Adoption and de-adoption of drotrecogin alfa for severe sepsis in the United States.

PURPOSE: Drotrecogin alfa was a landmark drug for treatment of severe sepsis, yet little is known about how it was adopted and de-adopted during its 10-year period of availability. METHODS: We used hospitalization data on fee-for-service Medicare beneficiaries from 2002 to 2011 to characterize trends in the use of drotrecogin alfa in the United States. RESULTS: Drotrecogin alfa use peaked at 5.87 per 1000 severe sepsis hospitalizations in 2003 and then steadily declined to 0.94 administrations per 1000 severe sepsis hospitalizations in 2010. Large teaching hospitals were more likely to use drotrecogin alfa than small, nonteaching hospitals. The addition of "add-on payments" to hospitals for using drotrecogin alfa in 2002 was associated with significantly increased use (P < .0001), and the withdrawal of those payments in 2004 was associated significantly decreased use (P < .0001). Neither the publication of international sepsis guidelines with favorable drotrecogin alfa recommendations (in 2004 and 2008) nor the publication of a clinical trial focused on drotrecogin alfa (in 2005) were associated with consistent changes use (P > .05). CONCLUSIONS: Drotrecogin alfa use declined over time, with marked changes in use associated with drug-specific financial incentives but not the publication of clinical practice guidelines or clinical trials.

[From the "note limitative" to the "registri AIFA"]. / Dalle note limitative ai registri AIFA.

In Italy, over the past 10 years, we have had a proliferation of registers associated with the reimbursement of drugs by the National Health Service. The regulatory path that made them grow comes from the so-called "note limitative" and treatment plans associated with the use of certain drugs. From these experiences different types of registries have been created that collect, at the time of prescription, information about the safety and appropriateness of use of medication where a benefit-risk profile in the general population is still not well defined. The critical analysis of some of these experiences can present positive and negative aspects associated with a regulatory reality now used in clinical practice nationwide.

Evaluating treatment effectiveness in patient subgroups: a comparison of propensity score methods with an automated matching approach.

Propensity score (Pscore) matching and inverse probability of treatment weighting (IPTW) can remove bias due to observed confounders, if the Pscore is correctly specified. Genetic Matching (GenMatch) matches on the Pscore and individual covariates using an automated search algorithm to balance covariates. This paper compares common ways of implementing Pscore matching and IPTW, with Genmatch for balancing time-constant baseline covariates}. The methods are considered when estimates of treatment effectiveness are required for patient subgroups, and the treatment allocation process differs by subgroup. We apply these methods in a prospective cohort study that estimates the effectiveness of Drotrecogin alfa activated, for subgroups of patients with severe sepsis. In a simulation study we compare the methods when the Pscore is correctly specified, and then misspecified by ignoring the subgroup-specific treatment allocation. The simulations also consider poor overlap in baseline covariates, and different sample sizes. In the case study, GenMatch reports better covariate balance than IPTW or Pscore matching. In the simulations with correctly specified Pscores, good overlap and reasonable sample sizes, all methods report minimal bias. When the Pscore is misspecified, GenMatch reports the least imbalance and bias. With small sample sizes, IPTW is the most efficient approach, but all methods report relatively high bias of treatment effects. This study shows that overall GenMatch achieves the best covariate balance for each subgroup, and is more robust to Pscore misspecification than common alternative Pscore approaches.

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.

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.

Controversies in the treatment of sepsis.

Sepsis is a common illness of intensive care unit patients that carries a high morbidity, mortality, and increases hospital cost. Although mortality from sepsis remains high when compared with other critical illnesses, it has declined over the last few decades due to several adjunctive therapies and focused care programs or guidelines. Many interventions, such as early appropriate antibiotic therapy and lung protective, low tidal volume ventilation are commonplace and carry little controversy in their benefit. However, other therapies still have an unclear benefit and remain controversial. This article discusses the controversial roles of intensive insulin therapy, corticosteroids, and activated protein C in the treatment of sepsis.

