A Compelling Case for the Use of Perioperative Zymogen Protein C for Increased Patient Safety.

It is imperative to maintain normal blood flow to provide adequate oxygen supply to specific organs and cells, as well as for the removal of metabolic byproducts. Therefore, any situation that results in blood clotting can injure or kill living tissues. In this paper, we describe a case where a protein C deficient subject who would, by all medical indicators, be at 100 % risk of experiencing thrombophlebitis, deep vein thrombosis, and or lung emboli, is able to escape all pathologies by using perioperative zymogen protein C (ZPC). This protein C deficient patient has a long history of blood clotting, particularly from surgical procedures. The patient is 81 years old and first experienced clotting due to hernia surgery in 1964, when he was hospitalized for 16 days post-surgery with life threatening complications. It was later determined in 1980, after many episodes, that the patient had hereditary protein C deficiency at the 38 % level. In his hernia surgery, perioperative ZPC was used along with accepted anticoagulation procedures with no blood clots or other related side effects occurring. This procedure can greatly benefit protein C deficient patients, and could potentially find use for non-PC deficient patients in surgeries and a variety of other medical treatments. This particular case helps to validate the importance of ZPC in effecting safer surgery in high-risk patients. It also supports the mechanism of ZPC acting as an anticoagulant without causing bleeding. Most importantly, each clinical case study represents a unique combination of surgeon, hematologist, medical staff, and patient functioning as a coordinated team. In this case, smaller amounts of very expensive ZPC achieved safe and efficacious results, which is hugely important for future clinical applications when considering the production cost of ZPC. More studies must be done to establish minimum dosing while achieving safe and efficacious outcomes.

Drotrecogin alfa (activated)...a sad final fizzle to a roller-coaster party.

Following the failure of PROWESS-SHOCK to demonstrate efficacy, Eli Lilly and Company withdrew drotrecogin alfa (activated) from the worldwide market. Drotrecogin was initially approved after the original trial, PROWESS, was stopped early for overwhelming efficacy. These events prompt consideration of both the initial approval decision and the later decision to withdraw. It is regrettable that the initial decision was made largely on a single trial that was stopped early. However, the decision to approve was within the bounds of normal regulatory practice and was made by many approval bodies around the world. Furthermore, the overall withdrawal rate of approved drugs remains very low. The decision to withdraw was a voluntary decision by Eli Lilly and Company and likely reflected key business considerations. Drotrecogin does have important biologic effects, and it is probable that we do not know how best to select patients who would benefit. Overall, there may still be a small advantage to drotrecogin alfa, even used non-selectively, but the costs of determining such an effect with adequate certainty are likely prohibitive, and the point is now moot. In the future, we should consider ways to make clinical trials easier and quicker so that more information can be available in a timely manner when considering regulatory approval. At the same time, more sophisticated selection of patients seems key if we are to most wisely test agents designed to manipulate the septic host response.

Stakeholder involvement in expensive drug recommendation decisions: an international perspective.

OBJECTIVES: To describe stakeholder involvement in the priority setting and appeals processes across five drug reimbursement recommendation committees. METHODS: We conducted qualitative case studies of how five independent drug advisory committees from Canada, Israel, England and Wales, Australia, and the USA made funding decisions for six expensive drugs. Interviews with 48 informants were conducted with committee members, patient groups, and industry representatives. RESULTS: Different stakeholders were allowed, in varying degrees, to participate in the formal mechanisms for revisions and appeals of decisions. Participants identified a number of stakeholder groups who were already involved in the process, as well as stakeholders whom they believed should be included in the decision-making process. CONCLUSIONS: A central component of a legitimate and fair priority setting process is to make priority setting explicit and to involve both pertinent values and stakeholders in decision-making. Study participants believed that the involvement of multiple stakeholder groups within the deliberative and appeals/revisions processes would contribute to a fair and legitimate drug reimbursement process.

Is Drotrecogin alfa (activated) for adults with severe sepsis, cost-effective in routine clinical practice?

