Current Practices and Challenges When Submitting Patient Experience Data for Regulatory Decisions by the US Food and Drug Administration: An Industry Survey.

OBJECTIVES: To understand industry practices and challenges when submitting patient experience data (PED) for regulatory decisions by the US Food and Drug Administration (FDA). METHODS: A two-part online survey related to collection, submission, and use of PED by FDA in regulatory decision-making (part 1) and a best-worst exercise for prioritizing potential PED initiatives (part 2) was completed by industry and contract research organization (CRO) members with ≥ 2 years of recent experience with patient-reported outcome (PRO), natural history study (NHS), or patient preference (PP) data; and direct experience with FDA filings including PED. RESULTS: A total of 50 eligible respondents (84% industry) completed part 1 of the survey, among which 46 completed part 2. Respondents mostly had PRO (86%) and PP (50%) experience. All indicated that FDA meetings should have a standing agenda item to discuss PED. Most (78%) reported meetings should occur before pivotal trials. A common challenge was justifying inclusion without knowing if and how data will be used. Most agreed that FDA and industry should co-develop the PED table in the FDA clinical review (74%), and the table should report reason(s) for not using PED (96%) in regulatory decision-making. Most important efforts to advance PED use in decision-making were a dedicated meeting pathway and expanded FDA guidance (51% each). CONCLUSIONS: FDA has policy targets expanding PED use, but challenges remain regarding pathways for PED submission and transparency in regulatory decision-making. Alignment on the use of existing meeting opportunities to discuss PED, co-development of the PED table, and expanded guidance are encouraged.

How can patient preferences be used and communicated in the regulatory evaluation of medicinal products? Findings and recommendations from IMI PREFER and call to action.

Objective: Patients have unique insights and are (in-)directly affected by each decision taken throughout the life cycle of medicinal products. Patient preference studies (PPS) assess what matters most to patients, how much, and what trade-offs patients are willing to make. IMI PREFER was a six-year European public-private partnership under the Innovative Medicines Initiative that developed recommendations on how to assess and use PPS in medical product decision-making, including in the regulatory evaluation of medicinal products. This paper aims to summarize findings and recommendations from IMI PREFER regarding i) PPS applications in regulatory evaluation, ii) when and how to consult with regulators on PPS, iii) how to reflect PPS in regulatory communication and iv) barriers and open questions for PPS in regulatory decision-making. Methods: PREFER performed six literature reviews, 143 interviews and eight focus group discussions with regulators, patient representatives, industry representatives, Health Technology Assessment bodies, payers, academics, and clincians between October 2016 and May 2022. Results: i) With respect to PPS applications, prior to the conduct of clinical trials of medicinal products, PPS could inform regulators' understanding of patients' unmet needs and relevant endpoints during horizon scanning activities and scientific advice. During the evaluation of a marketing authorization application, PPS could inform: a) the assessment of whether a product meets an unmet need, b) whether patient-relevant clinical trial endpoints and outcomes were studied, c) the understanding of patient-relevant effect sizes and acceptable trade-offs, and d) the identification of key (un-)favorable effects and uncertainties. ii) With respect to consulting with regulators on PPS, PPS researchers should ideally have early discussions with regulators (e.g., during scientific advice) on the PPS design and research questions. iii) Regarding external PPS communication, PPS could be reflected in the assessment report and product information (e.g., the European Public Assessment Report and the Summary of Product Characteristics). iv) Barriers relevant to the use of PPS in regulatory evaluation include a lack of PPS use cases and demonstrated impact on regulatory decision-making, and need for (financial) incentives, guidance and quality criteria for implementing PPS results in regulatory decision-making. Open questions concerning regulatory PPS use include: a) should a product independent broad approach to the design of PPS be taken and/or a product-specific one, b) who should optimally be financing, designing, conducting, and coordinating PPS, c) when (within and/or outside clinical trials) to perform PPS, and d) how can PPS use best be operationalized in regulatory decisions. Conclusion: PPS have high potential to inform regulators on key unmet needs, endpoints, benefits, and risks that matter most to patients and their acceptable trade-offs. Regulatory guidelines, templates and checklists, together with incentives are needed to foster structural and transparent PPS submission and evaluation in regulatory decision-making. More PPS case studies should be conducted and submitted for regulatory assessment to enable regulatory discussion and increase regulators' experience with PPS implementation and communication in regulatory evaluations.

