Transfusion and Apheresis Science 51 (2014) 17–24
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Transfusion and Apheresis Science j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t r a n s c i
Economic evaluation of pooled solvent/detergent treated plasma versus single donor fresh-frozen plasma in patients receiving plasma transfusions in the United States Eline L. Huisman a,*, Shamika U. de Silva b, Maria A. de Peuter a a b
Mapi, De Molen 84, 3995 AX Houten, The Netherlands Mapi, 73 Collier Street, London N1 9BE, UK
A R T I C L E
I N F O
Article history: Received 23 May 2014 Accepted 8 July 2014 Keywords: Cost-effectiveness analysis Octaplas™ Fresh-frozen plasma Transfusion United States
A B S T R A C T
This study assessed the cost-effectiveness of Octaplas™ versus fresh frozen plasma (FFP) in patients receiving plasma transfusions in the United States (US). Acute and long-term complications of plasma transfusions were modelled in a decision tree followed by a Markov model, using a healthcare payer perspective. Over a lifetime time horizon, patients receiving Octaplas™ accumulate slightly more life years (0.00613 [95% uncertainty interval (95%UI): 0.00166–0.01561]) and quality-adjusted life years (QALY) (0.023 [95%UI: 0.012–0.044]) at lower cost compared with those treated with FFP. Octaplas™ demonstrated to be the dominant treatment option over FFP (95%UI: Dominant–US$ 15,764/QALY). © 2014 Elsevier Ltd. All rights reserved.
1. Introduction Plasma transfusions in the US have increased steadily over the last 15 years; 2.3, 3.9 and 4.1 million units were transfused in 1991, 2001 and 2004, respectively [1]. Although plasma transfusion is largely a safe procedure, a proportion of patients experience complications, which may be categorized as infectious or non-infectious complications [2]. Studies have shown a direct relationship between the amount of blood products that patients receive and the occurrence of serious complications [3]. Although the risk of viral transmission has been reduced since the implementation of donor screening for human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), there is still a potential risk of acquiring viral infections when donors are undergoing seroconversion and can be infectious but not seropositive. Although the overall calculated risk for any of these viruses is low, there are some categories of patients who receive multiple plasma transfusions (including patients who repeatedly need plasma for
* Correspondence author. Tel.: +31 30 63 697 63; fax: +31 30 63 697 70. E-mail address: [email protected] (E.L. Huisman). http://dx.doi.org/10.1016/j.transci.2014.07.006 1473-0502/© 2014 Elsevier Ltd. All rights reserved.
coagulant factors and/or inhibitors), and are exposed to different donors, for whom the aggregate risk of viral transmission can be higher [4]. Furthermore, there remains a risk of infection by yet unknown or untested emerging pathogens, as was the case with West Nile virus (WNV) a couple of years ago [5]. Non-infectious complications include transfusion-related acute lung injury (TRALI) and (severe) allergic reactions. TRALI is the most common cause of transfusion-related morbidity and mortality worldwide, it emerged as the leading cause of transfusion related mortality reported to the Food and Drug Administration in 2003 [6]. Although the implementation of transfusion safety measures has reduced the risks associated with transfusion, these are not completely effective and transfusion-related complications continue to present a healthcare burden [3]. Therefore the use of alternative plasma products with improved safety, which are also cost-effective, is becoming increasingly relevant in the effort to contain the economic impact of rising rates of plasma transfusions in the US. Pooled solvent/detergent (S/D) treated FFP (Octaplas™) is a pharmaceutically manufactured product, that was introduced in Europe in 1991 with the aim of decreasing the incidence of viral transmission with plasma transfusion, and
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approximately 7.2 million units have been transfused worldwide [7]. ABO-specific plasma is collected from pools of up to 3040 donors and is subjected to a manufacturing process that aims to minimize the risk of complications following transfusion. The use of multiple donors results in a more standardized product compared with FFP. The S/D treatment technology is capable of inactivating all encapsulated viruses, including HBV, HCV and HIV [8]. Transmission of the non-enveloped viruses hepatitis A virus (HAV) and P-B19 is reduced through nucleic acid testing of the pooled plasma for these agents; whereas this is not carried out for FFP. Other production steps lead to the removal of bacteria and leukocytes and may reduce the risk of several adverse events, including TRALI. A newer version of the product incorporates a prion reduction stage in its manufacturing process, and has been marketed since 2009 in Europe and Australia, and was approved for use in the United States in January 2013 [9]. Introduction of Octaplas™ into routine use for plasma transfusion therefore has the potential for public health benefits as well as economic benefits arising from a reduction in transfusion-related complications. The economic impact of using Octaplas™ as a substitute for FFP can be assessed through cost-effectiveness studies; these have already been published for Canada and the UK [10,11]. The objective of the current study was to assess the cost-effectiveness of substituting Octaplas™ for single donor FFP in plasma transfusions in the US. This consisted of a model-based health economic study encompassing all patients receiving a plasma transfusion, performed from a healthcare payer perspective. 2. Methods 2.1. Model structure A decision-analytic framework was employed to evaluate the cost-effectiveness of Octaplas™ versus FFP. The analysis focused on all patients receiving a plasma transfusion, including males and females (50/50) with an average age of 50 years. The model assumed that patients had a life expectancy similar to the general population, i.e. 31 years [12]. The economic analysis, performed from a US healthcare payer perspective, included direct medical costs; indirect costs due to potential work loss were excluded. An economic model based on a technology report of the Canadian Agency for Drugs and Technologies in Health (CADTH) [10,11] that was previously created was updated with additional transfusion-related complications and adapted to the US healthcare setting. The economic model consists of two phases. Following transfusion with either FFP or Octaplas™, patients initially enter an acute phase, in which they may complete the transfusion safely or experience transfusion-related complications. This phase is represented by a decision tree that shows the probability of each of these events occurring. It is assumed that no time is spent in the health states of the decision tree. Patients then enter a long-term phase in which they may experience subsequent health states of chronic diseases arising from the transfusion. The long-term phase is represented by a Markov model in which patients are always
in a finite number of discrete health states. Patients can move from one health state to another depending on their probability for developing a complication. As patients transition between health states, they accumulate quality-adjusted life years (QALYs) and costs related to (treatment of) these diseases. The following transfusion-related complications were included in the Markov model: TRALI, HAV infection, HBV infection, HCV infection, HIV infection, P-B19 infection, prion disease such as variant Creutzfeldt–Jakob disease (vCJD), (severe) allergic reactions, bacterial infections and infection with an unknown virus (Fig. 1). Two types of unknown viruses were modelled; an acute unknown pathogen (WNVlike) and a chronic unknown pathogen (HIV-like). Details of the model have been provided in previous publications, including Markov states of chronic diseases [10,11]. The model was built in Excel, used a lifetime time horizon, a yearly cycle length and an annual discount factor of 3% for both costs and effects as recommended by the US Panel on Cost-Effectiveness in Health and Medicine (PCEHM) [13]. 2.2. Model inputs 2.2.1. Clinical inputs The model uses two types of transition probabilities: (1) probabilities governing transition for events that are a direct result of the transfusion (Table 1), and (2) probabilities associated with the sequelae and their progress (i.e. recovery, or worsening of disease). Model inputs were identified through a targeted literature search for transfusion risk data. The probabilities of transfusion related events were assumed to be country specific and US sources were used where possible. The assumption was made that transition probabilities were not country specific, i.e. a patient can move to subsequent health states according to transition probabilities that are similar to those in Canada and were published before [10]. The only exception was the probability of death due to TRALI, a US source was found in the literature search. The transition probability of dying because of TRALI was 0.0432 in the US, whereas this was 0.0318 in Canada. The transition probabilities are presented per event (E) for events in the acute phase modelled in the decision tree, or per year (A) for events in the long-term phase modelled in the Markov model. To incorporate uncertainty in the input data in the evaluation, all model inputs were entered as a beta distribution. When no other data were available, the upper and lower bounds were defined as ±20% of the expected value. 2.2.2. Economic inputs US specific costs arising from transfusion-related complications and their sequelae, were identified through a literature review (Table 2). Most cost inputs were retrieved from cost-effectiveness publications that used similar input parameters, such as the cost for an HAV infection or chronic HBV. When no literature describing the costs associated with a certain adverse event could be identified, the costs were estimated based on resource use as set out in the Merck Manual [14], which specifies the course of disease and treatment options. Costs for transfusionrelated complications occurring per transfusion event are
E.L. Huisman et al./Transfusion and Apheresis Science 51 (2014) 17–24
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No transfusion-related complications Alive TRALI Death from TRALI Alive
HAV
Death from HAV Alive HBV/HCV Chronic Transfusion
Alive
Rapid liver failure Death
HIV Alive P-B19 Death from P-B19 Prion disease Alive (Severe) allergic ti
Death from allergic reactions Resolved
Bacterial infection
Alive Unknown virus WNV-like
Alive
Acute illness Death Unknown virus HIV-like Fig. 1. Overview of decision tree with acute complications that may follow plasma transfusion. Note: HBV and HCV are presented together for simplicity. However, these outcomes were modeled separately, with their own risk of complications and death.