INTRODUCTION: Previous cost-effectiveness analyses (CEA) reported that Drotrecogin alfa (DrotAA) is cost-effective based on a Phase III clinical trial (PROWESS). There is little evidence on whether DrotAA is cost-effective in routine clinical practice. We assessed whether DrotAA is cost-effective in routine practice for adult patients with severe sepsis and multiple organ systems failing. METHODS: This CEA used data from a prospective cohort study that compared DrotAA versus no DrotAA (control) for severe sepsis patients with multiple organ systems failing admitted to critical care units in England, Wales, and Northern Ireland. The cohort study used case-mix and mortality data from a national audit, linked with a separate audit of DrotAA infusions. Re-admissions to critical care and corresponding mortality were recorded for four years. Patients receiving DrotAA (n = 1,076) were matched to controls (n = 1,650) with a propensity score (Pscore), and Genetic Matching (GenMatch). The CEA projected long-term survival to report lifetime incremental costs per quality-adjusted life year (QALY) overall, and for subgroups with two or three to five organ systems failing at baseline. RESULTS: The incremental costs per QALY for DrotAA were £30,000 overall, and £16,000 for the subgroups with three to five organ systems failing. For patients with two organ systems failing, DrotAA resulted in an average loss of one QALY at an incremental cost of £15,000. When the subgroup with two organ systems was restricted to patients receiving DrotAA within 24 hours, DrotAA led to a gain of 1.2 QALYs at a cost per QALY of £11,000. The results were robust to other assumptions including the approach taken to projecting long-term outcomes. CONCLUSIONS: DrotAA is cost-effective in routine practice for severe sepsis patients with three to five organ systems failing. For patients with two organ systems failing, this study could not provide unequivocal evidence on the cost-effectiveness of DrotAA.

Treatment of the critically ill patient with protein C: is it worth the cost?

INTRODUCTION: We have shown that low protein C levels predict poor survival up to five years in a general intensive care unit patient material and hypothesize that treatment with protein C is beneficial. The objectives were to calculate costs of protein C treatment, at best-case scenario, per statistical life saved. MATERIALS AND METHODS: Ninety-two patients with deranged global haemostatic tests admitted to the mixed surgical medical intensive care unit, Malmö University Hospital. We hypothesized that increasing protein C levels in patients with low levels would enhance survival to the same rate as a cohort with higher protein C. Number of statistical lives saved were estimated using survival analysis. Costs per life saved at 30days were calculated. RESULTS: Total costs per life saved in 2007 prices (upper limit of 95% CI) were calculated at euro 50,200 (recombinant activated protein C, drotrecogin alfa (activated), Xigris) and euro 46,000 (zymogen protein C, Ceprotin), which may be compared to the value of a statistical life (euro 937,000). CONCLUSIONS: Our theoretical model of converting a low protein C group to a higher protein C group by treating with activated protein C or the protein zymogen showed no major difference between the treatments in terms of costs, and that costs are lower than the value of a statistical life. Although our study has several caveats the results support the PROWESS study, in that patients with a very severe disease, having low protein C levels, may benefit from protein C treatment in a cost effective way.

Pharmacist intervention in activated protein C therapy for severe sepsis: influence on health and economic outcomes.