Regulatory benefit-risk assessment of oncology drugs: A systematic review of FDA and EMA approvals.

The European Medicines Agency (EMA) and FDA have policy goals of strengthening benefit-risk (B-R) capabilities; but how this has been translating into regulatory practice is unclear. A systematic review of oncology drug approvals between 2015 and 2020 was conducted with approvals identified through review of FDA and EMA annual reports, with extraction of information on submission, clinical program and B-R assessment from publicly available review documents. Data were extracted from 236 reviews (EMA: 66 new submissions, 100 label extensions; FDA: 70 new submissions). The standard of evidence for B-R assessments seems to have diversified over time; yet, despite policy targets to extend their use, these assessments rarely include patient experience or real-world data.

Comparing Outcomes of a Discrete Choice Experiment and Case 2 Best-Worst Scaling: An Application to Neuromuscular Disease Treatment.

BACKGROUND AND OBJECTIVES: Case 2 best-worst scaling (BWS-2) is an increasingly popular method to elicit patient preferences. Because BWS-2 potentially has a lower cognitive burden compared with discrete choice experiments, the aim of this study was to compare treatment preference weights and relative importance scores. METHODS: Patients with neuromuscular diseases completed an online survey at two different moments in time, completing one method per occasion. Patients were randomly assigned to either first a discrete choice experiment or BWS-2. Attributes included: muscle strength, energy endurance, balance, cognition, chance of blurry vision, and chance of liver damage. Multinomial logit was used to calculate overall relative importance scores and latent class logit was used to estimate heterogeneous preference weights and to calculate the relative importance scores of the attributes for each latent class. RESULTS: A total of 140 patients were included for analyses. Overall relative importance scores showed differences in attribute importance rankings between a discrete choice experiment and BWS-2. Latent class analyses indicated three latent classes for both methods, with a specific class in both the discrete choice experiment and BWS-2 in which (avoiding) liver damage was the most important attribute. Ex-post analyses showed that classes differed in sex, age, level of education, and disease status. The discrete choice experiment was easier to understand compared with BWS-2. CONCLUSIONS: This study showed that using a discrete choice experiment and BWS-2 leads to different outcomes, both in preference weights as well as in relative importance scores, which might have been caused by the different framing of risks in BWS-2. However, a latent class analysis revealed similar latent classes between methods. Careful consideration about method selection is required, while keeping the specific decision context in mind and pilot testing the methods.

Suitability of Preference Methods Across the Medical Product Lifecycle: A Multicriteria Decision Analysis.

OBJECTIVES: This study aimed to understand the importance of criteria describing methods (eg, duration, costs, validity, and outcomes) according to decision makers for each decision point in the medical product lifecycle (MPLC) and to determine the suitability of a discrete choice experiment, swing weighting, probabilistic threshold technique, and best-worst scale cases 1 and 2 at each decision point in the MPLC. METHODS: Applying multicriteria decision analysis, an online survey was sent to MPLC decision makers (ie, industry, regulatory, and health technology assessment representatives). They ranked and weighted 19 methods criteria from an existing performance matrix about their respective decisions across the MPLC. All criteria were given a relative weight based on the ranking and rating in the survey after which an overall suitability score was calculated for each preference elicitation method per decision point. Sensitivity analyses were conducted to reflect uncertainty in the performance matrix. RESULTS: Fifty-nine industry, 29 regulatory, and 5 health technology assessment representatives completed the surveys. Overall, "estimating trade-offs between treatment characteristics" and "estimating weights for treatment characteristics" were highly important criteria throughout all MPLC decision points, whereas other criteria were most important only for specific MPLC stages. Swing weighting and probabilistic threshold technique received significantly higher suitability scores across decision points than other methods. Sensitivity analyses showed substantial impact of uncertainty in the performance matrix. CONCLUSION: Although discrete choice experiment is the most applied preference elicitation method, other methods should also be considered to address the needs of decision makers. Development of evidence-based guidance documents for designing, conducting, and analyzing such methods could enhance their use.

