Cost-Effectiveness Uncertainty Analysis Methods: A Comparison of One-Way Sensitivity, Analysis of Covariance, and Expected Value of Partial Perfect Information.

OBJECTIVES: To compare model input influence on incremental net monetary benefit (INMB) across 3 uncertainty methods: 1) 1-way sensitivity analysis; 2) probabilistic analysis of covariance (ANCOVA); and 3) expected value of partial perfect information (EVPPI). METHODS: In a preliminary model, we used a published cost-effectiveness model and assumed £20,000 per quality-adjusted life-year (QALY) willingness-to-pay (Case 1: lower decision uncertainty) and £8000/QALY willingness-to-pay (Case 2: higher decision uncertainty). We conducted 1-way sensitivity, ANCOVA (10,000 Monte Carlo draws), and EVPPI for each model input (1000 inner and 1000 outer draws). We ranked inputs based on influence of INMB and compared input ranks across methods within case using Spearman's rank correlation. We replicated this approach in 3 follow-up models: an additional linear model, a less linear model with uncorrelated inputs, and a less linear model with correlated inputs. RESULTS: In the preliminary model, lower and higher decision uncertainty cases had the same top 3 influential parameters across uncertainty methods. The 2 most influential inputs contributed 78% and 49% of variation in outcome based on ANCOVA for lower decision uncertainty and higher decision uncertainty cases, respectively. In the follow-up models, input rank order correlations were higher across uncertainty methods in the linear model compared with both of the less linear models. CONCLUSIONS: Evidence across models suggests influential input rank agreement between 1-way and more advanced uncertainty analyses for relatively linear models with uncorrelated parameters but less agreement for less linear models. Although each method provides unique information, the additional resources needed to generate and communicate advanced analyses should be weighed, especially when outcome decision uncertainty is low. For less linear models or those with correlated inputs, performing and reporting deterministic and probabilistic uncertainty analyses appear prudent and conservative.

The validity of dependence as a health outcome measure in Alzheimer's disease.

BACKGROUND: Relating to Alzheimer's disease (AD), dependence has been defined as the increased need for assistance due to deterioration in cognition, physical functioning, and behavior. Our objective was to evaluate the association between dependence and measures of functional impairment. METHODS: Data were compiled by the National Alzheimer's Coordinating Center. We used multinomial logistic regression to estimate the association between dependence and cognition, physical functioning, and behavior. RESULTS: The independent association with dependence was positive. Dependence was most strongly associated with physical functioning. A secondary analysis suggested a strong association of dependence with multiple impairments, as measured by the interaction terms, in more severe patients. CONCLUSIONS: We find that dependence is simultaneously associated with physical functioning, cognition, and behavior, which support the construct validity of dependence. Dependence might be a more simple measure to explain the multifaceted disease progression of AD and convey the increasing need for care.

Measuring Alzheimer disease progression with transition probabilities: estimates from NACC-UDS.

OBJECTIVES: Estimate the probabilities, for Alzheimer's disease (AD) patients, of transitioning between stages of disease severity (mild, moderate, severe, dead) and care settings (community, institutional). METHODS: Data were compiled by the National Alzheimer Coordinating Center. The main analyses were limited to 3,852 patients who were 50 years old, diagnosed with possible/probable AD and had at least two center visits. A multinomial logistic model accounting for patient and center level correlation was used to calculate transition probabilities between stages of the Clinical Dementia Rating (CDR). Separately we calculated the probabilities of being institutionalized based on CDR stage. Both analyses controlled for baseline age, time between visits, sex, marital status, whether white, whether Hispanic and number of years of education. RESULTS: The annual probabilities of dying for patients in mild, moderate and severe health states were 5.5%, 21.5% and 48.0%, respectively, while the annual probabilities for institutionalization were 1.2%, 3.4% and 6.6%, respectively. The majority of mild and moderate patients remain in the same health state after one year, 77.4% and 50.1% respectively. Progressing patients are most likely to transition one stage, but 1.3% of mild patients become severe in one year. Some patients revert to lower severity stages, 7% from moderate to mild. CONCLUSIONS: Transition probabilities to higher CDR stages and to institutionalization are lower than those published previously, but the probability of death is higher. These results are useful for understanding AD progression and can be used in simulation models to evaluate costs and compare new treatments or policies.

Review and meta-analysis of biomarkers and diagnostic imaging in Alzheimer's disease.