only included in the first year of the analysis. Costs for chronic transfusion-related complications and their sequelae are presented per year. All costs have been corrected for inflation using the medical component of the consumer price index [15] and are presented in 2013 US dollars (USD). The product cost of FFP ($57.91) was taken from the 2011 National Blood Collection and Utilization Survey Report [16]. The anticipated product cost of Octaplas™ ($130) was
obtained through communication with the manufacturer (Octapharma AG). As the model is developed for any patient in need of plasma transfusion, we assume that the utility of patients who do not experience transfusion-related complications is 1. Table 2 presents the utility and cost estimates for transfusion-related complications and health states used in the economic model. Utilities were entered using a beta
Table 1 The probabilities of the occurrence of transfusion-related complications with FFP and Octaplas™. Complication TRALI HAV HBV HCV HIV P-B19 Prion disease (Severe) allergic reactions Bacterial infections Unknown WNV-like infection Unknown HIV-like infection No complication
Probability of complication per FFP unit (range) –6
(4.76*10–6–7.14*10–6)
[20,21] 5.71*10 2.69*10–7 (1.92*10–7–4.50*10–7) [22,23] –6 –6 –6 4.87*10 (4.15*10 – 5.90*10 ) [24–26] 6.02*10–7 (5.17*10–7– 7.19*10–7) [24,25] 5.47*10–7 (4.68*10–7–6.56*10–7) [24,25] 1.21*10–6 (8.0*10–7–2.52*10–6) [22,23,27] 5.01*10–8 (3.47*10–8–9.06*10–8) [28] 1.57*10–2 (1.49*10–2–1.67*10–2) [29–31] 3.36*10–7 (1.07*10–7–7.86–10–7) [32,33] 2.86*10–5 (0–8.58*10–5) [34] 1.41*10–4 (0–4.59*10–4) [34] 0.984
Complication probability per Octaplas™ unit 0 0 0 0 0 0 0 1.05*10–3 (8.39*10–4–1.26*10–3) [29–31] 0 0 0 0.999
Note: A beta distribution was used for the PSA. If multiple sources were used, the lower limit of the uncertainty range was set as the lowest limit reported, and the upper limit was set as the highest limit reported.
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Table 2 Costs and utilities arising from transfusion related complication (US$). Complication
Utility
No complication TRALI HAV HBV acute HBV chronic HBV compensated cirrhosis HBV hepatocellular carcinoma HCV acute HCV chronic HCV compensated cirrhosis HCV hepatocellular carcinoma Oesophageal varices Hepatic encephalopathy Ascites Liver transplant (first year) Liver transplant (subsequent years) HIV AIDS P-B19 complications Prion disease
1 0.60 [35] 0.90 [38] 1a 0.72 [41] 0.70 [41] 0.48 [41] 1a 0.79 [43] 0.80 [43] 0.72 [43] 0.55 [44] 0.53 [44] 0.64b [44] 0.73 [43] 0.73[43] 0.93 [46] 0.85 [46] 0.90 (assumption: same as HAV) 0.53 (assumption: same as hepatic encephalopathy) 0.6 (assumption: same as TRALI) 0.90 (assumption: same as HAV) 0.90 (assumption: same as HAV) 0.50c[53] 0.25c[53]
(Severe) allergic reactions Bacterial infection Unknown infection (WNV-like) Unknown chronic infection (HIV-like) Unknown chronic infection (AIDS like) progression to sickness
Range for PSA
Costs ($) in 2013
Range for PSA
0.71–0.87 0.70–0.90 0.62–0.82 ±20% ±20% ±20% 0.63–0.84 0.63–0.84 ±20% ±20% ±20% ±20%
0 39,083.09 [36,37] 2,688.93 [39] 1,233,43 [40] 1,233,43 [40] 4565.40 [42] 48,140.26 [42] 1,528.33 [42] 1,528.33 [42] 4565.40 [42] 48,140.26 [42] 23,097.77 [45] 20,715.46 [45] 5835.67 [45] 158,537.17 [42] 27,681.96 [42] 19,056.63 [47] 32,564.13 [47] 605.86 [14,48] 67,123.24 [49]
±20% ±20% ±20% ±20% ±20% 22,117–66,341 152–4,194 152–4,194 ±20% 22,117–66,341 ±20% ±20% ±20% 72,825–218,455 12,715–38,156 ±20% ±20% ±20% ±20%
±20% ±20% ±20% ±20% ±20%
1396.61 [50] 14,861.35 [51] 2438.59 [14,52] 19,056.63 [47] 32,564.13 [47]
±20% ±20% ±20% ±20% ±20%
0.45–0.75 ±20% ±20% ±20% ±20%
Note: If no uncertainty was identified in the literature, the lower and upper bound were defined as ±20% of the mean. For the PSA, a beta distribution was used for utility values and a gamma distribution for the costs. a It is assumed that no time is spent in these health states, therefore no utility was calculated. b Based on 50% sensitive to diuretics and 50% insensitive. c Based on HIV utilities from 1997.
distribution, while cost data were entered as a gamma distribution. Again, if no other data were available, lower and upper bounds were defined as ±20% of the expected value. 2.3. Analysis 2.3.1. Base case analysis The model permits the calculation of the following outcomes: transfusion-related complications per 10,000 transfused patients; cumulative life years, QALYs and costs per patient; incremental cost-effectiveness ratio of Octaplas™ vs. FFP. A willingness to pay (WTP) threshold of US$ 50,000 per QALY was used to determine the cost-effectiveness of Octaplas™ versus FFP [17,18]. A probabilistic sensitivity analysis (PSA) was used to account for uncertainty in the input data. With PSA a random value for each input parameter is sampled from distributions reflecting the uncertainty in that parameter. This procedure was repeated 1000 times to obtain uncertainty distributions of each expected outcome. All outcomes of the model were presented with a point estimate and the 2.5th and 97.5th percentile of the uncertainty distribution (the 95% uncertainty interval [UI]). Different scenarios were evaluated in the costeffectiveness model. The base case analysis included the following transfusion related complications: TRALI, HAV, HBV, HCV, HIV, prion disease, P-B19, (severe) allergic reactions, bacterial infections and two emerging infections:
acute (WNV-like) and chronic (HIV-like) infections. For the base case, the most recent price of FFP ($57.91) [16] was used. 2.3.2. Alternative scenario excluding the risk of emerging viruses The first alternative scenario determined the costeffectiveness of Octaplas™ compared with FFP when the risk of emerging viruses, which is considered an uncertain entity, was not taken into account in the analysis. In this scenario analysis, the risk of unknown emerging viruses was set to zero for both Octaplas™ and FFP. 2.3.3. Alternative scenario using a historic price for FFP The price of FFP was noted to have increased over the last few years. Therefore a second alternative scenario was conducted using a historic price of FFP. The price of FFP used ($47.46) was obtained from the 2009 National Blood Collection and Utilization Survey report, and was the lowest price for FFP that was reported in 2008 [19]. This scenario considered the same transfusion related complications as the base case scenario, including unknown emerging viruses. 3. Results 3.1. Base case scenario The incidence of transfusion-related complications for both products per 10,000 patients receiving a transfusion
E.L. Huisman et al./Transfusion and Apheresis Science 51 (2014) 17–24
Table 3 Transfusion related complications per 10,000 transfused patients, for FFP and Octaplas™ (base case). Complication
Number of complications per 10,000 FFP transfusions
TRALI HAV Chronic HBV Rapid liver failure HBV Chronic HCV Rapid liver failure HCV HIV P-B19 Prion disease (Severe) allergic reactions Bacterial infections Unknown WNV-like infection Unknown HIV-like infection Total
Number of complications per 10,000 Octaplas™ transfusions
0.23 0.01 0.18 0.02
0.00 0.00 0.00 0.00
0.02 0.00
0.00 0.00
0.02 0.05 0.00 629.92
0.00 0.00 0.00 41.97
0.01 1.14
0.00 0.00
5.65
0.00
637.25
41.97
Note: The table shows acute health states and the first health state of the chronic complications.