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.

Early drotrecogin alpha (activated) administration in severe sepsis is associated with lower mortality: a retrospective analysis of the Canadian ENHANCE cohort.

INTRODUCTION: Early multimodal treatment of severe sepsis, including the use of drotrecogin alfa (activated) (DrotAA) when indicated, is considered essential for optimum outcome. However, predicting which infected patients will progress to severe sepsis and the need for aggressive intervention continues to be problematic. We therefore wished to explore whether there were any potential early markers that might predict improved survival in response to early use of DrotAA in patients with severe sepsis. In particular, in the dynamic setting of severe sepsis, we postulated that changes in markers reflecting evolving rather than baseline clinical status might guide therapy. METHODS: Data on a cohort of 305 Canadian patients from the open label ENHANCE trial of DrotAA in severe sepsis was retrospectively analyzed to search for potential clinical predictors of outcome in severe sepsis. Patients received a 96-hour infusion of DrotAA and were followed for 28 days. The association between time to treatment and mortality within subgroups defined by dynamic changes in various potential markers was explored. RESULTS: Mortality at 28 days was 22.6% and the variables of age, time to treatment, and early changes in serum creatinine and platelet count were identified by logistic regression as independent predictors of mortality. Across all age ranges, 28-day mortality was lower when DrotAA was administered within 24 hours of first sepsis-induced organ dysfunction compared to administration after 24 hours for both subgroups of patients defined by changes in platelet count and creatinine within the first day. CONCLUSIONS: These findings suggest that when indicated, treatment with DrotAA should be initiated as soon as possible, regardless of age. TRIAL REGISTRATION: Previous trial registration number: NCT00568893.

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.

Patient-specific decision modeling to guide the use of drotrecogin alpha (activated) in patients with severe sepsis.

PURPOSE: The expected benefit of treating severe sepsis with drotrecogin alpha (activated) for an individual patient may depend upon several clinical factors including disease severity. Our objective was to create a decision support tool incorporating patient-specific inputs to estimate the balance between treatment risks and benefits for individual patients with severe sepsis. MATERIALS AND METHODS: Logistic regression models were developed to calculate patient-specific mortality risk with and without treatment, which were then used as inputs into a 75-state Markov model. Patient-specific inputs included patient age, sex, and 12 readily available clinical characteristics. RESULTS: The expected benefit from drotrecogin alpha (activated) treatment was most dependent upon the underlying disease severity. For example, for a 56-year-old white man with severe sepsis and a 28-day mortality risk of 29%, the model predicted a treatment-related gain of 1.2 quality-adjusted life years (17.3 vs 16.1). Probabilistic sensitivity analyses demonstrated that this patient would benefit from therapy 85% of the time. CONCLUSIONS: A customizable decision model using patient-specific inputs can be used to inform the treatment decision when considering the use of drotrecogin alpha (activated) therapy by weighing the risks vs the benefits of therapy in the treatment of severe sepsis.

Design, conduct, analysis and reporting of a multi-national placebo-controlled trial of activated protein C for persistent septic shock.

The role of drotrecogin alfa (activated) (DAA) in severe sepsis remains controversial and clinicians are unsure whether or not to treat their patients with DAA. In response to a request from the European Medicines Agency, Eli Lilly will sponsor a new placebo-controlled trial and history suggests the results will be subject to great scrutiny. An academic steering committee will oversee the conduct of the study and will write the study manuscripts. The steering committee intends that the study will be conducted with the maximum possible transparency; this includes publication of the study protocol and a memorandum of understanding which delineates the role of the sponsor. The trial has the potential to provide clinicians with valuable data but patients will only benefit if clinicians have confidence in the conduct, analysis and reporting of the trial. This special article describes the process by which the trial was developed, major decisions regarding trial design, and plans for independent analysis, interpretation and reporting of the data.

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.