjusted in the sensitivity analysis.

In the base case, the medication cost to resolve a bleed was lowest when using rFVIIa only, with an average cost of US$33,581. Using aPCC as first-line and rFVIIa as subsequent treatment resulted in an average cost of US$36,938, whereas the regimen using aPCC as first- and second-line, and rFVIIa as third-line treatment was the most expensive, with an average cost of US$38,453. The authors conducted extensive sensitivity analyses to test the robustness of the results. Univariate sensitivity analyses showed that the model was relatively sensitive to variations in the mean number of doses. aPCC would be cost saving if rFVIIa efficacy was below 82% or the unit price of rFVIIa was increased by 16%. The probabilistic sensitivity analysis found that the rFVIIa-only regimen was the least expensive strategy in more than 68% of the simulations.

Ozelo et al. evaluated the total medical cost of using aPCC and rFVIIa from the Brazilian National Health Service payer perspective25. The data used in the decision-analysis model were obtained both retrospectively and prospectively and reviewed by the consensus of an expert panel of Brazilian hematologists. The current Brazilian prescription guideline recommends aPCC as first-line therapy and rFVIIa as second-line. As a result, the outcomes and utilization data for aPCC were collected retrospectively by chart review, while data for rFVIIa were collected prospectively. Total medical costs include: factor and concomitant medication costs, outpatient visit and inpatient care costs, and cost for ambulance transportation.

A total of 103 bleeds in 25 patients were treated with aPCC or rFVIIa. Bleeding severity was similar in both groups. A total of 67 bleeding episodes were treated with aPCC. The average dose administered was 260.2 IU/kg and the efficacy was 56.7%. Thirty-six bleeding episodes were treated with rFVIIa as first-line treatment. The average dose was 189.9 μg/kg and the efficacy reached 100%. The total medical cost for bleeds treated with rFVIIa was cost saving, compared to the treatment with aPCC (US$9,078 vs. 16,147). Sensitivity analyses showed that the total direct medical cost of rFVIIa and aPCC would be the same if the efficacy of rFVIIa were valued as low as 66% or the efficacy of aPCC was assumed to be 80%.

The study was designed as a combination of retrospective and prospective data collection. More than 80% of bleeding episodes were treated inpatient or outpatient. The patients in a prospective clinical trial may be treated very differently from those who received ‘usual care’. Patients may receive better care and be followed more closely. As reported by the authors, the mean time to treatment from the onset of bleeds was 19.6 hours (range: 1–168 hours) for aPCC and 8.6 hours (range: 1–29 hours) for rFVIIa. The delay of treatment could be one of the reasons why efficacy of aPCC was much lower than that reported in other studies. Although the authors accounted for this issue by conducting a subgroup analysis on patients who received treatment within the first 12 hours from the onset of bleeds, a comparison using two data sources may still affect the outcomes and cost substantially.

A similar study was carried out by You et al. from the Korean National Health Service payer perspective27. The model was adopted from Knight’s decision-analysis model. In Korea, rFVIIa is also listed as a second-line treatment option, so data collection was the same as the Brazil study25: outcomes and utilization of bleeds treated with aPCC were obtained from retrospective analysis, while data for rFVIIa were obtained from a prospective study. An expert panel of Korean hematologists provided information on the rebleed rate and the probability of patients switching bypassing agents. Total medical costs included factor and concomitant medication costs, outpatient visit and inpatient care costs, and cost for ambulance transportation.

A total of 56 bleeds occurring in 21 patients were evaluated in the study. Twenty-five bleeding episodes in 16 patients were treated with aPCC and 31 episodes in 11 patients treated with rFVIIa. The mean efficacy of rFVIIa was 87.1% with a mean dose of 136 μg/kg, while aPCC achieved 64% hemostasis with a mean dose of 168 IU/kg. rFVIIa had a more rapid hemostatic effect, resolving bleeding in a mean of 6.6 hours compared to 25.2 hours for aPCC. From bleed initiation to cessation, the total direct medical cost was US$14,725 for rFVIIa given as first-line agent and US$21,631 for aPCC. One-way sensitivity analysis indicated that rFVIIa was cost effective when simulating any value of the effectiveness of aPCC between 50% and 100%. rFVIIa was still a cost-saving strategy when applying the efficacy data from the FENOC study11.

The major limitation was very similar to the previous study conducted by Ozelo et al.25, namely that different approaches were used to collect data on the outcomes and resource utilization of rFVIIa (prospectively) and aPCC (retrospectively). In Korea, rFVIIa was restricted to clinical use only. Among patients included in the study, 97% of bleeding episodes treated with rFVIIa were on an outpatient basis, while 68% of bleed episodes treated with aPCC were at home. Again, patients treated at a clinic will be more closely watched by physicians or nurses, which results in a better efficacy of rFVIIa compared to aPCC. A combination of two data source may bias the results and should not be generalized to different clinical practices.