OBJECTIVE: To assess the health and cost outcomes of pharmacist intervention versus non-intervention in activated protein C (drotrecogin alpha) therapy for patients with severe sepsis. METHOD: This is a retrospective study. We reviewed the medical records of patients aged 18 years and older who were admitted to our hospital for severe sepsis from January 1, 2003 to December 31, 2007. Only patients who are prescribed activated protein C for the treatment of severe sepsis according to the reimbursement criteria can be reimbursed by the Taiwan Bureau of National Health Insurance (BNHI). Our hospital stipulated that the criteria check list must be evaluated by a clinical pharmacist and the prescribing physician as to whether the patient is eligible to receive activated protein C. To assess the influence of pharmacist intervention on outcomes, we divided eligible patients into two groups, pharmacist-intervention group (Group A; n = 19) and non-pharmacist intervention group (Group B; n = 19). Both groups received a 96-h intravenous infusion of activated protein C at 24 microg/kg/h. We defined evident severe sepsis as concurrent antibiotic plus ventilator and/or vasopressor use. We compared group characteristics, 28-day in-hospital mortality, length of stay and direct medical costs between the two groups. One-way ANOVA was used for analysis. RESULTS: 50% of patients in each group met the reimbursement criteria of the BNHI. Activated protein C therapy was initiated within 1.37 +/- 0.4 days and 7.21 +/- 7.8 days of admission to the ICU in Group A and Group B, respectively (p < 0.01). All of the patients in Group A (19/19) and 42.1% of the patients in Group B (8/19) received activated protein C within 12 - 48 h of admission to the Intensive care unit (ICU) (p < 0.01). 28-day mortality was lower for Group A than for Group B (26.7% and 43.8%, respectively). The length of stay in the ICU for patients in Group A was shorter than that in Group B (14.1 +/- 7.7 vs. 19.7 +/- 11.1, respectively; p < 0.079). Total direct medical costs for survivors in Group A were less than those in Group B (US$ 20,632.3 vs. US$ 24,785.8, respectively; p < 0.05). CONCLUSIONS: Pharmacist intervention in prescribing activated protein C for patients with severe sepsis might reduce direct medical costs and promote earlier initiation of therapy. The potential impact of pharmacist intervention on the timing of activated protein C therapy and the direct medical costs of treatment warrant further study.

Drotrecogin alfa's impact on intensive care workload in real life practice: a propensity score approach.

OBJECTIVES: To estimate the impact of drotrecogin alfa (DA) on intensive care workload in an observational study while illustrating the use of propensity score (PS) matching to control for recruitment bias. METHODS: PREMISS is a prospective, multicenter pre-post study. Its goal was to evaluate DA in the treatment of severe sepsis with multiple organ failure. Inclusions took place before (control patients) and after (DA-treated patients) the drug's market authorization. Workload was measured in euros using the French classification of medical procedures. It was compared between the groups via random effects gamma regression using two techniques: 1) regression adjusting for the patients' initial characteristics on the whole population; and 2) PS matching. A structural equation model was used to explore the pathways leading to a workload increase. RESULTS: Drotrecogin alfa is estimated to increase intensive care unit (ICU) workload by 20% (P = 0.045) according to the multivariate model and 34% (P = 0.002) according to the PS-matched one. In the structural equation model fitted, only DA's direct effect on the occurrence of bleeding events reaches significance (P = 0.024). CONCLUSIONS: We found a significant effect of DA on ICU workload with both standard methods of adjustment and PS matching. This effect appears to be mainly due to DA's effect on bleeding events. The analysis illustrated the usefulness of PS methods in the analysis of observational data, as it leads to conclusions similar to the traditional multivariate regression approaches while avoiding making too many adjustments, allowing focusing on the treatment effect.

Activated protein C: cost-effective or costly?

The authors offer a commentary on the study by Dhainaut et al. on the cost-effectiveness of activated protein C in severe sepsis. Using data from "real world" conditions, the results of this economic evaluation are consistent with previous analyses, and highlight the need for "real world" investigations of new health technologies in critical care.

Cost-effectiveness of activated protein C in real-life clinical practice.