Mild Alzheimer's disease (AD) is often difficult to differentiate from mild cognitive impairment (MCI) or non-AD dementias. A multitude of diagnostic biomarkers and advanced imaging strategies have been developed to aid in the diagnosis and management of AD. We sought to review and analyze the published evidence on key test characteristics of major diagnostic strategies to formulate best estimates of sensitivity (SN) and specificity (SP). A systematic review was undertaken to locate and abstract all studies of biomarkers or diagnostic imaging for AD published in English from January 1990 to March 2010 that provided estimates of SN and SP. Meta-analysis was performed using a bivariate mixed-effects binary regression model. We calculated -SN, SP, and area under the receiver operating curves (AUROC), with confidence and prediction contours. Of 1,840 unique studies identified, 119 presented primary data sufficient for analysis. SN and SP were calculated against non-demented controls, non-AD dementias with and without MCI, if available. Compared to non-demented controls, FDG-PET demonstrated the highest AUROC (0.96), with 90% SN (95%CI 84% to 94%), and 89% SP (95% CI 81% to 94%). FDG-PET also was most accurate in discriminating AD from demented controls (including MCI) with AUROC 0.91, and 92% SN (95%CI 84% to 96%) and 78% SP (95% CI 69% to 85%). For discrimination of AD from non-AD dementias (excluding MCI), CSF Ptau, and SPECT produced identical AUROC (0.86). Diagnostic strategies for AD show wide variation in test characteristics and some show promise for use in clinical practice.

CDR state transition probabilities in Alzheimer's disease with and without cholinesterase inhibitor intervention in an observational cohort.

Cholinesterase inhibitors and memantine are medications used in the treatment of Alzheimer's disease (AD). These agents have been shown to reduce the rate of AD progression in randomized trials. The objective of this study is to evaluate the association between treatment with cholinesterase inhibitors or memantine and the probability of transitioning to a more severe Clinical Dementia Rating (CDR) state. Analysis was limited to possible or probable AD patients from NACC-UDS with three or more observations, baseline CDR score of 0.5 or 1, and without reported use AD drugs at enrollment. Use of an AD drug at any observation after baseline was classified as treatment. Odds of CDR stage were calculated by multinomial logistic regression controlling for baseline age, baseline MMSE score, education, marital status, race, gender, place of residence, and time since last measure. The resulting coefficients from logistic regression were used to calculate transitional probabilities. A total of 1,114 patients were included. No differences were observed in the probability of transitioning to more severe CDR states based on treatment, but treated patients had lower odds of death, OR 0.49 (95% CI 0.31 to 0.79) compared to untreated. Ultimately, this study failed to detect a difference in the probability of progressing to a more severe AD state as a result of treatment in an observational cohort of AD patients, but is limited by non-randomized treatment selection and small dataset. The NACC-UDS dataset is ongoing and this analysis may be improved if repeated when more data is available.

Dependence as a unifying construct in defining Alzheimer's disease severity.

This article reviews measures of Alzheimer's disease (AD) progression in relation to patient dependence and offers a unifying conceptual framework for dependence in AD. Clinicians typically characterize AD by symptomatic impairments in three domains: cognition, function, and behavior. From a patient's perspective, changes in these domains, individually and in concert, ultimately lead to increased dependence and loss of autonomy. Examples of dependence in AD range from a need for reminders (early AD) to requiring safety supervision and assistance with basic functions (late AD). Published literature has focused on the clinical domains as somewhat separate constructs and has given limited attention to the concept of patient dependence as a descriptor of AD progression. This article presents the concept of dependence on others for care needs as a potential method for translating the effect of changes in cognition, function, and behavior into a more holistic, transparent description of AD progression.

Does the funding source influence the results in economic evaluations? A case study in bisphosphonates for the treatment of osteoporosis.