Cost-effectiveness analysis: per bleeding episode

Only one cost-effectiveness analysis was found to model the use of aPCC versus rFVIIa to treat mild or moderate bleeding episodes in patients with hemophilia and inhibitors26. The study adopted results from the FEIBA-NovoSeven Comparative (FENOC) study, one of the only two head-to-head clinical trials comparing efficacy of aPCC and rFVIIa in the treatment of joint bleed in hemophilia patients with inhibitors11,31. In this prospective, open-label, cross-over study, 48 patients participated and a total of 98 joint bleeds were evaluated. Patients were given one dose of aPCC (75–100 IU/kg, target dose: 85 IU/kg) or two doses of rFVIIa (95–120 μg/kg, target dose: 105 μg/kg ×2) at 2-hour intervals. The incremental cost-effectiveness ratio (ICER) for a joint bleed was calculated as the average difference in cost of treatment between aPCC and NovoSeven divided by the average difference in effectiveness. The treatment costs consisted of the total consumption of clotting factor plus the cost of concomitant medications and analgesics, whereas the effectiveness was assessed by three outcome measures: (1) patient-reported treatment effective; (2) cessation of bleeds, and (3) reduction in pain from baseline. ICERs were calculated for 2, 6, 12, 24, 36 and 48 hours according to each point in time of measurement in the FENOC study. In the sensitivity analysis, three countries (US, Sweden, and Turkey) unit price of aPCC and rFVIIa was used to evaluate the impact of the level of price and relative price difference between the two products on ICERs.

The median cost per episode for aPCC was US$11,485 and the median cost for rFVIIa was US$25,490 using US prices. aPCC was the dominant strategy at most time points when using patient-reported effectiveness and cessation of bleeds as a measure of effectiveness. When reduction in pain was used as a measure of effectiveness, the ICER ranged from US$–8,732 to US$135,569 in different time points. However, ICERs with a negative magnitude are meaningless, so it is inappropriate to calculate an ICER when the numerator and denominator of the ICER have a different sign. In the sensitivity analysis, the different relative prices in the US, Turkey and Sweden affected the ICERs, but did not reverse the main results.

This study is currently the only economic study which is based on evidence from a randomized head-to-head comparison study using aPCC versus rFVIIa in the treatment of acute bleeds. However, the FENOC efficacy study has indicated that aPCC was statistically equivalent to rFVIIa for the treatment of joint bleeds. Thus, cost-effectiveness analysis is an inappropriate methodology to use if there is no evidence of difference in effectiveness outcomes between the two treatments. Moreover, a relative lower-dose rFVIIa was used in the FENOC study compared to typical US treatment patterns, and this dose was used in the cost-effectiveness analysis without testing its robustness using sensitivity analyses. Third, as binary measures of outcomes, the difference of treatment effectiveness and cessation of bleeds were incorporated into the denominator of the incremental cost-effectiveness ratios (ICERs) using a vague proportion-based calculation. No univariate sensitivity analysis was conducted using data from different literature sources to assess the variability and uncertainty in the other parameters used in the modeling.

Cost-effectiveness analyses: longitudinal perspective

Two cost-effectiveness studies were from a longitudinal perspective. Therefore, they are non-comparable to the studies on cost per bleeding episode aforementioned and reviewed separately. The first study was a lifetime cost analysis from the UK NHS perspective23. The decision model has been reviewed in the previous section. The efficacy and dosing assumptions of aPCC and rFVIIa were based on two single-arm open-label clinical studies by Hilgartner et al. and Key et al., respectively9,29. The treatment regimens involved not only aPCC or rFVIIa, but also porcine factor VIII (pFVIII). Both minor and major bleed episodes were considered in the model. Three on-demand (OD) regimens were compared (minor: first-, second- and third-line, major):

• OD1: aPCC–aPCC–pFVIII, pFVIII;

• OD2: aPCC–rFVIIa-rFVIIa and rFVIIa;

• OD3: rFVIIa–rFVIIa-rFVIIa, rFVIIa.

A lifetime cost was calculated with annual discounting of 6%. The lifetime cost in 2010 US dollars for OD1, OD2, and OD3 are US$5,178,688, US$5,247,344, and $4,763,577, respectively. However, the results were very sensitive to assumptions on efficacy and unit price. Less than a 10% change in many of the parameters would make OD1 cheaper than the rFVIIa-based regimen. Lifetime costs of aPCC versus rFVIIa may not be directly comparable with cost per episode. It is possible for the bleeding episodes to be either minor or major; however in our cost-per-episode studies, we only considered minor bleeds.

Study by Ekert et al. was a cost-utility study based on a convenience sample of only six Australian pediatric patients17. This study compared 6-month ‘usual care’ and 1-year rFVIIa treatment using a before–after study design. The ‘usual care’ included not only the use of aPCC, but also PCC, porcine FVIII (pFVIII) or human FVIII. Data of ‘usual care’ were collected retrospectively (phase I) and data of rFVIIa treatment were collected both retrospectively (phase II) and prospectively (phase III). Three health-state scenarios were constructed from outcomes (treatment delay, duration of pain, number of major bleeds, frequency of re-treatment, days requiring wheelchair/crutch) for each study phase. Then EuroQol questionnaire was used to measure utility. The total medical cost for usual care and rFVIIa was annualized to one year cost.

