Integrating Cost into Shared Decision-Making for Heart Failure with Reduced Ejection Fraction (POCKET-COST-HF): A Trial Providing Out-of-Pocket Costs for Heart Failure Medications during Clinical Encounters.

BACKGROUND: Evidence-based medical therapy for heart failure with reduced ejection fraction (HFrEF) often entails substantial out-of-pocket costs that can vary appreciably between patients. This has raised concerns regarding financial toxicity, equity, and adherence to medical therapy. In spite of these concerns, cost discussions in the HFrEF population appear to be rare, partly because out-of-pocket costs are generally unavailable during clinical encounters. In this trial, out-of-pocket cost information is given to patients and clinicians during outpatient encounters with the aim to assess the impact of providing this information on medication discussions and decisions. HYPOTHESIS: Cost-informed decision-making will be facilitated by providing access to patient-specific out-of-pocket cost estimates at the time of clinical encounter. DESIGN: Integrating Cost into Shared Decision-Making for Heart Failure with Reduced Ejection Fraction (POCKET-COST-HF) is a multicenter trial based at Emory Healthcare and University of Colorado Health. Adapting an existing patient activation tool from the EPIC-HF trial, patients and clinicians are presented a checklist with medications approved for treatment of HFrEF with or without patient-specific out-of-pocket costs (obtained from a financial navigation firm). Clinical encounters are audio-recorded, and patients are surveyed about their experience. The trial utilizes a stepped-wedge cluster randomized design, allowing for each site to enroll control and intervention group patients while minimizing contamination of the control arm. DISCUSSION: This trial will elucidate the potential impact of robust cost disclosure efforts and key information regarding patient and clinician perspectives related to cost and cost communication. It also will reveal important challenges associated with providing out-of-pocket costs for medications during clinical encounters. Acquiring medication costs for this trial requires an involved process and outsourcing of work. In addition, costs may change throughout the year, raising questions regarding what specific information is most valuable. These data will represent an important step towards understanding the role of integrating cost discussions into heart failure care. GOV IDENTIFIER: NCT04793880.

Structural insights into loss of function of a pore forming toxin and its role in pneumococcal adaptation to an intracellular lifestyle.

The opportunistic pathogen Streptococcus pneumoniae has dual lifestyles: one of an asymptomatic colonizer in the human nasopharynx and the other of a deadly pathogen invading sterile host compartments. The latter triggers an overwhelming inflammatory response, partly driven via pore forming activity of the cholesterol dependent cytolysin (CDC), pneumolysin. Although pneumolysin-induced inflammation drives person-to-person transmission from nasopharynx, the primary reservoir for pneumococcus, it also contributes to high mortality rates, creating a bottleneck that hampers widespread bacterial dissemination, thus acting as a double-edged sword. Serotype 1 ST306, a widespread pneumococcal clone, harbours a non-hemolytic variant of pneumolysin (Ply-NH). Performing crystal structure analysis of Ply-NH, we identified Y150H and T172I as key substitutions responsible for loss of its pore forming activity. We uncovered a novel inter-molecular cation-π interaction, governing formation of the transmembrane ß-hairpins (TMH) in the pore state of Ply, which can be extended to other CDCs. H150 in Ply-NH disrupts this interaction, while I172 provides structural rigidity to domain-3, through hydrophobic interactions, inhibiting TMH formation. Loss of pore forming activity enabled improved cellular invasion and autophagy evasion, promoting an atypical intracellular lifestyle for pneumococcus, a finding that was corroborated in in vivo infection models. Attenuation of inflammatory responses and tissue damage promoted tolerance of Ply-NH-expressing pneumococcus in the lower respiratory tract. Adoption of this altered lifestyle may be necessary for ST306 due to its limited nasopharyngeal carriage, with Ply-NH, aided partly by loss of its pore forming ability, facilitating a benign association of SPN in an alternative, intracellular host niche.

Experimenting with modifications to consent forms in comparative effectiveness research: understanding the impact of language about financial implications and key information.