BACKGROUND: Recombinant human activated protein C (rhAPC) has been reported to be cost-effective in severely ill septic patients in studies using data from a pivotal randomized trial. We evaluated the cost-effectiveness of rhAPC in patients with severe sepsis and multiple organ failure in real-life intensive care practice. METHODS: We conducted a prospective observational study involving adult patients recruited before and after licensure of rhAPC in France. Inclusion criteria were applied according to the label approved in Europe. The expected recruitment bias was controlled by building a sample of patients matched for propensity score. Complete hospitalization costs were quantified using a regression equation involving intensive care units variables. rhAPC acquisition costs were added, assuming that all costs associated with rhAPC were already included in the equation. Cost comparisons were conducted using the nonparametric bootstrap method. Cost-effectiveness quadrants and acceptability curves were used to assess uncertainty of the cost-effectiveness ratio. RESULTS: In the initial cohort (n = 1096), post-license patients were younger, had less co-morbid conditions and had failure of more organs than did pre-license patients (for all: P < 0.0001). In the matched sample (n = 840) the mean age was 62.4 +/- 14.9 years, Simplified Acute Physiology Score II was 56.7 +/- 18.5, and the number of organ failures was 3.20 +/- 0.83. When rhAPC was used, 28-day mortality tended to be reduced (34.1% post-license versus 37.4% pre-license, P = 0.34), bleeding events were more frequent (21.7% versus 13.6%, P = 0.002) and hospital costs were higher (47,870 euros versus 36,717 euros, P < 0.05). The incremental cost-effectiveness ratios gained were as follows: 20,278 euros per life-year gained and 33,797 euros per quality-adjusted life-year gained. There was a 74.5% probability that rhAPC would be cost-effective if there were willingness to pay 50,000 euros per life-year gained. The probability was 64.3% if there were willingness to pay 50,000 euros per quality-adjusted life-year gained. CONCLUSION: This study, conducted in matched patient populations, demonstrated that in real-life clinical practice the probability that rhAPC will be cost-effective if one is willing to pay 50,000 euros per life-year gained is 74.5%.

Simplified pharmacoeconomics of critical care and severe sepsis.

Understanding pharmacoeconomic evaluation can empower clinicians to be stronger decision makers. However, cost-effectiveness analyses (CEAs) in critical care are sometimes not easy to understand and often not placed in context with other interventions. The purpose of this article is to clarify and simplify the CEA process using examples from critical care and severe sepsis. First discussed is cost-effectiveness as a framework for clinical decision making and how it compares to other types of economic evaluations. Then important considerations when conducting or reviewing CEAs are explored, such as perspective, discounting, sensitivity analysis, and grading of CEAs, as well as shortcomings and resistance to using CEAs. Next, applications of CEA in critical care and severe sepsis are reviewed. Included is the Food and Drug Administration-approved drug for severe sepsis, drotrecogin alfa (activated), as an example of a recently new critical care intervention that resulted in significant interest in understanding cost-effectiveness. Finally, CEAs of other medical and nonmedical interventions are placed in context with CEAs from critical care. Understanding pharmacoeconomic evaluation can empower clinicians to be stronger decision makers. CEAs provide decision makers a quantitative measure of the value of therapeutic options that can guide clinicians toward balancing the cost burdens of therapy with their profound effects and choosing between options that compete for funding.

Practical aspects of treatment with drotrecogin alfa (activated).

In November 2001, drotrecogin alfa (activated) was approved by the US Food and Drug Administration; in August 2002 it was approved by the European Medicines Agency. Since the approval of drotrecogin alfa (activated), however, critical care physicians have been faced with several challenges, namely its costs, selection of patients who are more likely to benefit from it, and the decision regarding when to start drotrecogin alfa (activated) treatment. There are also operational issues such as how to manage the infusion to deliver an effective treatment while minimizing the risk for bleeding, particularly in patients with deranged clotting, at around the time of surgery or during renal replacement therapy. While addressing these issues, this review remains practical but evidence based as much as possible.

Management of sepsis in the critically ill patient: key aspects.

Severe sepsis is a major cause of morbidity and mortality in the critically ill patient. Management involves identification and treatment of the underlying causative infection, with antimicrobial agents and surgery where necessary, haemodynamic resuscitation with fluids and vasoactive agents, steroids (for septic shock) and immunomodulation with drotrecogin-alpha (activated), where not contraindicated. Every effort must be made to identify sepsis early so as to optimise the patient's chances of a good outcome.

Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis with multiple organ failure.