is shown in Table 3. For each of the complications considered, the incidence was lower with Octaplas™ versus FFP. The incidence was zero with Octaplas™ for all complications considered except for allergic reactions. In total, 595.28 fewer complications occurred with the use of Octaplas™ compared with FFP. As a result, patients treated with Octaplas™ gain slightly more life years and QALYs on average compared with those treated with FFP (Table 4). The costs arising from transfusion-related complications were lower for Octaplas™ versus FFP. Therefore despite the higher product cost of Octaplas™, the overall cost for
Table 4 The cumulative life years, QALYs and costs per patient for the base case scenario. FFP Life years (95% UI)
20.59427 (20.58479 − 20.59875) QALYs (95% UI) 20.576 (20.556 − 20.588) Costs, US$ (95% UI) 549.73 (334.98 − 1035.91) Cost of product, 231.64 US$ 318.09 Cost due to complications, US$ Incremental cost per QALY (Octaplas™ vs. FFP) in US$/QALY Incremental cost per life year (Octaplas™ vs. FFP) in US$/ Life year
Octaplas™ 20.60041 (20.60037−20.60043) 20.600 (20.599−20.600) 525.86 (524.35−527.67) 520.00 5.86
Dominant (Dominant−15,764)
Dominant (Dominant−111,077)
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treatment was lower with Octaplas™ (US$ 525.86 [95% UI: 524.35−527.67]) compared with FFP (US$ 549.73 [95% UI: 334.98−1035.91]); (Table 4). The use of Octaplas™ is expected to produce an increase in QALYs at lower costs, hence Octaplas™ can be considered the dominant treatment option over FFP (95% UI: Dominant–15,764); (Table 4). As indicated by Fig. 2 and Fig. 3, the probability of Octaplas™ being cost-effective compared with FFP at a WTP of US$ 50,000 per QALY is over 99%. 3.2. Alternative scenario analyses 3.2.1. Scenario excluding emerging viruses When the risk of unknown emerging viruses was excluded from the analysis, a patient receiving FFP experienced on average 20.59971 life years after transfusion (95% UI: 20.59915–20.60011), which is 0.00544 life year more than in the base case scenario. When quality of life was taken into consideration, the use of FFP resulted in 20.587 QALYs (95% UI: 20.580–20.592); overall costs were reduced by US$ 226.56 compared with the base case scenario as a result of the exclusion of costs arising from the transmission of unknown viruses (Table 5). In this alternative scenario, Octaplas™ is expected to provide 0.0007 additional life years and 0.013 additional QALYs in comparison with FFP (Table 5). However, excluding unknown emerging viruses from the analysis resulted in higher overall costs for treatment with Octaplas™ compared with FFP (US$ 525.86 vs. US$323.17, respectively); this was driven by the higher product cost of Octaplas™ compared with FFP. For Octaplas™, the incremental cost per QALY was US$ 16,159 (95% UI: 8682−32,705), which is below the WTP threshold of US$ 50,000 per QALY. 3.2.2. Scenario using a historic price of FFP In the scenario analysis in which a historic price of FFP ($47.46; from 2008) was used, the overall costs for Octaplas™ and FFP were US$ 525.86 and US$ 507.93, respectively. In this scenario, the overall cost of FFP was reduced by $41.80 compared with the base case. Octaplas™ is expected to provide 0.006 additional life years and 0.023 additional QALYs in comparison with FFP resulting in an ICER of US$ 771 per QALY gained (Table 5). 4. Discussion and conclusions Octaplas™ is associated with a lower incidence of transfusion-related complications compared with FFP, giving a slight gain of life years and QALYs for patients treated with Octaplas™ compared with FFP. The costs associated with treating transfusion-related complications were also lower for Octaplas™ as a consequence of their reduced occurrence, and this produced a numerically lower overall cost for transfusion with Octaplas™ compared with using FFP, despite the higher product cost of the former. Thus Octaplas™ is expected to produce cost savings while improving QALYs, and can therefore be considered the dominant treatment option over FFP. In both scenario analyses considered, Octaplas™ remained a cost-effective option versus FFP at a WTP threshold
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Incremental Costs (US$)
0.00 400.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
200.00 0.00 -200.00 -400.00 -600.00 -800.00 -1000.00 -1200.00 Incremental QALY
Fig. 2. The cost-effectiveness plane: incremental cost and QALY for Octaplas™ versus FFP (base case).
because in all scenarios the upper limits of the 95% UI were below the US$ 50,000 per QALY threshold. The cost-effectiveness of Octaplas™ versus FFP was previously analysed for the UK and Canada. Octaplas™ was found to be the dominant treatment option over FFP in Canada [10], while Octaplas™ resulted in an ICER of £1030 (corresponding to $ 1640) compared with FFP in the UK [11]. The difference in results for the UK analysis compared with the current and Canadian analyses may be due to differences in the patient population described. In the UK model, a critically ill population with a reduced life expectancy was considered. As the life expectancy is lower, any long-term effects of chronic conditions (related to costs and quality of life) are diminished. Furthermore, the UK model used a lower risk of allergic reactions per plasma transfusion compared with those for Canada and the US, which took into account that the risk of allergic reactions is increased in patients who have an on-going need for regular plasma transfusions. When a model-based economic evaluation is performed, assumptions are made. It was assumed that patients only receive one transfusion, consisting of four plasma units, and that a patient cannot experience more than one transfusionrelated complication. Furthermore, the transfusion-related risks are based on the use of male plasma only, which reduces the TRALI risk associated with FFP transfusions
100,000
90,000
80,000
70,000
60,000
50,000
40,000
30,000
20,000
10,000
100 90 80 70 60 50 40 30 20 10 0 0
Probability cost-effective (per QALY; %)
of US$ 50,000 per QALY. In the scenario in which unknown emerging viruses were excluded, the benefit of using Octaplas™ versus FFP was negated as the risk of this complication was zero for both products. Since the costs for (treatment of) unknown emerging viruses were an important driver of the model, excluding these costs had a large impact on the total costs of FFP in the alternative scenario in which unknown emerging viruses were excluded. As a result, the use of Octaplas™ was no longer the dominant treatment option in this scenario. However since the incremental cost per QALY was well below the US$ 50,000 threshold, Octaplas™ could still be considered cost-effective if unknown emerging viruses are excluded from the analysis. The second scenario analysis using a historic (lower) price of FFP (from 2008) showed that Octaplas™ would have been cost-effective in comparison with FFP even if the latter had not undergone a price increase over the last 5 years. The model inputs were derived from the literature and are characterized by uncertainty. A PSA was performed to quantify the uncertainty in the results based on uncertainty in the source data. Octaplas™ was found to be the dominant treatment option over FFP in the base case analysis, but the upper limit of the 95% UI was US$ 15.764 per QALY, indicating uncertainty in these results. Nevertheless Octaplas™ is considered a cost-effective option versus FFP
Willingness to pay (US$) Fig. 3. The acceptability curve representing the probability that Octaplas™ is cost-effective in comparison with FFP for different values of willingness to pay for a QALY (base case).
Octaplas™
20.60041 (20.60036–20.60043) 20.600 (20.599–20.600) 525.86 (524.47–527.75) 520.00 5.86 771 (Dominant–18,964) 2925 (Dominant–145,987)
FFP
20.59427 (20.58544–20.59888) 20.576 (20.556−20.588) 507.93 (292.49−968.66) 189.84 318.09
Octaplas™
20.60041 (20.60036–20.60043) 20.600 (20.599–20.600) 525.86 (524.28–527.75) 520.00 5.86 16,159 (8682–32,705) 289,633 (141,066–771,709)
FFP
20.59971 (20.59915−20.60011) 20.587 (20.580–20.592) 323.17 (286.25−367.61) 231.64 91.53 Life years (95% UI) QALYs (95% UI) Overall costs, US$ (95% UI) Cost of product, US$ Cost due to complications, US$ Incremental cost per QALY (Octaplas™ vs. FFP) in US$/QALY Incremental cost per life year (Octaplas™ vs. FFP) in US$/Life year
Excluding unknown emerging viruses
Table 5 The cumulative life years, QALYs and costs per patient for the alternative scenarios.