BACKGROUND: Informed consent forms are intended to facilitate research enrollment decisions. However, the technical language in institutional templates can be unfamiliar and confusing for decision-makers. Standardized language describing financial implications of participation, namely compensation for injury and costs of care associated with participating, can be complex and could be a deterrent for potential participants. This standardized language may also be misleading in the context of comparative effectiveness trials of standard care interventions, in which costs and risk of injury associated with participating may not differ from regular medical care. In addition, the revised U.S. Common Rule contains a new requirement to present key information upfront; the impact of how this requirement is operationalized on comprehension and likelihood of enrollment for a given study is unknown. METHODS: Two online surveys assessed the impact of (1) changes to compensation for injury language (standard vs. tailored language form) and (2) changes to the key information page (using the tailored compensation language form with standard key information vs. modified key information vs. modified key information plus financial information) on both likelihood of enrollment in and understanding of a hypothetical comparative effectiveness trial. RESULTS: Likelihood of enrolling was not observed to be different between the standard and tailored language forms in Study 1 (73 vs. 75%; p = 0.6); however, the tailored language group had a higher frequency of understanding the compensation for injury process specific to the trial (25 vs. 51%; p < 0.0001). Modifications to the key information sheet in Study 2 did not affect likelihood of enrolling (88 vs. 85 vs. 85%; p = 0.6); however, understanding of randomization differed by form (44 vs. 59 vs. 46%; p = 0.002). CONCLUSIONS: These findings suggest that refining consent forms to clarify key information and tailoring compensation for injury language to the nature of the study, especially in the context of comparative effectiveness trials, may help to improve study comprehension but may not impact enrollment.

Patient and Surrogate Postenrollment Perspectives on Research Using the Exception From Informed Consent: An Integrated Survey.

STUDY OBJECTIVE: It is important for researchers interested in trials using the exception from informed consent to understand the views and experiences of enrolled individuals. Previous studies have shown that patient and surrogate attitudes are generally positive. These studies were small and did not include pediatric patients, and interviews were often conducted long after trial enrollment. This study sought to explore attitudes toward exception from informed consent in a larger sample and more contemporaneous setting. METHODS: A 10-item paper-and-pencil survey was integrated into the Established Status Epilepticus Treatment Trial, a randomized trial of 3 treatments for benzodiazepine-refractory status epilepticus in pediatric and adult patients. Primary domains included attitudes toward trial enrollment, exception from informed consent, and community consultation. Simple descriptive statistics, χ2, and Fisher's exact tests were conducted. RESULTS: Of 317 patients and surrogates, 90% agreed with or were neutral about the statement "I am glad that I/my family member was included in the Established Status Epilepticus Treatment Trial research study," whereas 10% disagreed. Twenty-seven percent disagreed with enrollment in the study without prospective consent. Black participants were more likely than white, other race, and unknown-race participants to disagree with enrollment without prospective consent (36% versus 23%, 14%, and 14%, respectively). Participants indicated that patients (81%), their families (65%), and those at risk for seizures (51%) were most important to include in community consultation. CONCLUSION: This study aimed to explore attitudes toward exception from informed consent enrollment among participants at all sites in a large, multicenter exception from informed consent trial. General acceptance of trial enrollment was high; acceptance of exception from informed consent specifically was somewhat lower, especially among black participants. Our findings provide further support for targeted community consultation focusing on individuals with connections to the disease under study. Future research should focus on communication in the postenrollment period, especially with individuals who may have concerns about exception from informed consent.

Partnering With Patients to Bridge Gaps in Consent for Acute Care Research.