Molecular analysis and favorable clinical outcomes in real-world patients with metastatic renal cell carcinoma.

BACKGROUND: Prior biomarker studies have mainly been restricted to advanced RCC patients treated in clinical trials or have had limited integration of immunotherapy features such as programmed death ligand (PD-L)-1 with gene expression signatures intended to capture other canonical pathways to confirm their prognostic value. MATERIAL AND METHODS: PD-L1 and PD-L2 by immunohistochemistry (IHC), PD-L2 messenger RNA (mRNA), and 10 gene expression profile (GEP) signatures targeting immune, angiogenesis and canonical pathways were analyzed in nephrectomy specimens from 227 advanced clear cell RCC (ccRCC) and 42 non-clear cell RCC (nccRCC) patients treated with targeted therapies including VEGF and mTOR inhibitors. Biomarker association with best overall response (BOR), progression-free survival (PFS), and overall survival (OS) were evaluated using multivariable modeling. Except for PD-L1 IHC and angiogenesis, tested with a nominal p-value of .05, multiplicity control was applied with a 0.1 significance level given limited experience in this setting. RESULTS: The strongest biomarker correlations were observed for hypoxia inducible factor (HIF)-2a and angiogenesis signatures (rho = 0.860 [ccRCC], 0.819 [nccRCC]); hypoxia and glycolysis signatures (rho = 0.943 [ccRCC], 0.973 [nccRCC]); PD-L2 mRNA and T-cell-inflamed GEP signatures (rho = 0.764 [ccRCC], 0.897 [nccRCC]); and PD-L2 mRNA and monocytic myeloid-derived suppressor cell signature (rho = 0.787 [ccRCC], 0.815 [nccRCC]). For ccRCC, higher angiogenesis expression was associated with improved BOR (OR:2.85 [95%CI:1.37, 5.93]), longer PFS (HR:0.61 [95%CI:0.45, 0.82]) and OS (HR:0.74 [95%CI:0.54, 1.00]); higher PD-L1 expression with shorter OS (HR:1.44 [95%CI:1.01, 2.07]). For nccRCC, there was more than a two-fold increased risk with longer OS associated with lower angiogenesis (HR:2.43 [95%CI:1.04, 5.68]), glycolysis (HR:7.03 [95%CI:1.51, 32.76]) and hypoxia (HR:8.83 [95%CI:1.69, 46.05]) gene signature expression. CONCLUSION: Data pointed at PD-L1 IHC and angiogenesis expression in ccRCC and hypoxia, glycolysis, and angiogenesis expression in nccRCC as potential prognostic factors. These findings may have implications for the design and interpretation of advanced RCC trials and to identify potential targets for combination therapy strategies.

Net clinical benefit of antiplatelet therapy was affected by patient preferences: A personalized benefit-risk assessment.