Using historic price of FFP
E.L. Huisman et al./Transfusion and Apheresis Science 51 (2014) 17–24
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compared with normal FFP. Allowing for more transfusions in a lifetime would increase the difference between FFP and Octaplas™. This would be further magnified if individual patients could experience more than one transfusion related adverse event, or if both male and female plasma were used. In conclusion, Octaplas™ is expected to be the dominant treatment option versus FFP, due to the higher QALYs gained at lower cost. Despite the uncertainties associated with the outcomes, the probability of Octaplas™ being costeffective relative to FFP is over 99% at a WTP threshold of US$ 50,000 per QALY. Introduction of Octaplas™ into routine use may therefore be considered a cost-effective option for addressing the increasing healthcare burden of plasma transfusions in the US. Acknowledgments This study was funded by Octapharma AG. All authors participated in the design and conduct of the study, as well as drafting and revising the manuscript. References [1] Yim R. Frozen plasma for transfusion: a review. 2006. . [2] Solheim BG, Seghatchian J. Update on pathogen reduction technology for therapeutic plasma: an overview. Transfus Apher Sci 2006;35(1):83–90. [3] Boucher BA, Hannon TJ. Blood management: a primer for clinicians. Pharmacotherapy 2007;27(10):1394–411. [4] O’Shaughnessy DF, Atterbury C, Bolton MP, Murphy M, Thomas D, Yates S, et al. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 2004;126(1):11– 28. [5] Centers for Disease Control and Prevention. West nile virus transmission via organ transplantation and blood transfusion – Louisiana, 2008. 2009. . [6] Pandey S, Vyas GN Adverse effects of plasma transfusion. [7] Octapharma. OctaplasLG®. 2013. . [8] Council of Europe. Guide to the preparation, use and quality assurance of blood components. Recommendation No R (95) 15 on the preparation, use and quality assurance of blood components. 14th ed. Strasbourg: Council of Europe Press; 2008. [9] Food and Drug Administration – Department of Health and Human Services. FDA approval letter octaplas – January 17, 2013. 2013. . [10] Huisman EL, Van Eerd MC, Ouwens JN, De Peuter MA. Costeffectiveness and budget impact study of solvent/detergent (SD) treated plasma (octaplasLG(R)) versus fresh-frozen plasma (FFP) in any patient receiving transfusion in Canada. Transfus Apher Sci 2013. [11] Van Eerd MC, Ouwens JNM, De Peuter MA. Cost-effectiveness study comparing pharmaceutically licensed plasma for tranfusions (octaplasLG®) versus Fresh Frozen Plasma (FFP) in critically ill patients in the UK. Transfus Apher Sci 2010;43(3):251–9. [12] Division of Vital Statistics. United States life tables, 2008. 2013. . [13] Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the panel on cost-effectiveness in health and medicine. JAMA 1996;276(15):1253–8. [14] Merck Manual 2010–2013. 2013. . [15] Bureau of Labor Statistics. 2013. . [16] Department of Health & Human Services USA. The 2011 National Blood Collection and Utilization Survey Report. 2011. .
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[17] Owens DK. Interpretation of cost-effectiveness analyses. J Gen Intern Med 1998;13(10):716–17. [18] Hirth RA, Chernew ME, Miller E, Fendrick AM, Weissert WG. Willingness to pay for a quality-adjusted life year: in search of a standard. Med Decis Making 2000;20(3):332–42. [19] Department of Health & Human Services USA. The 2009 National Blood Collection and Utilization Survey. 2009. . [20] Eder AF, Herron RM Jr, Strupp A, Dy B, White J, Notari EP, et al. Effective reduction of transfusion-related acute lung injury risk with male-predominant plasma strategy in the American Red Cross (2006–2008). Transfusion 2010;50(8):1732–42. [21] Eder AF, Herron R, Strupp A, Dy B, Notari EP, Chambers LA, et al. Transfusion-related acute lung injury surveillance (2003–2005) and the potential impact of the selective use of plasma from male donors in the American Red Cross. Transfusion 2007;47(4):599– 607. [22] Tabor E, Epstein JS. NAT screening of blood and plasma donations: evolution of technology and regulatory policy. Transfusion 2002;42(9):1230–7. [23] Stramer SL. Impact of NAT on serological screening of transfusiontransmitted agents. ISBT Sci Ser 2006;1(1):194–202. [24] Dodd RY, Notari EP, Stramer SL. Current prevalence and incidence of infectious disease markers and estimated window-period risk in the American Red Cross blood donor-ápopulation. Transfusion 2002;42(8):975–9. [25] Dodd RY. Emerging infections, transfusion safety, and epidemiology. N Engl J Med 2003;349(13):1205–6. [26] Wasley A, Kruszon-Moran D, Kuhnert W, Simard EP, Finelli L, McQuillan G, et al. The prevalence of hepatitis B virus infection in the United States in the era of vaccination. J Infect Dis 2010;202(2):192–201. [27] Cohen BJ, Buckley MM. The prevalence of antibody to human parvovirus B19 in England and Wales. J Med Microbiol 1988;25(2):151–3. [28] Svae TE, Neisser-Svae A, Bailey A, Reichl H, Biesert L, Schmidt T, et al. Prion safety of transfusion plasma and plasma-derivatives typically used for prophylactic treatment. Transfus Apher Sci 2008;39(1):59–67. [29] Vaara I, Nilsson CD. [SD plasma safer than fresh-frozen plasma. Comparative studies show advantages of industrially produced plasma]. Lakartidningen 2010;107(3):106–7. [30] Domen RE, Hoeltge GA. Allergic transfusion reactions. Arch Pathol Lab Med 2003;127(3):316–20. [31] Reutter JC, Sanders KF, Brecher ME, Jones HG, Bandarenko N. Incidence of allergic reactions with fresh frozen plasma or cryo-supernatant plasma in the treatment of thrombotic thrombocytopenic purpura. J Clin Apher 2001;16(3):134–8. [32] Paul-Ehrlich-Institut. Hamovigilanzdaten von 1997 bis 2008. 2012. . [33] Funk MB, Guenay S, Lohmann A, Henseler O, Heiden M, Hanschmann KMO, et al. Benefit of transfusion-related acute lung injury riskminimization measures ΓÇô German haemovigilance data (2006ΓÇô2010). Vox Sang 2011. [34] Kleinman S, Cameron C, Custer B, Busch M, Katz L, Kralj B, et al. Modeling the risk of an emerging pathogen entering the Canadian blood supply. Transfusion 2010;50(12):2592–606. [35] Angus DC, Musthafa AA, Clermont G, Griffin MF, Linde-Zwirble WT, Dremsizov TT, et al. Quality-adjusted survival in the first year after
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
the acute respiratory distress syndrome. Am J Respir Crit Care Med 2001;163(6):1389–94. Riedler GF, Haycox AR, Duggan AK, Dakin HA. Cost-effectiveness of solvent/detergent-treated fresh-frozen plasma. Vox Sang 2003;85(2):88–95. Cooke CR, Kahn JM, Watkins TR, Hudson LD, Rubenfeld GD. Costeffectiveness of implementing low-tidal volume ventilation in patients with acute lung injury. Chest 2009;136:79–88. Bauch CT, Anonychuk AM, Pham BZ, Gilca V, Duval B, Krahn MD. Cost-utility of universal hepatitis A vaccination in Canada. Vaccine 2007;25(51):8536–48. Centers for Disease Control and Prevention. Hepatitis A. In Epidemiology and prevention of vaccine-preventable diseases (pink book). 2013. . Eckman MH, Kaiser TE, Sherman KE. The cost-effectiveness of screening for chronic hepatitis B infection in the United States. Clin Infect Dis 2011;52(11):1294–306. Levy AR, Kowdley KV, Iloeje U, Tafesse E, Mukherjee J, Gish R, et al. The impact of chronic hepatitis B on quality of life: a multinational study of utilities from infected and uninfected persons. Value Health 2008;11(3):527–38. Liu S, Cipriano LE, Holodniy M, Goldhaber-Fiebert JD. Costeffectiveness analysis of risk-factor guided and birth-cohort screening for chronic hepatitis C infection in the United States. PLoS ONE 2013;8(3):e58975. Chong CA, Gulamhussein A, Heathcote EJ, Lilly L, Sherman M, Naglie G, et al. Health-state utilities and quality of life in hepatitis C patients. Am J Gastroenterol 2003;98(3):630–8. Wong JB, Bennett WG, Koff RS, Pauker SG. Pretreatment evaluation of chronic hepatitis C: risks, benefits, and costs. JAMA 1998;280(24):2088–93. Salomon JA, Weinstein MC, Hammitt JK, Goldie SJ. Cost-effectiveness of treatment for chronic hepatitis C infection in an evolving patient population. J Am Med Assoc 2003;290(2):228–37. Simpson KN, Roberts G, Hicks CB, Finnern HW. Cost-effectiveness of tipranavir in treatment-experienced HIV patients in the United States. HIV Clin Trials 2008;9(4):225–37. Gebo KA, Fleishman JA, Conviser R, Hellinger J, Hellinger FJ, Josephs JS, et al. Contemporary costs of HIV healthcare in the HAART era. AIDS 2010;24(17):2705–15. Centers for Disease Control and Prevention. Parvovirus B19 and Fifth Disease. 2013. . Annual Change in Medicaid Hospice Payment Rates. 2013 September 7. . Kacker S, Ness PM, Savage WJ, Frick KD, McCullough J, King KE, et al. The cost-effectiveness of platelet additive solution to prevent allergic transfusion reactions. Transfusion 2013. Hall MJ. NCHS data brief – inpatient care for septicemia or sepsis: a challenge for patients and hospitals. 2013. . Center for Disease Prevention and Control – West Nile Virus Treatment and Symptoms. 2013. . Pereira A. Cost-effectiveness of transfusing virus-inactivated plasma instead of standard plasma. Transfusion 1999;39(5):479–87.