Clinical trials for acute conditions such as myocardial infarction and stroke pose challenges related to informed consent due to time limitations, stress, and severe illness. Consent processes should be sensitive to the context in which trials are conducted and to needs of patients and surrogate decision-makers. This manuscript describes a collaborative effort between ethicists, researchers, patients, and surrogates to develop patient-driven, patient-centered approaches to consent for clinical trials in acute myocardial infarction and stroke.Our group identified important ways in which existing consent processes and forms for clinical trials fail to meet patients' and surrogates' needs in the acute context. We collaborated to create model forms and consent processes that are substantially shorter and, hopefully, better-matched to patients' and surrogates' needs and expectations from the perspective of content, structure, and tone. These changes, however, challenge some common conventions regarding consent.

Dominant role of nucleotide substitution in the diversification of serotype 3 pneumococci over decades and during a single infection.

Streptococcus pneumoniae of serotype 3 possess a mucoid capsule and cause disease associated with high mortality rates relative to other pneumococci. Phylogenetic analysis of a complete reference genome and 81 draft sequences from clonal complex 180, the predominant serotype 3 clone in much of the world, found most sampled isolates belonged to a clade affected by few diversifying recombinations. However, other isolates indicate significant genetic variation has accumulated over the clonal complex's entire history. Two closely related genomes, one from the blood and another from the cerebrospinal fluid, were obtained from a patient with meningitis. The pair differed in their behaviour in a mouse model of disease and in their susceptibility to antimicrobials, with at least some of these changes attributable to a mutation that up-regulated the patAB efflux pump. This indicates clinically important phenotypic variation can accumulate rapidly through small alterations to the genotype.

Resolving Salmonella infection reveals dynamic and persisting changes in murine bone marrow progenitor cell phenotype and function.

The generation of immune cells from BM precursors is a carefully regulated process. This is essential to limit the potential for oncogenesis and autoimmunity yet protect against infection. How infection modulates this is unclear. Salmonella can colonize systemic sites including the BM and spleen. This resolving infection has multiple IFN-γ-mediated acute and chronic effects on BM progenitors, and during the first week of infection IFN-γ is produced by myeloid, NK, NKT, CD4(+) T cells, and some lineage-negative cells. After infection, the phenotype of BM progenitors rapidly but reversibly alters, with a peak ∼ 30-fold increase in Sca-1(hi) progenitors and a corresponding loss of Sca-1(lo/int) subsets. Most strikingly, the capacity of donor Sca-1(hi) cells to reconstitute an irradiated host is reduced; the longer donor mice are exposed to infection, and Sca-1(hi) c-kit(int) cells have an increased potential to generate B1a-like cells. Thus, Salmonella can have a prolonged influence on BM progenitor functionality not directly related to bacterial persistence. These results reflect changes observed in leucopoiesis during aging and suggest that BM functionality can be modulated by life-long, periodic exposure to infection. Better understanding of this process could offer novel therapeutic opportunities to modulate BM functionality and promote healthy aging.

Monocytes regulate the mechanism of T-cell death by inducing Fas-mediated apoptosis during bacterial infection.

Monocytes and T-cells are critical to the host response to acute bacterial infection but monocytes are primarily viewed as amplifying the inflammatory signal. The mechanisms of cell death regulating T-cell numbers at sites of infection are incompletely characterized. T-cell death in cultures of peripheral blood mononuclear cells (PBMC) showed 'classic' features of apoptosis following exposure to pneumococci. Conversely, purified CD3(+) T-cells cultured with pneumococci demonstrated necrosis with membrane permeabilization. The death of purified CD3(+) T-cells was not inhibited by necrostatin, but required the bacterial toxin pneumolysin. Apoptosis of CD3(+) T-cells in PBMC cultures required 'classical' CD14(+) monocytes, which enhanced T-cell activation. CD3(+) T-cell death was enhanced in HIV-seropositive individuals. Monocyte-mediated CD3(+) T-cell apoptotic death was Fas-dependent both in vitro and in vivo. In the early stages of the T-cell dependent host response to pneumococci reduced Fas ligand mediated T-cell apoptosis was associated with decreased bacterial clearance in the lung and increased bacteremia. In summary monocytes converted pathogen-associated necrosis into Fas-dependent apoptosis and regulated levels of activated T-cells at sites of acute bacterial infection. These changes were associated with enhanced bacterial clearance in the lung and reduced levels of invasive pneumococcal disease.