OBJECTIVES: To assess the effect of patient preferences on the net clinical benefit (NCB) of an antiplatelet therapy for the secondary prevention of cardiovascular complications. STUDY DESIGN AND SETTING: Risk equations were developed to estimate the individual predicted risk of key outcomes of antiplatelet treatment in patients with a prior myocardial infarction using the Clinical Practice Research Datalink linked to the Hospital Episode Statistics and UK Office of National Statistics databases. Patient preferences for outcomes of antiplatelet therapies were elicited in a separate discrete choice experiment survey. Trial hazard ratios, relative to placebo, were used to calculate the per-patient NCB using equal or preference weighting of outcomes. RESULTS: Risk equations were estimated using 31,941 adults in the Clinical Practice Research Datalink population, of which 22,125 were included in the benefit-risk assessment. The mean NCB was lower in the preference-weighted than in the equal-weighted analysis (0.040 vs. 0.057; P < 0.0001), but the direction of effect was unchanged by the weighting. In analyses stratified by the presence of bleeding risk factors, including preference weighting altered the ranking of subgroups by NCB. CONCLUSION: Patient preference weighting may have a significant effect on NCB and should be included in personalized benefit-risk assessments.

Comparing Patient Preferences for Antithrombotic Treatment During the Acute and Chronic Phases of Myocardial Infarction: A Discrete-Choice Experiment.

BACKGROUND: Antithrombotic drugs are used as preventive treatment in patients with a prior myocardial infarction (MI) in both the acute and chronic phases of the disease. To support patient-centered benefit-risk assessment, it is important to understand the influence of disease stage on patient preferences. OBJECTIVE: The aim of this study was to examine patient preferences for antithrombotic treatments and whether they differ by MI disease phase. METHODS: A discrete-choice experiment was used to elicit preferences of adults in the acute (≤ 365 days before enrolment) or chronic phase (> 365 days before enrolment) of MI for key ischemic events (risk of cardiovascular [CV] death, non-fatal MI, and non-fatal ischemic stroke) and bleeding events (risk of non-fatal intracranial hemorrhage and non-fatal other severe bleeding). Preference data were analyzed using the multinomial logit model. Trade-offs between attributes were calculated as the maximum acceptable increase in the risk of CV death for a decrease in the risk of the other outcomes. To assess the potential effect of sociodemographic and clinical characteristics on patient preferences, subgroups were introduced as interaction terms in logit models. RESULTS: The evaluable population included 155 patients with MI in the acute phase of disease and 180 in the chronic phase. The overall population was 82% male, mean age was 64.2 ± 9.6 years, and 93% had not experienced bleeding events or key ischemic events other than MI. Patients valued reduction in the risk of non-fatal intracranial hemorrhage more than CV death (p < 0.01) and CV death more than non-fatal ischemic events (p < 0.01). Preferences were similar in the acute and chronic populations (p = 0.17). However, older patients valued reduction in risk of MI more than younger patients (p = 0.04), and patients with bleeding risk factors valued reduction in the risk of CV death (p = 0.01) and MI (p = 0.01) less than patients without bleeding risk factors. Also, patients who were at high risk of future ischemic events valued reduction of the risk of CV death less than those at low risk (p = 0.01). CONCLUSION: Patient preferences for antithrombotic treatments were unaffected by disease stage but varied by bleeding risk and other factors. This heterogeneity in preferences is an important consideration because it can affect the benefit-risk balance and the acceptability of antithrombotic treatments to patients.

Taking into Account Patient Preferences: A Consensus Study on the Assessment of Psychological Dimensions Within Patient Preference Studies.

Patient preferences are gaining recognition among key stakeholders involved in benefit-risk decision-making along the medical product lifecycle. However, one of the main challenges of integrating patient preferences in benefit-risk decision-making is understanding differences in patient preference, which may be attributable to clinical characteristics (eg age, medical history) or psychosocial factors. Measuring the latter may provide valuable information to decision-makers but there is limited guidance regarding which psychological dimensions may influence patient preferences and which psychological instruments should be considered for inclusion in patient preference studies. This paper aims to provide such guidance by advancing evidence and consensus-based recommendations and considerations. Findings of a recent systematic review on psychological constructs having an impact on patients' preferences and health-related decisions were expanded with input from an expert group (n = 11). These data were then used as the basis for final recommendations developed through two rounds of formal evaluation via an online Delphi consensus process involving international experts in the field of psychology, medical decision-making, and risk communication (n = 27). Three classes of recommendations emerged. Eleven psychological constructs reached consensus to be recommended for inclusion with the strongest consensus existing for health literacy, numeracy, illness perception and treatment-related beliefs. We also proposed a set of descriptive and checklist criteria to appraise available psychological measures to assist researchers and other stakeholders in including psychological assessment when planning patient preference studies. These recommendations can guide researchers and other stakeholders when designing and interpreting patient preference studies with a potential high impact in clinical practice and medical product benefit-risk decision-making processes.