OBJECTIVES: The aim of this study was to estimate the expected cost and clinical benefits associated with the use of drotrecogin alfa (activated) (Xigris; Eli Lilly and Company; Indianapolis, IN) in the French hospital setting. METHODS: The recombinant human activated PROtein C Worldwide Evaluation in Severe Sepsis (PROWESS) study results (1271 patients with multiple organ failure) were adjusted to 9,948 hospital stays from a database of Parisian area intensive-care units (ICUs)-the CubRea (Intensive Care Database User Group) database. The analysis features a decision tree with a probabilistic sensitivity analysis. RESULTS: The cost per life year gained (LYG) of drotrecogin treatment for severe sepsis with multiple organ failure (European indication) was estimated to be dollars 11,812. At the hospital level, the drug is expected to induce an additional cost of dollars 7545 per treated patient. The incremental cost-effectiveness ratio ranges from dollars 7873 per LYG for patients receiving three organ supports during ICU stay to dollars 17,704 per LYG for patients receiving less than two organ supports. CONCLUSIONS: Drotrecogin alfa (activated) is cost-effective in the treatment of severe sepsis with multiple organ failure when added to best standard care. The cost-effectiveness of the drug increases with baseline disease severity, but it remains cost-effective for all patients when used in compliance with the European approved indication.

Evaluation of the cost-effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis in the United Kingdom.

OBJECTIVES: The aim of this study was to assess the cost-effectiveness of drotrecogin alfa (activated) compared with best supportive care in a UK cohort of adult intensive-care patients with severe sepsis. METHODS: A systematic review of evidence on the clinical- and cost-effectiveness of drotrecogin alfa (activated) was undertaken, and a decision-analytic model was developed to estimate the cost-effectiveness of treatment in the United Kingdom. Trial data from the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study have been synthesized with other data, including UK data on severe sepsis, to estimate the costs and consequences of treatment over time. RESULTS: For patients with severe sepsis and multiple organ dysfunction, the estimates of cost per life year and cost per quality-adjusted life year (QALY) are pounds 4931 and pounds 8228, respectively. For patients with severe sepsis alone, the cost per life-year and cost per QALY are pouhds 5495 and pounds 9161, respectively. CONCLUSIONS: Whereas the therapeutic cost for drotrecogin alfa (activated) appears high (at around pounds 5000 per patient) and the potential impact on the provider budget is considerable, drotrecogin alfa (activated) is clinically effective, represents a cost-effective use of resources, and is a significant advance in the treatment of severe sepsis in patients requiring intensive care.

Estimate of the number of patients eligible for treatment with drotrecogin alfa (activated) based on differing international indications: post-hoc analysis of an inception cohort study in Australia and New Zealand.

We aimed to estimate the potential number of patients eligible for treatment with drotrecogin alfa (activated) when applying different international criteria. The study was a post-hoc analysis of inception cohort study of 691 patients with severe sepsis during 5878 consecutive intensive care unit admission episodes in 23 closed multi-disciplinary ICUs of 21 hospitals (16 tertiary and 5 university-affiliated) in Australia and New Zealand. Outcomes assessed were presence of contraindications to treatment with drotrecogin alfa (activated), an admission APACHE II score of 25 or greater and dysfunction of two or more organs. During 5878 consecutive intensive care admission episodes, 691 patients had severe sepsis, 553 (80.0%, 95% CI 77.0-83.0%) had no relative or absolute contraindication, 64 (9.3%, 7.1-11.4%) had a relative contraindication and 74 (10.7%, 8.4-13.0%) had an absolute contraindication. Two hundred and six patients (3.5%, 3.0-4.0%) had an APACHE II score of 25 or greater, 452 (7.7%, 7.0-8.4%) had dysfunction of two or more organs, 469 (8.0%, 7.3-8.7%) had either dysfunction of two or more organs or an APACHE II score of 25 or greater Relatively few patients had an absolute contraindication to treatment with drotrecogin alfa (activated). Selection based on the APACHE II score results in fewer eligible patients than selection based on multiple organ dysfunction. Depending on the selection criteria used, for every hundred admissions to intensive care, between 3.5 and 8.0 of patients may be eligible for treatment with drotrecogin alfa (activated).