Contents lists available at ScienceDirect
Transfusion and Apheresis Science j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t r a n s c i
Economic evaluation of pooled solvent/detergent treated plasma versus single donor fresh-frozen plasma in patients receiving plasma transfusions in the United States Eline L. Huisman a,*, Shamika U. de Silva b, Maria A. de Peuter a a b
Mapi, De Molen 84, 3995 AX Houten, The Netherlands Mapi, 73 Collier Street, London N1 9BE, UK
A R T I C L E
I N F O
Article history: Received 23 May 2014 Accepted 8 July 2014 Keywords: Cost-effectiveness analysis Octaplas™ Fresh-frozen plasma Transfusion United States
A B S T R A C T
This study assessed the cost-effectiveness of Octaplas™ versus fresh frozen plasma (FFP) in patients receiving plasma transfusions in the United States (US). Acute and long-term complications of plasma transfusions were modelled in a decision tree followed by a Markov model, using a healthcare payer perspective. Over a lifetime time horizon, patients receiving Octaplas™ accumulate slightly more life years (0.00613 [95% uncertainty interval (95%UI): 0.00166–0.01561]) and quality-adjusted life years (QALY) (0.023 [95%UI: 0.012–0.044]) at lower cost compared with those treated with FFP. Octaplas™ demonstrated to be the dominant treatment option over FFP (95%UI: Dominant–US$ 15,764/QALY). © 2014 Elsevier Ltd. All rights reserved.
1. Introduction Plasma transfusions in the US have increased steadily over the last 15 years; 2.3, 3.9 and 4.1 million units were transfused in 1991, 2001 and 2004, respectively [1]. Although plasma transfusion is largely a safe procedure, a proportion of patients experience complications, which may be categorized as infectious or non-infectious complications [2]. Studies have shown a direct relationship between the amount of blood products that patients receive and the occurrence of serious complications [3]. Although the risk of viral transmission has been reduced since the implementation of donor screening for human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), there is still a potential risk of acquiring viral infections when donors are undergoing seroconversion and can be infectious but not seropositive. Although the overall calculated risk for any of these viruses is low, there are some categories of patients who receive multiple plasma transfusions (including patients who repeatedly need plasma for
* Correspondence author. Tel.: +31 30 63 697 63; fax: +31 30 63 697 70. E-mail address: [email protected] (E.L. Huisman). http://dx.doi.org/10.1016/j.transci.2014.07.006 1473-0502/© 2014 Elsevier Ltd. All rights reserved.
coagulant factors and/or inhibitors), and are exposed to different donors, for whom the aggregate risk of viral transmission can be higher [4]. Furthermore, there remains a risk of infection by yet unknown or untested emerging pathogens, as was the case with West Nile virus (WNV) a couple of years ago [5]. Non-infectious complications include transfusion-related acute lung injury (TRALI) and (severe) allergic reactions. TRALI is the most common cause of transfusion-related morbidity and mortality worldwide, it emerged as the leading cause of transfusion related mortality reported to the Food and Drug Administration in 2003 [6]. Although the implementation of transfusion safety measures has reduced the risks associated with transfusion, these are not completely effective and transfusion-related complications continue to present a healthcare burden [3]. Therefore the use of alternative plasma products with improved safety, which are also cost-effective, is becoming increasingly relevant in the effort to contain the economic impact of rising rates of plasma transfusions in the US. Pooled solvent/detergent (S/D) treated FFP (Octaplas™) is a pharmaceutically manufactured product, that was introduced in Europe in 1991 with the aim of decreasing the incidence of viral transmission with plasma transfusion, and
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approximately 7.2 million units have been transfused worldwide [7]. ABO-specific plasma is collected from pools of up to 3040 donors and is subjected to a manufacturing process that aims to minimize the risk of complications following transfusion. The use of multiple donors results in a more standardized product compared with FFP. The S/D treatment technology is capable of inactivating all encapsulated viruses, including HBV, HCV and HIV [8]. Transmission of the non-enveloped viruses hepatitis A virus (HAV) and P-B19 is reduced through nucleic acid testing of the pooled plasma for these agents; whereas this is not carried out for FFP. Other production steps lead to the removal of bacteria and leukocytes and may reduce the risk of several adverse events, including TRALI. A newer version of the product incorporates a prion reduction stage in its manufacturing process, and has been marketed since 2009 in Europe and Australia, and was approved for use in the United States in January 2013 [9]. Introduction of Octaplas™ into routine use for plasma transfusion therefore has the potential for public health benefits as well as economic benefits arising from a reduction in transfusion-related complications. The economic impact of using Octaplas™ as a substitute for FFP can be assessed through cost-effectiveness studies; these have already been published for Canada and the UK [10,11]. The objective of the current study was to assess the cost-effectiveness of substituting Octaplas™ for single donor FFP in plasma transfusions in the US. This consisted of a model-based health economic study encompassing all patients receiving a plasma transfusion, performed from a healthcare payer perspective. 2. Methods 2.1. Model structure A decision-analytic framework was employed to evaluate the cost-effectiveness of Octaplas™ versus FFP. The analysis focused on all patients receiving a plasma transfusion, including males and females (50/50) with an average age of 50 years. The model assumed that patients had a life expectancy similar to the general population, i.e. 31 years [12]. The economic analysis, performed from a US healthcare payer perspective, included direct medical costs; indirect costs due to potential work loss were excluded. An economic model based on a technology report of the Canadian Agency for Drugs and Technologies in Health (CADTH) [10,11] that was previously created was updated with additional transfusion-related complications and adapted to the US healthcare setting. The economic model consists of two phases. Following transfusion with either FFP or Octaplas™, patients initially enter an acute phase, in which they may complete the transfusion safely or experience transfusion-related complications. This phase is represented by a decision tree that shows the probability of each of these events occurring. It is assumed that no time is spent in the health states of the decision tree. Patients then enter a long-term phase in which they may experience subsequent health states of chronic diseases arising from the transfusion. The long-term phase is represented by a Markov model in which patients are always
in a finite number of discrete health states. Patients can move from one health state to another depending on their probability for developing a complication. As patients transition between health states, they accumulate quality-adjusted life years (QALYs) and costs related to (treatment of) these diseases. The following transfusion-related complications were included in the Markov model: TRALI, HAV infection, HBV infection, HCV infection, HIV infection, P-B19 infection, prion disease such as variant Creutzfeldt–Jakob disease (vCJD), (severe) allergic reactions, bacterial infections and infection with an unknown virus (Fig. 1). Two types of unknown viruses were modelled; an acute unknown pathogen (WNVlike) and a chronic unknown pathogen (HIV-like). Details of the model have been provided in previous publications, including Markov states of chronic diseases [10,11]. The model was built in Excel, used a lifetime time horizon, a yearly cycle length and an annual discount factor of 3% for both costs and effects as recommended by the US Panel on Cost-Effectiveness in Health and Medicine (PCEHM) [13]. 2.2. Model inputs 2.2.1. Clinical inputs The model uses two types of transition probabilities: (1) probabilities governing transition for events that are a direct result of the transfusion (Table 1), and (2) probabilities associated with the sequelae and their progress (i.e. recovery, or worsening of disease). Model inputs were identified through a targeted literature search for transfusion risk data. The probabilities of transfusion related events were assumed to be country specific and US sources were used where possible. The assumption was made that transition probabilities were not country specific, i.e. a patient can move to subsequent health states according to transition probabilities that are similar to those in Canada and were published before [10]. The only exception was the probability of death due to TRALI, a US source was found in the literature search. The transition probability of dying because of TRALI was 0.0432 in the US, whereas this was 0.0318 in Canada. The transition probabilities are presented per event (E) for events in the acute phase modelled in the decision tree, or per year (A) for events in the long-term phase modelled in the Markov model. To incorporate uncertainty in the input data in the evaluation, all model inputs were entered as a beta distribution. When no other data were available, the upper and lower bounds were defined as ±20% of the expected value. 2.2.2. Economic inputs US specific costs arising from transfusion-related complications and their sequelae, were identified through a literature review (Table 2). Most cost inputs were retrieved from cost-effectiveness publications that used similar input parameters, such as the cost for an HAV infection or chronic HBV. When no literature describing the costs associated with a certain adverse event could be identified, the costs were estimated based on resource use as set out in the Merck Manual [14], which specifies the course of disease and treatment options. Costs for transfusionrelated complications occurring per transfusion event are
E.L. Huisman et al./Transfusion and Apheresis Science 51 (2014) 17–24
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No transfusion-related complications Alive TRALI Death from TRALI Alive
HAV
Death from HAV Alive HBV/HCV Chronic Transfusion
Alive
Rapid liver failure Death
HIV Alive P-B19 Death from P-B19 Prion disease Alive (Severe) allergic ti
Death from allergic reactions Resolved
Bacterial infection
Alive Unknown virus WNV-like
Alive
Acute illness Death Unknown virus HIV-like Fig. 1. Overview of decision tree with acute complications that may follow plasma transfusion. Note: HBV and HCV are presented together for simplicity. However, these outcomes were modeled separately, with their own risk of complications and death.