Research sponsored by the pharmaceutical industry is often assumed to be more likely to report favourable cost-effectiveness results. To determine whether there was a relationship between the source of funding and the reporting of positive results. We conducted a systematic review of the literature to identify economic evaluations of bisphosphonates for the treatment of osteoporosis. We extracted the source of funding, region of study, the journal name and impact factor, and all reported incremental cost-effectiveness ratios (ICERs). We identified which ICERs were under the thresholds of $US20 000, $US50 000 and $US100 000 per QALY. A quality score between 0 and 7 was also given to each of the studies. We used generalized estimating equations for the analysis. The systematic review yielded 532 potential abstracts; 17 of these met our final eligibility criteria. Ten studies (59%) were funded by non-industry sources. A total of 571 ICERs were analysed. There was no significant difference between the number of industry- and non-industry-funded studies reporting ICERs below the thresholds of $US20 000 and $US50 000. However, industry-sponsored studies were more likely to report ICERs below $US100 000 (odds ratio = 4.69, 95% CI 1.77, 12.43). Studies of higher methodological quality (scoring >4.5 of 7) were less likely to report ICERs below $US20 000 and $US50 000 than studies of lower methodological quality (scores <4). Methodological quality was not significantly different between studies reporting ICERs under $US100 000. In this relatively small sample of studies of bisphosphonates, the funding source (industry vs non-industry) did not seem to significantly affect the reporting of ICERs below the $US20 000 and $US50 000 thresholds. We hypothesize that methodological quality might be a more significant factor than the source of funding in differentiating which studies are likely to report favourable ICERs, with the higher-quality studies significantly less likely to report ICERs below $US20 000 and $US50 000 per QALY. Further research should explore this finding.

The costs and consequences of omalizumab in uncontrolled asthma from a USA payer perspective.

BACKGROUND: Omalizumab, an anti-immunoglobulin E antibody, reduces exacerbations and symptoms in uncontrolled allergic asthma. The study objective was to estimate the costs and consequences of omalizumab compared to usual care from a US payer perspective. METHODS: We estimated payer costs, quality-adjusted survival (QALYs), and the incremental cost-effectiveness ratio (ICER) of omalizumab compared to usual care using a state-transition simulation model that included sensitivity analyses. Every 2 weeks, patients could transition between chronic asthma and exacerbation health states. The best available evidence informed the clinical and cost input estimates. Five years of omalizumab treatment followed by usual care was assumed to estimate a lifetime horizon. Omalizumab responders (60.5% of treated) were modeled as a separate scenario where nonresponders reverted back to usual care after 16 weeks of active treatment. RESULTS: The mean lifetime discounted costs and QALYs were $83,400 and 13.87 for usual care and $174,500 and 14.19 for omalizumab plus usual care resulting in $287 200/QALY (95% interval: $219,300, $557, 900). The ICER was $172 300/QALY when comparing omalizumab to usual care in the responder scenario. One-way sensitivity analyses indicated that the results were sensitive to the difference in treatment-specific utilities for the chronic state, exacerbation-associated mortality, omalizumab price, exacerbation rates, and response definition. CONCLUSIONS: The results suggest that adding omalizumab to usual care improves QALYs at an increase in direct medical costs. The cost-effectiveness of omalizumab is similar to other chronic disease biologics. The value increases when omalizumab response is used to guide long-term treatment.

Avian encephalomyelitis virus in reared pheasants: a case study.

An outbreak of neurological disease occurred in pheasant chicks on a game farm in 2007. The disease was first seen in the 10th hatching of chicks on the farm. Affected chicks showed trembling and incoordination from the time of hatching, and subsequently blindness and cataract formation was seen in some of the affected chicks at 3 weeks of age. The peak mortality and culling figure was 21.0% in the worst affected hatch, compared with a maximum of 11.7% in the first nine hatches. No further cases were evident by 7.5 weeks of age. Histopathological examination showed a moderate acute encephalomyelitis in some, but not all, of the chicks with neurological signs. The clinical presentation and histopathological findings were typical of vertically transmitted avian encephalomyelitis as seen in chickens, although avian encephalomyelitis virus could not be detected in inoculated embryonated chicken eggs. However, serological testing by enzyme-linked immunosorbent assay for antibodies to the virus was positive in four of five affected 3-week-old birds and in 23 out of 29 adult breeding birds, and reverse transcriptase-polymerase chain reaction testing of RNA extracted from brain and pancreas tissue of affected chicks yielded nucleotide sequences aligned 82% and 83% with three avian encephalomyelitis sequences in a sequence database. The evidence suggested that the neurological disease was attributable to infection with a strain of avian encephalomyelitis virus that appeared to have entered the flock at the start of the breeding season, and was possibly introduced by carrier pheasants brought on to the farm early in the season.

Health economics of asthma: assessing the value of asthma interventions.