The total medical cost for usual care and rFVIIa were US$183,275 and US$212,222, respectively (in 2010 US dollars). The QALY for usual care was −0.11 and 0.47 for rFVIIa treatment. As a result, the incremental cost per QALY gained with rFVIIa compared to usual care in the base-case analysis was US$49,889. As mentioned earlier, this type of study design introduced selection bias because patients may be treated differently in two time periods. In fact, as the author pointed out, the average time to treat was 37.4 hours in usual care and 6 hours on rFVIIa treatment. The delay of treatment may affect the clinical outcomes and quality of life substantially and resulted in the discrepancy between utility of aPCC and that of rFVIIa. In addition, only six patients were included in the analysis. Sensitivity analysis was not conducted. Although the author stated that the six patients represented around one-quarter of the total 26 pediatric hemophilia patients with inhibitors in Australia, the small sample size and the before–after study design may influence the results and hard to generalize to other population.

Discussion

All of these economic studies contain crucial parameter assumptions on treatment efficacy and dosing that drive their reported findings. As pointed by Hay et al.32, all nine cost-per-episode economic studies were sponsored by the two competing manufacturers of rFVIIa and aPCC. Eight of these nine studies favored their sponsor’s product. Such results crucially hinge on assumptions of a higher efficacy and lower dosing for their sponsor’s product based on clinical trial results from non-comparable single-arm clinical studies; even though the two head-to-head rFVIIa versus aPCC studies published to date do not support superior efficacy for either product10. We have shown that altering such efficacy and dosing assumptions totally alters the cost-effectiveness results. In particular, assuming equivalent efficacy for rFVIIa and aPCC and following FDA-approved labeling for dosing implies lower total costs for aPCC33. The seven cost-minimization studies are based on essentially the same economic model using favorable information from non-controlled single-arm trials, with minor modifications to deal with cost or treatment variations in different countries. Reiterating these assumptions in seven articles may affect the preponderance of results in published studies, but it does not affect the preponderance of the objective scientific evidence on therapeutic efficacy.

Besides sponsor bias, selection bias was introduced when calculating the crucial model assumptions using observational data without adjusting for any observable and unobservable confounders. It is understandable that the number of hemophilia patients with inhibitors is quite small in studies carried out in some countries. However simply using reported means for the efficacy point estimates without accounting for the 95% confidence intervals or other measures for statistical imprecision raises questions about the validity of the comparisons. Moreover, the results are very likely to be influenced by the clinical practice and unit price for each agent in each geographic region.

Due to the local restriction of home-using rFVIIa, the Novo Nordisk-sponsored Brazilian and Korean studies used data from two sources to estimate the efficacy and dosing for aPCC and rFVIIa. The data for aPCC were collected retrospectively and the data for rFVIIa were collected prospectively. Selection bias also occurs when comparing efficacy for aPCC and rFVIIa from two separate sources without any justification for the comparators. The differential efficacy could simply reflect that patients were selected and treated differently in the two settings.

In fact, both bypassing agents play essential roles in the comprehensive care of patients with hemophilia and inhibitors. aPCC and rFVIIa involves different and complex mechanism of action and pharmacokinetics. Several patient-specific factors affect hemostatic response to bypassing agents. Some patients respond better to aPCC whereas others respond better to rFVIIa. This inter-individual variation has been observed in the FENOC study by the occurrence of discordant pairs11. Using a more objective laboratory assay, thrombin generation assay (TGA), disparities were also found in the clinical response in patients treated with aPCC and rFVIIa34. Neither product is able to achieve hemostasis in all patients or all bleeding episodes. For some unresponsive bleeds, switching product or using combination sequential therapy is highly recommended28. For these reasons it may be short-sighted to simply conduct head-to-head comparisons evaluating clinical and cost effectiveness of aPCC versus rFVIIa. It is necessary to have a better understanding of how to utilize these products synergistically to improve patient outcomes and reduce cost. Researchers should consider this point when designing future cost and cost-effectiveness analyses to evaluate bypassing agents for inhibitor patients.

Conclusion

Rather than improving clarity in decision making for inhibitor bypass agents, the manufacturer-sponsored economic analyses have merely shifted a debate about which therapy has a better dosing and efficacy profile into a parallel debate about which therapy is less costly and more cost effective. The cost-effectiveness analyses of these bypass agents have only obfuscated the current clinical uncertainties under a patina of complex mathematical models. The results of these models are driven by favorable selection of baseline clinical parameters for each of the bypass agents. Until head-to-head clinical trials of rFVIIa and aPCC clearly resolve the underlying clinical efficacy and dosing differences, including the possibility that the medications may be synergistic and have heterogeneous treatment efficacy responses, cost-effectiveness analysis will confuse rather than clarify the underlying clinical decisions.

Transparency

Declaration of funding

J.W.H. and Z.Y.Z. are supported through an unrestricted research agreement between Baxter Healthcare Corporation and the University of Southern California.

Declaration of financial/other relationship

The authors stated that they had no other interests which might be perceived as posing a conflict or bias.