only included in the first year of the analysis. Costs for chronic transfusion-related complications and their sequelae are presented per year. All costs have been corrected for inflation using the medical component of the consumer price index [15] and are presented in 2013 US dollars (USD). The product cost of FFP ($57.91) was taken from the 2011 National Blood Collection and Utilization Survey Report [16]. The anticipated product cost of Octaplas™ ($130) was
obtained through communication with the manufacturer (Octapharma AG). As the model is developed for any patient in need of plasma transfusion, we assume that the utility of patients who do not experience transfusion-related complications is 1. Table 2 presents the utility and cost estimates for transfusion-related complications and health states used in the economic model. Utilities were entered using a beta
Table 1 The probabilities of the occurrence of transfusion-related complications with FFP and Octaplas™. Complication TRALI HAV HBV HCV HIV P-B19 Prion disease (Severe) allergic reactions Bacterial infections Unknown WNV-like infection Unknown HIV-like infection No complication
Probability of complication per FFP unit (range) –6
(4.76*10–6–7.14*10–6)
[20,21] 5.71*10 2.69*10–7 (1.92*10–7–4.50*10–7) [22,23] –6 –6 –6 4.87*10 (4.15*10 – 5.90*10 ) [24–26] 6.02*10–7 (5.17*10–7– 7.19*10–7) [24,25] 5.47*10–7 (4.68*10–7–6.56*10–7) [24,25] 1.21*10–6 (8.0*10–7–2.52*10–6) [22,23,27] 5.01*10–8 (3.47*10–8–9.06*10–8) [28] 1.57*10–2 (1.49*10–2–1.67*10–2) [29–31] 3.36*10–7 (1.07*10–7–7.86–10–7) [32,33] 2.86*10–5 (0–8.58*10–5) [34] 1.41*10–4 (0–4.59*10–4) [34] 0.984
Complication probability per Octaplas™ unit 0 0 0 0 0 0 0 1.05*10–3 (8.39*10–4–1.26*10–3) [29–31] 0 0 0 0.999
Note: A beta distribution was used for the PSA. If multiple sources were used, the lower limit of the uncertainty range was set as the lowest limit reported, and the upper limit was set as the highest limit reported.
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Table 2 Costs and utilities arising from transfusion related complication (US$). Complication
Utility
No complication TRALI HAV HBV acute HBV chronic HBV compensated cirrhosis HBV hepatocellular carcinoma HCV acute HCV chronic HCV compensated cirrhosis HCV hepatocellular carcinoma Oesophageal varices Hepatic encephalopathy Ascites Liver transplant (first year) Liver transplant (subsequent years) HIV AIDS P-B19 complications Prion disease
1 0.60 [35] 0.90 [38] 1a 0.72 [41] 0.70 [41] 0.48 [41] 1a 0.79 [43] 0.80 [43] 0.72 [43] 0.55 [44] 0.53 [44] 0.64b [44] 0.73 [43] 0.73[43] 0.93 [46] 0.85 [46] 0.90 (assumption: same as HAV) 0.53 (assumption: same as hepatic encephalopathy) 0.6 (assumption: same as TRALI) 0.90 (assumption: same as HAV) 0.90 (assumption: same as HAV) 0.50c[53] 0.25c[53]
(Severe) allergic reactions Bacterial infection Unknown infection (WNV-like) Unknown chronic infection (HIV-like) Unknown chronic infection (AIDS like) progression to sickness
Range for PSA
Costs ($) in 2013
Range for PSA
0.71–0.87 0.70–0.90 0.62–0.82 ±20% ±20% ±20% 0.63–0.84 0.63–0.84 ±20% ±20% ±20% ±20%
0 39,083.09 [36,37] 2,688.93 [39] 1,233,43 [40] 1,233,43 [40] 4565.40 [42] 48,140.26 [42] 1,528.33 [42] 1,528.33 [42] 4565.40 [42] 48,140.26 [42] 23,097.77 [45] 20,715.46 [45] 5835.67 [45] 158,537.17 [42] 27,681.96 [42] 19,056.63 [47] 32,564.13 [47] 605.86 [14,48] 67,123.24 [49]
±20% ±20% ±20% ±20% ±20% 22,117–66,341 152–4,194 152–4,194 ±20% 22,117–66,341 ±20% ±20% ±20% 72,825–218,455 12,715–38,156 ±20% ±20% ±20% ±20%
±20% ±20% ±20% ±20% ±20%
1396.61 [50] 14,861.35 [51] 2438.59 [14,52] 19,056.63 [47] 32,564.13 [47]
±20% ±20% ±20% ±20% ±20%
0.45–0.75 ±20% ±20% ±20% ±20%
Note: If no uncertainty was identified in the literature, the lower and upper bound were defined as ±20% of the mean. For the PSA, a beta distribution was used for utility values and a gamma distribution for the costs. a It is assumed that no time is spent in these health states, therefore no utility was calculated. b Based on 50% sensitive to diuretics and 50% insensitive. c Based on HIV utilities from 1997.
distribution, while cost data were entered as a gamma distribution. Again, if no other data were available, lower and upper bounds were defined as ±20% of the expected value. 2.3. Analysis 2.3.1. Base case analysis The model permits the calculation of the following outcomes: transfusion-related complications per 10,000 transfused patients; cumulative life years, QALYs and costs per patient; incremental cost-effectiveness ratio of Octaplas™ vs. FFP. A willingness to pay (WTP) threshold of US$ 50,000 per QALY was used to determine the cost-effectiveness of Octaplas™ versus FFP [17,18]. A probabilistic sensitivity analysis (PSA) was used to account for uncertainty in the input data. With PSA a random value for each input parameter is sampled from distributions reflecting the uncertainty in that parameter. This procedure was repeated 1000 times to obtain uncertainty distributions of each expected outcome. All outcomes of the model were presented with a point estimate and the 2.5th and 97.5th percentile of the uncertainty distribution (the 95% uncertainty interval [UI]). Different scenarios were evaluated in the costeffectiveness model. The base case analysis included the following transfusion related complications: TRALI, HAV, HBV, HCV, HIV, prion disease, P-B19, (severe) allergic reactions, bacterial infections and two emerging infections:
acute (WNV-like) and chronic (HIV-like) infections. For the base case, the most recent price of FFP ($57.91) [16] was used. 2.3.2. Alternative scenario excluding the risk of emerging viruses The first alternative scenario determined the costeffectiveness of Octaplas™ compared with FFP when the risk of emerging viruses, which is considered an uncertain entity, was not taken into account in the analysis. In this scenario analysis, the risk of unknown emerging viruses was set to zero for both Octaplas™ and FFP. 2.3.3. Alternative scenario using a historic price for FFP The price of FFP was noted to have increased over the last few years. Therefore a second alternative scenario was conducted using a historic price of FFP. The price of FFP used ($47.46) was obtained from the 2009 National Blood Collection and Utilization Survey report, and was the lowest price for FFP that was reported in 2008 [19]. This scenario considered the same transfusion related complications as the base case scenario, including unknown emerging viruses. 3. Results 3.1. Base case scenario The incidence of transfusion-related complications for both products per 10,000 patients receiving a transfusion
E.L. Huisman et al./Transfusion and Apheresis Science 51 (2014) 17–24
Table 3 Transfusion related complications per 10,000 transfused patients, for FFP and Octaplas™ (base case). Complication
Number of complications per 10,000 FFP transfusions
TRALI HAV Chronic HBV Rapid liver failure HBV Chronic HCV Rapid liver failure HCV HIV P-B19 Prion disease (Severe) allergic reactions Bacterial infections Unknown WNV-like infection Unknown HIV-like infection Total
Number of complications per 10,000 Octaplas™ transfusions
0.23 0.01 0.18 0.02
0.00 0.00 0.00 0.00
0.02 0.00
0.00 0.00
0.02 0.05 0.00 629.92
0.00 0.00 0.00 41.97
0.01 1.14
0.00 0.00
5.65
0.00
637.25
41.97
Note: The table shows acute health states and the first health state of the chronic complications.