The aim of this systematic review was to summarize and assess the quality of asthma intervention health economic studies from 2002 to 2007, compare the study findings with clinical management guidelines, and suggest avenues for future improvement of asthma health economic studies. Forty of the 177 studies met our inclusion criteria. We assessed the quality of studies using The Quality of Health Economic Studies validated instrument (total score range: 0-100). Six studies (15%) had quality category 2, 26 studies (65%) achieved quality category 3, and the remaining eight (20%) studies were scored as the highest quality level, category 4. Overall, the findings from this review are in line with the Global Initiative for Asthma clinical guidelines. Many asthma health economic studies lacked appropriate long term time horizons to match the chronic nature of the disease and suffered from using effectiveness measures that did not capture all disease related risks and benefits. We recommend that new asthma simulation models: be flexible to allow for long term time horizons, focus on using levels of asthma control in their structure, and estimate both long term asthma specific outcomes like well-controlled time as well as generic outcomes such as quality adjusted survival.

A cost-effectiveness analysis of currently approved treatments for HBeAg-positive chronic hepatitis B.

BACKGROUND: A variety of pharmaceuticals are currently approved for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB), but their relative economic value is unclear. The goal of this analysis was to compare the cost effectiveness of adefovir, entecavir, lamivudine, pegylated interferon and telbivudine. METHODS: We conducted a cost-utility analysis from a US payer perspective over a lifetime time horizon using a Markov model, in a hypothetical population with HBeAg-positive CHB and a mean age of 35 years. Disease progression probabilities, costs and quality-of-life data were derived from the literature. We assumed a treatment duration of 4 years, with the use of combination therapy for drug resistance. Nonresponders to pegylated interferon were assumed to receive entecavir in years 3-4. Sensitivity analyses, including probabilistic sensitivity analysis, were conducted to evaluate uncertainty in the results. All costs were valued in $US, year 2008 values. Costs and outcomes were discounted at 3% per annum. RESULTS: The 10-year cumulative incidence of cirrhosis for no treatment was 26.1%, and ranged from 19.7% to 23.8% with treatment; undiscounted life-years were 36.2 for no treatment, or ranged from 36.82 to 37.54 with treatment. Initiation with entecavir (18.70 QALYs) and pegylated interferon (18.64 QALYs) provided the largest treatment benefits overall, followed by telbivudine (18.55 QALYs). The probabilities of the interventions being cost effective at a threshold of USD 50,000 per QALY were 57%, 37% and 2% for initiation with entecavir, pegylated interferon and telbivudine, respectively. The results were dependent on baseline seroconversion rate and the effect of viral suppression on cirrhosis risk. CONCLUSIONS: Initiation of treatments for HBeAg-positive CHB with a favourable combination of seroconversion, viral suppression and resistance profile appear to offer the greatest clinical and economic value.

Evaluating anti-viral drug selection and treatment duration in HBeAg-negative chronic hepatitis B: a cost-effectiveness analysis.

BACKGROUND: Several anti-viral treatments are now available for HBeAg-negative chronic hepatitis B (CHB), but the clinical and economic outcomes of potential treatment strategies and durations are unclear. AIM: To examine the clinical and economic outcomes of potential treatment strategies and durations for HBeAg-negative CHB. METHODS: We conducted a cost-utility analysis from a payer perspective over a lifetime time horizon. Disease progression probabilities, costs and quality of life data were derived from the literature. We evaluated 5-year, 10-year, lifetime and 5 on-1 off treatment durations. For each of these treatment durations, we evaluated initial therapy with entecavir, lamivudine or adefovir, with addition of adefovir or entecavir for patients who developed virological breakthrough because of resistance (12 strategies total). RESULTS: Increasing treatment duration improved quality-adjusted life-years (QALYs) and was generally cost-effective for all three drugs. However, a 5 on-1 off strategy was the most cost-effective: lifetime vs. 5 on-1 off entecavir had an ICER of $148,200/QALY. In probabilistic sensitivity analyses, entecavir 5 on-1 off was the preferred strategy over the range of commonly reimbursed cost-effectiveness thresholds. Lifetime treatment was preferred to a 5 on-1 off strategy, if treatment durability was < 10%. CONCLUSION: The results of our analysis suggest that in HBeAg-negative CHB infection, a 5 on-1 off treatment strategy with entecavir improves health outcomes in a cost-effective manner compared to alternative strategies.

Emerging methods in economic modeling of imaging costs and outcomes a short report on discrete event simulation.