Patient Preferences in Rare Diseases: A Qualitative Study in Neuromuscular Disorders to Inform a Quantitative Preference Study.

INTRODUCTION: It has become increasingly important to include patient preference information in decision-making processes for drug development. As neuromuscular disorders represent multisystem, debilitating, and progressive rare diseases with few treatment options, this study aimed to explore unmet health care needs and patient treatment preferences for two neuromuscular disorders, myotonic dystrophy type 1 (DM1) and mitochondrial myopathies (MM) to inform early stages of drug development. METHODS: Fifteen semi-structured interviews and five focus group discussions (FGDs) were held with DM1 and MM adult patients and caregivers. Topics discussed included (1) reasons for study participation; (2) disease signs/symptoms and their impact on daily lives; (3) top desired benefits; and (4) acceptability of risks and tolerance levels for a hypothetical new treatment. Data were analyzed following a thematic 'code' approach. RESULTS: A total of 52 participants representing a wide range of disease severities participated. 'Muscle strength' and 'energy and endurance' were the disease-related unmet needs most often mentioned. Additionally, improved 'balance', 'cognition' and 'gut function' were the top desired treatment benefits, while 'damage to the liver, kidneys or eyes' was the most concerning risk. Factors influencing their tolerance to risks related to previously having experienced the risk and differentiation between permanent and temporary risks. A few differences were elicited between patients and caregivers. CONCLUSIONS: This qualitative study provided an open forum to elicit treatment-desired benefits and acceptable risks to be established by patients themselves. These findings can inform decisions for developing new treatments and the design of clinical trials for DM1 and MM.

An overview of critical decision-points in the medical product lifecycle: Where to include patient preference information in the decision-making process?

BACKGROUND: Patient preference (PP) information is not effectively integrated in decision-making throughout the medical product lifecycle (MPLC), despite having the potential to improve patients' healthcare options. A first step requires an understanding of existing processes and decision-points to know how to incorporate PP information in order to improve patient-centric decision-making. OBJECTIVES: The aims were to: 1) identify the decision-making processes and decision-points throughout the MPLC for industry, regulatory authorities, and reimbursement/HTA, and 2) determine which decision-points can potentially include PP information. METHODS: A scoping literature review was conducted using five scientific databases. Semi-structured interviews were conducted with representatives from seven European countries and the US, including industry (n = 24), regulatory authorities (n = 23), reimbursement/HTA (n = 23). Finally, validation meetings with key stakeholders (n = 11) were conducted. RESULTS: Six critical decision-points were identified for industry decision-making, three for regulatory decision-making, and six for reimbursement/HTA decision-making. Stakeholder groups agreed that PP information is not systematically integrated, either as obligatory information or pre-set criteria, but would benefit all the listed decision-points in the future. CONCLUSION: Currently, PP information is not considered as obligatory information to submit for any of the MPLC decision-points. However, PP information is considered an important component by most stakeholders to inform future decision-making across the MPLC. The integration of PP information into 15 identified decision-points needs continued discussion and collaboration between stakeholders.

Appraising patient preference methods for decision-making in the medical product lifecycle: an empirical comparison.