is shown in Table 3. For each of the complications considered, the incidence was lower with Octaplas™ versus FFP. The incidence was zero with Octaplas™ for all complications considered except for allergic reactions. In total, 595.28 fewer complications occurred with the use of Octaplas™ compared with FFP. As a result, patients treated with Octaplas™ gain slightly more life years and QALYs on average compared with those treated with FFP (Table 4). The costs arising from transfusion-related complications were lower for Octaplas™ versus FFP. Therefore despite the higher product cost of Octaplas™, the overall cost for
Table 4 The cumulative life years, QALYs and costs per patient for the base case scenario. FFP Life years (95% UI)
20.59427 (20.58479 − 20.59875) QALYs (95% UI) 20.576 (20.556 − 20.588) Costs, US$ (95% UI) 549.73 (334.98 − 1035.91) Cost of product, 231.64 US$ 318.09 Cost due to complications, US$ Incremental cost per QALY (Octaplas™ vs. FFP) in US$/QALY Incremental cost per life year (Octaplas™ vs. FFP) in US$/ Life year
Octaplas™ 20.60041 (20.60037−20.60043) 20.600 (20.599−20.600) 525.86 (524.35−527.67) 520.00 5.86
Dominant (Dominant−15,764)
Dominant (Dominant−111,077)
21
treatment was lower with Octaplas™ (US$ 525.86 [95% UI: 524.35−527.67]) compared with FFP (US$ 549.73 [95% UI: 334.98−1035.91]); (Table 4). The use of Octaplas™ is expected to produce an increase in QALYs at lower costs, hence Octaplas™ can be considered the dominant treatment option over FFP (95% UI: Dominant–15,764); (Table 4). As indicated by Fig. 2 and Fig. 3, the probability of Octaplas™ being cost-effective compared with FFP at a WTP of US$ 50,000 per QALY is over 99%. 3.2. Alternative scenario analyses 3.2.1. Scenario excluding emerging viruses When the risk of unknown emerging viruses was excluded from the analysis, a patient receiving FFP experienced on average 20.59971 life years after transfusion (95% UI: 20.59915–20.60011), which is 0.00544 life year more than in the base case scenario. When quality of life was taken into consideration, the use of FFP resulted in 20.587 QALYs (95% UI: 20.580–20.592); overall costs were reduced by US$ 226.56 compared with the base case scenario as a result of the exclusion of costs arising from the transmission of unknown viruses (Table 5). In this alternative scenario, Octaplas™ is expected to provide 0.0007 additional life years and 0.013 additional QALYs in comparison with FFP (Table 5). However, excluding unknown emerging viruses from the analysis resulted in higher overall costs for treatment with Octaplas™ compared with FFP (US$ 525.86 vs. US$323.17, respectively); this was driven by the higher product cost of Octaplas™ compared with FFP. For Octaplas™, the incremental cost per QALY was US$ 16,159 (95% UI: 8682−32,705), which is below the WTP threshold of US$ 50,000 per QALY. 3.2.2. Scenario using a historic price of FFP In the scenario analysis in which a historic price of FFP ($47.46; from 2008) was used, the overall costs for Octaplas™ and FFP were US$ 525.86 and US$ 507.93, respectively. In this scenario, the overall cost of FFP was reduced by $41.80 compared with the base case. Octaplas™ is expected to provide 0.006 additional life years and 0.023 additional QALYs in comparison with FFP resulting in an ICER of US$ 771 per QALY gained (Table 5). 4. Discussion and conclusions Octaplas™ is associated with a lower incidence of transfusion-related complications compared with FFP, giving a slight gain of life years and QALYs for patients treated with Octaplas™ compared with FFP. The costs associated with treating transfusion-related complications were also lower for Octaplas™ as a consequence of their reduced occurrence, and this produced a numerically lower overall cost for transfusion with Octaplas™ compared with using FFP, despite the higher product cost of the former. Thus Octaplas™ is expected to produce cost savings while improving QALYs, and can therefore be considered the dominant treatment option over FFP. In both scenario analyses considered, Octaplas™ remained a cost-effective option versus FFP at a WTP threshold
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Incremental Costs (US$)
0.00 400.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
200.00 0.00 -200.00 -400.00 -600.00 -800.00 -1000.00 -1200.00 Incremental QALY
Fig. 2. The cost-effectiveness plane: incremental cost and QALY for Octaplas™ versus FFP (base case).
because in all scenarios the upper limits of the 95% UI were below the US$ 50,000 per QALY threshold. The cost-effectiveness of Octaplas™ versus FFP was previously analysed for the UK and Canada. Octaplas™ was found to be the dominant treatment option over FFP in Canada [10], while Octaplas™ resulted in an ICER of £1030 (corresponding to $ 1640) compared with FFP in the UK [11]. The difference in results for the UK analysis compared with the current and Canadian analyses may be due to differences in the patient population described. In the UK model, a critically ill population with a reduced life expectancy was considered. As the life expectancy is lower, any long-term effects of chronic conditions (related to costs and quality of life) are diminished. Furthermore, the UK model used a lower risk of allergic reactions per plasma transfusion compared with those for Canada and the US, which took into account that the risk of allergic reactions is increased in patients who have an on-going need for regular plasma transfusions. When a model-based economic evaluation is performed, assumptions are made. It was assumed that patients only receive one transfusion, consisting of four plasma units, and that a patient cannot experience more than one transfusionrelated complication. Furthermore, the transfusion-related risks are based on the use of male plasma only, which reduces the TRALI risk associated with FFP transfusions
100,000
90,000
80,000
70,000
60,000
50,000
40,000
30,000
20,000
10,000
100 90 80 70 60 50 40 30 20 10 0 0
Probability cost-effective (per QALY; %)
of US$ 50,000 per QALY. In the scenario in which unknown emerging viruses were excluded, the benefit of using Octaplas™ versus FFP was negated as the risk of this complication was zero for both products. Since the costs for (treatment of) unknown emerging viruses were an important driver of the model, excluding these costs had a large impact on the total costs of FFP in the alternative scenario in which unknown emerging viruses were excluded. As a result, the use of Octaplas™ was no longer the dominant treatment option in this scenario. However since the incremental cost per QALY was well below the US$ 50,000 threshold, Octaplas™ could still be considered cost-effective if unknown emerging viruses are excluded from the analysis. The second scenario analysis using a historic (lower) price of FFP (from 2008) showed that Octaplas™ would have been cost-effective in comparison with FFP even if the latter had not undergone a price increase over the last 5 years. The model inputs were derived from the literature and are characterized by uncertainty. A PSA was performed to quantify the uncertainty in the results based on uncertainty in the source data. Octaplas™ was found to be the dominant treatment option over FFP in the base case analysis, but the upper limit of the 95% UI was US$ 15.764 per QALY, indicating uncertainty in these results. Nevertheless Octaplas™ is considered a cost-effective option versus FFP
Willingness to pay (US$) Fig. 3. The acceptability curve representing the probability that Octaplas™ is cost-effective in comparison with FFP for different values of willingness to pay for a QALY (base case).
Octaplas™
20.60041 (20.60036–20.60043) 20.600 (20.599–20.600) 525.86 (524.47–527.75) 520.00 5.86 771 (Dominant–18,964) 2925 (Dominant–145,987)
FFP
20.59427 (20.58544–20.59888) 20.576 (20.556−20.588) 507.93 (292.49−968.66) 189.84 318.09
Octaplas™
20.60041 (20.60036–20.60043) 20.600 (20.599–20.600) 525.86 (524.28–527.75) 520.00 5.86 16,159 (8682–32,705) 289,633 (141,066–771,709)
FFP
20.59971 (20.59915−20.60011) 20.587 (20.580–20.592) 323.17 (286.25−367.61) 231.64 91.53 Life years (95% UI) QALYs (95% UI) Overall costs, US$ (95% UI) Cost of product, US$ Cost due to complications, US$ Incremental cost per QALY (Octaplas™ vs. FFP) in US$/QALY Incremental cost per life year (Octaplas™ vs. FFP) in US$/Life year
Excluding unknown emerging viruses
Table 5 The cumulative life years, QALYs and costs per patient for the alternative scenarios.