RATIONALE AND OBJECTIVES: This short report provides a non-technical overview of one emerging modeling technique, discrete event simulation (DES). METHODS: A selective review of the literature that has applied DES methods to evaluate imaging technologies. RESULTS: Mathematical models to evaluate the likely costs and outcomes of health technologies have become increasingly accepted. Increasing experience has also brought a mounting awareness of the limitations of conventional modeling techniques such as decision trees and Markov processes. Patient-level simulation, including DES, may provide a more flexible approach to modeling for economic evaluation of health technologies. CONCLUSIONS: The strengths of DES suggest that it may have an increasingly important role in the future modeling of annual screening programs, diagnosis, and treatment of chronic recurrent disease and modeling the utilization of imaging equipment.

Factors determining the duration of tracheal intubation in cardiac surgery: a single-centre sequential patient audit.

BACKGROUND AND OBJECTIVE: The study was designed to identify those factors associated with early tracheal extubation following cardiac surgery. Previous studies have tended to concentrate on surgery for coronary artery bypass or on other selected cohorts. METHODS: Sequential cohort analysis of 296 unselected adult cardiac surgery patients was performed over 3 months. RESULTS: In total, 39% of all patients were extubated within 6 h, 89% within 24 h and 95% within 48 h. Delayed extubation (>6 h after surgery) appeared unrelated to age, gender, body mass index, a previous pattern of angina or myocardial infarction, diabetes, preoperative atrial fibrillation, and preoperative cardiovascular assessment, as well as other factors. Delayed tracheal extubation was associated with poor left ventricular, renal and pulmonary function, a high Euroscore, as well as the type, duration and urgency of surgery. Early extubation (<6 h) was not associated with a reduced length of stay in either the intensive care unit or in hospital compared with patients who were extubated between 6 and 24 h. In these groups, it is presumed that organizational and not clinical factors appear to be responsible for a delay in discharge from intensive care. Patients who were extubated after 24 h had a longer duration of hospital stay and a greater incidence of postoperative complications. Postoperative complications were not adversely affected by early tracheal extubation. CONCLUSIONS: In an unselected sequential cohort, both patient- and surgery-specific factors may be influential in determining the duration of postoperative ventilation of the lungs following cardiac surgery. In view of the changing nature of the surgical population, regular re-evaluation is useful in reassessing performance.

Role of endogenous opioid peptides in mediating progesterone-induced disruption of the activation and transmission stages of the GnRH surge induction process.

How progesterone blocks the E2-induced GnRH surge in females is not known. In this study we assessed whether the endogenous opioid peptides (EOPs) that mediate progesterone negative feedback on pulsatile GnRH secretion also mediate the blockade of the GnRH surge. We treated ovariectomized ewes with physiological levels of E2 and progesterone to stimulate and block the GnRH surge, respectively, using LH secretion as an index of GnRH release. A pilot study confirmed that blocking opioidergic neurotransmission with the opioid receptor antagonist, naloxone (NAL; 1 mg/kg.h, i.v.), could prevent the suppression of pulsatile LH secretion by progesterone in our model. By contrast, antagonizing EOP receptors with NAL did not restore LH surges in ewes in which the E2-induced GnRH surge was blocked by progesterone treatment during the E2-dependent activation stage (Exp 1) of the GnRH surge induction process. However, in ewes treated with progesterone during the E2-independent transmission stage (Exp 2), NAL partially restored blocked LH surges, as indicated by increased fluctuations in LH that, in some cases, resembled LH surges. We conclude, therefore, that the EOPs that mediate progesterone negative feedback on pulsatile GnRH secretion are not involved in blockade of activation of the E2-induced GnRH surge by progesterone, but do appear to be part of the mechanism by which progesterone disrupts the transmission stage.

Effect of epidural blockade on indicators of splanchnic perfusion and gut function in critically ill patients with peritonitis: a randomised comparison of epidural bupivacaine with systemic morphine.