BACKGROUND: Incorporating patient preference (PP) information into decision-making has become increasingly important to many stakeholders. However, there is little guidance on which patient preference assessment methods, including preference exploration (qualitative) and elicitation (quantitative) methods, are most suitable for decision-making at different stages in the medical product lifecycle (MPLC). This study aimed to use an empirical approach to assess which attributes of PP assessment methods are most important, and to identify which methods are most suitable, for decision-makers' needs during different stages in the MPLC. METHODS: A four-step cumulative approach was taken: 1) Identify important criteria to appraise methods through a Q-methodology exercise, 2) Determine numerical weights to ascertain the relative importance of each criterion through an analytical hierarchy process, 3) Assess the performance of 33 PP methods by applying these weights, consulting international health preference research experts and review of literature, and 4) Compare and rank the methods within taxonomy groups reflecting their similar techniques to identify the most promising methods. RESULTS: The Q-methodology exercise was completed by 54 stakeholders with PP study experience, and the analytical hierarchy process was completed by 85 stakeholders with PP study experience. Additionally, 17 health preference research experts were consulted to assess the performance of the PP methods. Thirteen promising preference exploration and elicitation methods were identified as likely to meet decision-makers' needs. Additionally, eight other methods that decision-makers might consider were identified, although they appeared appropriate only for some stages of the MPLC. CONCLUSIONS: This transparent, weighted approach to the comparison of methods supports decision-makers and researchers in selecting PP methods most appropriate for a given application.

A study protocol for quantifying patient preferences in neuromuscular disorders: a case study of the IMI PREFER Project.

Objectives: Patient preference studies are increasingly used to inform decision-making during the medical product lifecycle but are rarely used to inform early stages of drug development.  The primary aim of this study is to quantify treatment preferences of patients with neuromuscular disorders, which represent serious and debilitating conditions with limited or no treatment options available. Methods: This quantitative patient preferences study was designed as an online survey, with a cross-over design.  This study will target two different diseases from the neuromuscular disorders disease group, myotonic dystrophy type 1 (DM1) and mitochondrial myopathies (MM). Despite having different physio-pathological pathways both DM1 and MM manifest in a clinically similar manner and may benefit from similar treatment options.  The sample will be stratified into three subgroups: two patient groups differentiated by age of symptom onset and one caregivers group.   Each subgroup will be randomly assigned to complete two of three different preference elicitation methods at two different time points: Q-methodology survey, discrete choice experiment, and best-worst scaling type 2, allowing cross-comparisons of the results across each study time within participants and within elicitation methods. Additional variables such as sociodemographic, clinical and health literacy will be collected to enable analysis of potential heterogeneity. Ethics and Dissemination: This study protocol has undergone ethical review and approval by the Newcastle University R&D Ethics Committee (Ref: 15169/2018). All participants will be invited to give electronic informed consent to take part in the study prior accessing the online survey. All electronic data will be anonymised prior analysis. This study is part of the Patient Preferences in Benefit-Risk Assessments during the Drug Life Cycle (IMI-PREFER) project, a public-private collaborative research project aiming to develop expert and evidence-based recommendations on how and when patient preferences can be assessed and used to inform medical product decision making.

Methods for exploring and eliciting patient preferences in the medical product lifecycle: a literature review.

Preference studies are becoming increasingly important within the medical product decision-making context. Currently, there is limited understanding of the range of methods to gain insights into patient preferences. We developed a compendium and taxonomy of preference exploration (qualitative) and elicitation (quantitative) methods by conducting a systematic literature review to identify these methods. This review was followed by analyzing prior preference method reviews, to cross-validate our results, and consulting intercontinental experts, to confirm our outcomes. This resulted in the identification of 32 unique preference methods. The developed compendium and taxonomy can serve as an important resource for assessing these methods and helping to determine which are most appropriate for different research questions at varying points in the medical product lifecycle.

Understanding Patients' Preferences: A Systematic Review of Psychological Instruments Used in Patients' Preference and Decision Studies.