Using historic price of FFP
E.L. Huisman et al./Transfusion and Apheresis Science 51 (2014) 17–24
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compared with normal FFP. Allowing for more transfusions in a lifetime would increase the difference between FFP and Octaplas™. This would be further magnified if individual patients could experience more than one transfusion related adverse event, or if both male and female plasma were used. In conclusion, Octaplas™ is expected to be the dominant treatment option versus FFP, due to the higher QALYs gained at lower cost. Despite the uncertainties associated with the outcomes, the probability of Octaplas™ being costeffective relative to FFP is over 99% at a WTP threshold of US$ 50,000 per QALY. Introduction of Octaplas™ into routine use may therefore be considered a cost-effective option for addressing the increasing healthcare burden of plasma transfusions in the US. Acknowledgments This study was funded by Octapharma AG. All authors participated in the design and conduct of the study, as well as drafting and revising the manuscript. References [1] Yim R. Frozen plasma for transfusion: a review. 2006. . [2] Solheim BG, Seghatchian J. Update on pathogen reduction technology for therapeutic plasma: an overview. Transfus Apher Sci 2006;35(1):83–90. [3] Boucher BA, Hannon TJ. Blood management: a primer for clinicians. Pharmacotherapy 2007;27(10):1394–411. [4] O’Shaughnessy DF, Atterbury C, Bolton MP, Murphy M, Thomas D, Yates S, et al. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 2004;126(1):11– 28. [5] Centers for Disease Control and Prevention. West nile virus transmission via organ transplantation and blood transfusion – Louisiana, 2008. 2009. . [6] Pandey S, Vyas GN Adverse effects of plasma transfusion. [7] Octapharma. OctaplasLG®. 2013. . [8] Council of Europe. Guide to the preparation, use and quality assurance of blood components. Recommendation No R (95) 15 on the preparation, use and quality assurance of blood components. 14th ed. Strasbourg: Council of Europe Press; 2008. [9] Food and Drug Administration – Department of Health and Human Services. FDA approval letter octaplas – January 17, 2013. 2013. . [10] Huisman EL, Van Eerd MC, Ouwens JN, De Peuter MA. Costeffectiveness and budget impact study of solvent/detergent (SD) treated plasma (octaplasLG(R)) versus fresh-frozen plasma (FFP) in any patient receiving transfusion in Canada. Transfus Apher Sci 2013. [11] Van Eerd MC, Ouwens JNM, De Peuter MA. Cost-effectiveness study comparing pharmaceutically licensed plasma for tranfusions (octaplasLG®) versus Fresh Frozen Plasma (FFP) in critically ill patients in the UK. Transfus Apher Sci 2010;43(3):251–9. [12] Division of Vital Statistics. United States life tables, 2008. 2013. . [13] Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the panel on cost-effectiveness in health and medicine. JAMA 1996;276(15):1253–8. [14] Merck Manual 2010–2013. 2013. . [15] Bureau of Labor Statistics. 2013. . [16] Department of Health & Human Services USA. The 2011 National Blood Collection and Utilization Survey Report. 2011. .
24
E.L. Huisman et al./Transfusion and Apheresis Science 51 (2014) 17–24
[17] Owens DK. Interpretation of cost-effectiveness analyses. J Gen Intern Med 1998;13(10):716–17. [18] Hirth RA, Chernew ME, Miller E, Fendrick AM, Weissert WG. Willingness to pay for a quality-adjusted life year: in search of a standard. Med Decis Making 2000;20(3):332–42. [19] Department of Health & Human Services USA. The 2009 National Blood Collection and Utilization Survey. 2009. . [20] Eder AF, Herron RM Jr, Strupp A, Dy B, White J, Notari EP, et al. Effective reduction of transfusion-related acute lung injury risk with male-predominant plasma strategy in the American Red Cross (2006–2008). Transfusion 2010;50(8):1732–42. [21] Eder AF, Herron R, Strupp A, Dy B, Notari EP, Chambers LA, et al. Transfusion-related acute lung injury surveillance (2003–2005) and the potential impact of the selective use of plasma from male donors in the American Red Cross. Transfusion 2007;47(4):599– 607. [22] Tabor E, Epstein JS. NAT screening of blood and plasma donations: evolution of technology and regulatory policy. Transfusion 2002;42(9):1230–7. [23] Stramer SL. Impact of NAT on serological screening of transfusiontransmitted agents. ISBT Sci Ser 2006;1(1):194–202. [24] Dodd RY, Notari EP, Stramer SL. Current prevalence and incidence of infectious disease markers and estimated window-period risk in the American Red Cross blood donor-ápopulation. Transfusion 2002;42(8):975–9. [25] Dodd RY. Emerging infections, transfusion safety, and epidemiology. N Engl J Med 2003;349(13):1205–6. [26] Wasley A, Kruszon-Moran D, Kuhnert W, Simard EP, Finelli L, McQuillan G, et al. The prevalence of hepatitis B virus infection in the United States in the era of vaccination. J Infect Dis 2010;202(2):192–201. [27] Cohen BJ, Buckley MM. The prevalence of antibody to human parvovirus B19 in England and Wales. J Med Microbiol 1988;25(2):151–3. [28] Svae TE, Neisser-Svae A, Bailey A, Reichl H, Biesert L, Schmidt T, et al. Prion safety of transfusion plasma and plasma-derivatives typically used for prophylactic treatment. Transfus Apher Sci 2008;39(1):59–67. [29] Vaara I, Nilsson CD. [SD plasma safer than fresh-frozen plasma. Comparative studies show advantages of industrially produced plasma]. Lakartidningen 2010;107(3):106–7. [30] Domen RE, Hoeltge GA. Allergic transfusion reactions. Arch Pathol Lab Med 2003;127(3):316–20. [31] Reutter JC, Sanders KF, Brecher ME, Jones HG, Bandarenko N. Incidence of allergic reactions with fresh frozen plasma or cryo-supernatant plasma in the treatment of thrombotic thrombocytopenic purpura. J Clin Apher 2001;16(3):134–8. [32] Paul-Ehrlich-Institut. Hamovigilanzdaten von 1997 bis 2008. 2012. . [33] Funk MB, Guenay S, Lohmann A, Henseler O, Heiden M, Hanschmann KMO, et al. Benefit of transfusion-related acute lung injury riskminimization measures ΓÇô German haemovigilance data (2006ΓÇô2010). Vox Sang 2011. [34] Kleinman S, Cameron C, Custer B, Busch M, Katz L, Kralj B, et al. Modeling the risk of an emerging pathogen entering the Canadian blood supply. Transfusion 2010;50(12):2592–606. [35] Angus DC, Musthafa AA, Clermont G, Griffin MF, Linde-Zwirble WT, Dremsizov TT, et al. Quality-adjusted survival in the first year after
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
the acute respiratory distress syndrome. Am J Respir Crit Care Med 2001;163(6):1389–94. Riedler GF, Haycox AR, Duggan AK, Dakin HA. Cost-effectiveness of solvent/detergent-treated fresh-frozen plasma. Vox Sang 2003;85(2):88–95. Cooke CR, Kahn JM, Watkins TR, Hudson LD, Rubenfeld GD. Costeffectiveness of implementing low-tidal volume ventilation in patients with acute lung injury. Chest 2009;136:79–88. Bauch CT, Anonychuk AM, Pham BZ, Gilca V, Duval B, Krahn MD. Cost-utility of universal hepatitis A vaccination in Canada. Vaccine 2007;25(51):8536–48. Centers for Disease Control and Prevention. Hepatitis A. In Epidemiology and prevention of vaccine-preventable diseases (pink book). 2013. . Eckman MH, Kaiser TE, Sherman KE. The cost-effectiveness of screening for chronic hepatitis B infection in the United States. Clin Infect Dis 2011;52(11):1294–306. Levy AR, Kowdley KV, Iloeje U, Tafesse E, Mukherjee J, Gish R, et al. The impact of chronic hepatitis B on quality of life: a multinational study of utilities from infected and uninfected persons. Value Health 2008;11(3):527–38. Liu S, Cipriano LE, Holodniy M, Goldhaber-Fiebert JD. Costeffectiveness analysis of risk-factor guided and birth-cohort screening for chronic hepatitis C infection in the United States. PLoS ONE 2013;8(3):e58975. Chong CA, Gulamhussein A, Heathcote EJ, Lilly L, Sherman M, Naglie G, et al. Health-state utilities and quality of life in hepatitis C patients. Am J Gastroenterol 2003;98(3):630–8. Wong JB, Bennett WG, Koff RS, Pauker SG. Pretreatment evaluation of chronic hepatitis C: risks, benefits, and costs. JAMA 1998;280(24):2088–93. Salomon JA, Weinstein MC, Hammitt JK, Goldie SJ. Cost-effectiveness of treatment for chronic hepatitis C infection in an evolving patient population. J Am Med Assoc 2003;290(2):228–37. Simpson KN, Roberts G, Hicks CB, Finnern HW. Cost-effectiveness of tipranavir in treatment-experienced HIV patients in the United States. HIV Clin Trials 2008;9(4):225–37. Gebo KA, Fleishman JA, Conviser R, Hellinger J, Hellinger FJ, Josephs JS, et al. Contemporary costs of HIV healthcare in the HAART era. AIDS 2010;24(17):2705–15. Centers for Disease Control and Prevention. Parvovirus B19 and Fifth Disease. 2013. . Annual Change in Medicaid Hospice Payment Rates. 2013 September 7. . Kacker S, Ness PM, Savage WJ, Frick KD, McCullough J, King KE, et al. The cost-effectiveness of platelet additive solution to prevent allergic transfusion reactions. Transfusion 2013. Hall MJ. NCHS data brief – inpatient care for septicemia or sepsis: a challenge for patients and hospitals. 2013. . Center for Disease Prevention and Control – West Nile Virus Treatment and Symptoms. 2013. . Pereira A. Cost-effectiveness of transfusing virus-inactivated plasma instead of standard plasma. Transfusion 1999;39(5):479–87.