OBJECTIVES: (a) To measure gastric tonometry values in critically ill patients with peritonitis and to assess the impact of epidural analgesia on these values. (b) To assess the impact of epidural analgesia on gastro-intestinal motility by abdominal ultrasound and paracetamol absorption. (c) To observe any change in clinical outcome that may result from the use of epidural analgesia in such patients. DESIGN: A double-blinded, prospective, randomised and controlled study of general intensive therapy unit (ITU) patients. PATIENTS: Twenty-one patients admitted with peritonitis and adynamic small bowel following abdominal surgery were randomly allocated to receive either intravenous morphine or epidural bupivacaine for analgesia. MEASUREMENTS AND RESULTS: Gastric intramucosal pH (pHig) and the mucosal:arterial PCO2 gradient (Pg-PaCO2) were measured at admission and after 24 h of analgesia. Analysis of mean changes in tonometry values showed a rise in Pg-PaCO2 and a fall in pHig in the morphine group and a significant difference between groups in the Pg-PaCO2 trends (p = 0.024). Significant improvements in the ultrasound appearance of the small bowel were observed in the epidural group (p = 0.0037, Mann-Whitney U test of median changes in a locally developed scoring system). There were no significant differences between the groups in any of the variables derived from the paracetamol absorption test (n = 10); both groups showed persistently delayed gastric outflow throughout the study period. CONCLUSIONS: Epidural analgesia resulted in improvements in gastric mucosal perfusion and the ultrasound appearance of the small bowel, indicating potential clinical benefit in a group of patients in whom epidural catheterisation is traditionally contraindicated.

High frequency jet ventilation and gas trapping.

We have compared three types of high frequency jet ventilation (HFJV) with conventional positive pressure ventilation in patients recovering from elective coronary artery bypass surgery. Twelve patients were allocated randomly to receive HFJV at ventilatory frequencies of 60, 100, 150 and 200 bpm from a standard jet ventilator at either the proximal or distal airway (HFJV.p and HFJV.d), or from a valveless high frequency jet ventilator acting as a pneumatic piston (VPP). Trapped gas volume (Vtr), cardiac index (CI) and right ventricular ejection fraction (RVEF) were measured. Vtr was related to the type of HFJV used (P < 0.05) and ventilatory frequency (P < 0.05). CI decreased with increasing rate of HFJV (P < 0.05) and there were significant differences between the three types of HFJV (P < 0.05). RVEF showed a linear relationship with ventilatory frequency (P < 0.05) decreasing most with the VPP. The decrease in RVEF was associated with an increase in right ventricular end-systolic volume (P < 0.05) suggesting that an increase in right ventricular afterload was the cause. The same three types of HFJV were compared using a lung model with variable values of compliance and resistance, to assess the impact of lung mechanics on gas trapping (Vtr, ml). Lung model compliance (C) was set at 50 or 25 ml cm H2O-1 and resistance (R) at 5 or 20 cm H2O litre-1 s, where values of 50 and 5, respectively, are normal. Vtr increased with ventilatory frequency for all types of jet ventilation (P < 0.05), varying with the type of jet ventilation used (P < 0.05).

Inhibition of the pig to human xenograft reaction, using soluble Gal alpha 1-3Gal and Gal alpha 1-3Gal beta 1-4GlcNAc.

Natural anti-carbohydrate antibodies are central to hyperacute rejection in ABO-incompatible allotransplantation and in discordant xenotransplantation. ABO-incompatible rejection has been inhibited successfully using intravenous soluble carbohydrates as antibody inhibitors. The approach has been less successful previously in pig to primate xenotransplantation, where the necessary concentrations of a partial inhibitor (Gal alpha 1-6Glc) proved highly toxic. In this study, we have identified more effective inhibitors of the dominant human anti-pig antibodies that bind to the pentasaccharide Gal alpha 1-3Gal beta 1-4GlcNAc beta 1-3Gal beta 1-4Glc beta 1-. The inhibitors are the terminal disaccharide (Gal alpha 1-3Gal) and terminal trisaccharide (Gal alpha 1-3Gal beta 1-4GlcNAc) of the target pentasaccharide. Twelve sera (3 from each ABO blood group) were tested in 3 different assays: lymphocytotoxic, lymphocyte flow cytometry, and solid-phase antigen ELISA. Fifty percent to 75% inhibition of human IgG and IgM was achieved using the disaccharide and trisaccharide inhibitors in the range of 10-50 mM. Disaccharide (70 mM) was used to inhibit hyperacute thrombosis in pig kidneys perfused for 40 min with heparinized human AB whole blood. The disaccharide completely inhibited red cell occlusion of glomerular but not of intertubular capillaries, although there was residual platelet thrombus in glomeruli. Disaccharide and trisaccharide can, therefore, be used in concentrations shown for other carbohydrate inhibitors to be nontoxic, for inhibition of hyperacute pig-to-human xenograft rejection. The inhibition is incomplete, however, and other antigen specificities and other rejection mechanisms are likely to be involved.