BACKGROUND: Research has been mainly focused on how to elicit patient preferences, with less attention on why patients form certain preferences. OBJECTIVES: To assess which psychological instruments are currently used and which psychological constructs are known to have an impact on patients' preferences and health-related decisions including the formation of preferences and preference heterogeneity. METHODS: A systematic database search was undertaken to identify relevant studies. From the selected studies, the following information was extracted: study objectives, study population, design, psychological dimensions investigated, and instruments used to measure psychological variables. RESULTS: Thirty-three studies were identified that described the association between a psychological construct, measured using a validated instrument, and patients' preferences or health-related decisions. We identified 33 psychological instruments and 18 constructs, and categorized the instruments into 5 groups, namely, motivational factors, cognitive factors, individual differences, emotion and mood, and health beliefs. CONCLUSIONS: This review provides an overview of the psychological factors and related instruments in the context of patients' preferences and decisions in healthcare settings. Our results indicate that measures of health literacy, numeracy, and locus of control have an impact on health-related preferences and decisions. Within the category of constructs that could explain preference and decision heterogeneity, health locus of control is a strong predictor of decisions in several healthcare contexts and is useful to consider when designing a patient preference study. Future research should continue to explore the association of psychological constructs with preference formation and heterogeneity to build on these initial recommendations.

Personalized benefit-risk assessments combining clinical trial and real-world data provide further insights into which patients may benefit most from therapy: Demonstration for a new oral antiplatelet therapy.

PURPOSE: Quantitative benefit-risk (B-R) assessments are used to characterize treatment by combining key benefits and risks into a single metric but have historically been done for the "average" patient. Our aim was to conduct an individualized assessment for the oral antiplatelet vorapaxar by combining trial and real-world data to further personalize the treatment profiles. METHODS: Using linked UK health care databases, we developed risk prediction equations for key ischemic and bleeding events using Cox proportional hazards models. Trial hazard ratios, relative to placebo, were applied to baseline risk estimates to compute expected attributable risks, summed to derive a per-patient net clinical benefit (NCB). High risk subgroups were defined a priori, and Gaussian mixture models (GMM) were fit to characterize the NCB distribution and identify subgroups with similar NCBs. RESULTS: NCB was consistently positive for all subgroups, likely due to the outcome correlation, and would remain positive with a 12-fold increase in bleeding risk. GMMs identified three distinct NCB subgroups. Compared with the middle/lower NCB subgroups, those with a higher NCB tended to be older, female, and have higher CV disease burden. CONCLUSIONS: Personalized B-R assessments are feasible and clinically valuable and can be used to better predict who would benefit most from therapy.

Changes in LDL particle concentrations after treatment with the cholesteryl ester transfer protein inhibitor anacetrapib alone or in combination with atorvastatin.

OBJECTIVES: Our aim was to assess the effects of the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib and atorvastatin, both as monotherapy and in combination, on particle concentrations of low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), and intermediate-density lipoproteins in dyslipidemic patients. BACKGROUND: Although increases in high-density lipoproteins with CETP inhibition are well-documented, effects on atherogenic lipoprotein particle subclasses in dyslipidemic patients have not been extensively characterized. METHODS: Ion mobility was performed on stored plasma samples collected from patients before and after treatment with anacetrapib alone (150 and 300 mg/d) or in combination with atorvastatin (20 mg/d) in a previously conducted 8-week phase IIb study. RESULTS: Anacetrapib produced significant placebo-adjusted reductions of total LDL particles and all subfractions except for increases in very small LDL 4a and 4b. Atorvastatin reduced all LDL subfractions except LDL 4b. Results were generally additive for anacetrapib + atorvastatin. For patients treated with anacetrapib, the placebo-adjusted reduction in LDL 3a was attenuated and there was an increase in LDL 3b and 4a for those with low vs high triglyceride (TG) levels. For the atorvastatin alone vs placebo treatment comparison, there were small reductions in LDL 3a, 3b, and 4a for those with low vs high TG levels. CONCLUSIONS: Anacetrapib and atorvastatin produced similar reductions from baseline in total LDL particles, but did not have comparable effects on all LDL particle subfractions, and neither drug reduced the smallest LDL 4b particles. The clinical significance of these changes and the differential effects on very small LDL 4a in patients with higher vs lower TG remain to be determined (clinicaltrials.gov, NCT00325455).

Cardiopulmonary bypass has a modest association with cancer progression: a retrospective cohort study.

BACKGROUND: Given their frequency of occurrence in the United States, cancer and heart disease often coexist. For patients requiring open-heart surgery, this raises concern that the use of cardiopulmonary bypass (CPB) may cause a transient immunosuppression with the potential to promote the spread and growth of coexisting cancer cells. This study examined the association of cardiopulmonary bypass with cancer progression in a large population-based setting using linked data from several state-wide registries. METHODS: A retrospective cohort study of cancer risk, stage, and mortality in 43,347 patients who underwent coronary artery bypass graft (CABG) surgery with and without CPB in New Jersey between 1998-2004 was conducted. A competing risk analogue of the Cox proportional hazards model with propensity score adjustment and regression on the cause-specific hazard was used to compute relative risk ratios (95% confidence intervals [CIs]) for patients undergoing CABG surgery with and without CPB. RESULTS: An increased risk for overall cancer incidence (17%) and cancer-specific mortality (16% overall, 12% case fatality) was observed; yet these results did not reach statistical significance. Of 11 tumor-specific analyses, an increased risk of skin melanoma (1.66 [95% CI, 1.08-2.55: p=0.02]) and lung cancer (1.36 [95% CI, 1.02-1.81: p=0.03]) was observed for patients with pump versus off-pump open-heart surgery. No association was found with cancer stage. CONCLUSIONS: These results suggest that there may be a relationship between CPB and cancer progression. However, if real, the effect is likely modest at most. Further research may still be warranted with particular focus on skin melanoma and lung cancer which had the strongest association with CPB.

Correlation between arterial FDG uptake and biomarkers in peripheral artery disease.

OBJECTIVES: A prospective, multicenter (18)fluorine-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET)/computed tomography (CT) imaging study was performed to estimate the correlations among arterial FDG uptake and atherosclerotic plaque biomarkers in patients with peripheral artery disease. BACKGROUND: Inflammation within atherosclerotic plaques is associated with instability of the plaque and future cardiovascular events. Previous studies have shown that (18)F-FDG-PET/CT is able to quantify inflammation within carotid artery atherosclerotic plaques, but no studies to date have investigated this correlation in peripheral arteries with immunohistochemical confirmation. METHODS: Thirty patients across 5 study sites underwent (18)F-FDG-PET/CT imaging before SilverHawk atherectomy (FoxHollow Technologies, Redwood City, California) for symptomatic common or superficial femoral arterial disease. Vascular FDG uptake (expressed as target-to-background ratio) was measured in the carotid arteries and aorta and femoral arteries, including the region of atherectomy. Immunohistochemistry was performed on the excised atherosclerotic plaque extracts, and cluster of differentiation 68 (CD68) level as a measure of macrophage content was determined. Correlations between target-to-background ratio of excised lesions, as well as entire arterial regions, and CD68 levels were determined. Imaging was performed during the 2 weeks before surgery in all cases. RESULTS: Twenty-one patients had adequate-quality (18)F-FDG-PET/CT peripheral artery images, and 34 plaque specimens were obtained. No significant correlation between lesion target-to-background ratio and CD68 level was observed. CONCLUSIONS: There were no significant correlations between CD68 level (as a measure of macrophage content) and FDG uptake in the peripheral arteries in this multicenter study. Differences in lesion extraction technique, lesion size, the degree of inflammation, and imaging coregistration techniques may have been responsible for the failure to observe the strong correlations with vascular FDG uptake observed in previous studies of the carotid artery and in several animal models of atherosclerosis.