Research recruitment through the patient portal: perspectives of community focus groups in Seattle and Atlanta.

Objective: Research recruitment through patient portals (ie, patient-facing, web-based clinical interfaces) has the potential to be effective, efficient, and inclusive, but best practices remain undefined. We sought to better understand how patients view this recruitment approach. Materials and Methods: We conducted 6 focus groups in Atlanta, GA and Seattle, WA with members of patient advisory committees and the general public. Discussions addressed acceptability of patient portal recruitment and communication preferences. Focus groups were audio-recorded, transcribed, and analyzed using deductive and inductive codes. Iterative team discussions identified major themes. Results: Of 49 total participants, 20 were patient advisory committee members. Participants' mean age was 49 (range 18-74); 59% identified as non-Hispanic White and 31% as Black/African American. Participants were supportive of patient portal recruitment and confident that messages were private and legitimate. Participants identified transparency and patient control over whether and how to participate as essential features. Concerns included the frequency of research messages and the ability to distinguish between research and clinical messages. Participants also discussed how patient portal recruitment might affect diversity and inclusion. Discussion: Focus group participants generally found patient portal recruitment acceptable and perceived it as secure and trustworthy. Transparency, control, and attention to inclusiveness were identified as key considerations for developing best practices. Conclusion: For institutions implementing patient portal recruitment programs, continued engagement with patient populations can help facilitate translation of these findings into best practices and ensure that implemented strategies accomplish intended goals.

Deciding Whether to Take Sacubitril/Valsartan: How Cardiologists and Patients Discuss Out-of-Pocket Costs.

Background Out-of-pocket costs have significant implications for patients with heart failure and should ideally be incorporated into shared decision-making for clinical care. High out-of-pocket cost is one potential reason for the slow uptake of newer guideline-directed medical therapies for heart failure with reduced ejection fraction. This study aims to characterize patient-cardiologist discussions involving out-of-pocket costs associated with sacubitril/valsartan during the early postapproval period. Methods and Results We conducted content analysis on 222 deidentified transcripts of audio-recorded outpatient encounters taking place between 2015 and 2018 in which cardiologists (n=16) and their patients discussed whether to initiate, continue, or discontinue sacubitril/valsartan. In the 222 included encounters, 100 (45%) contained discussions about cost. Cost was discussed in a variety of contexts: when sacubitril/valsartan was initiated, not initiated, continued, and discontinued. Of the 97 cost conversations analyzed, the majority involved isolated discussions about insurance coverage (64/97 encounters; 66%) and few addressed specific out-of-pocket costs or affordability (28/97 encounters; 29%). Discussion of free samples of sacubitril/valsartan was common (52/97 encounters; 54%), often with no discussion of a longer-term plan for addressing cost. Conclusions Although cost conversations were somewhat common in patient-cardiologist encounters in which sacubitril/valsartan was discussed, these conversations were generally superficial, rarely addressing affordability or cost-value judgments. Cardiologists frequently provided patients with a course of free sacubitril/valsartan samples without a plan to address the cost after the samples ran out.

Getting the Most out of Consent: Patient-Centered Consent for an Acute Stroke Trial.

Informed consent for clinical trials in acute stroke is characterized by challenges related to urgency, cognitive impairment, and geographical separation. Context-appropriate approaches are needed for this setting. We conducted a mixed-methods project involving focus groups and interviews as well as collaboration with a patient advisory panel and a central institutional review board (CIRB) to design and implement a patient-driven consent process for a multicenter trial incorporating adaptive randomization. Remote consent was recognized as challenging but acceptable. Adaptive randomization was viewed positively, but significant potential for misunderstanding was appreciated. Collaboration between the patient advisory panel and the CIRB resulted in a shortened, more patient-centered consent form that was approved at all sites with few modifications. An information sheet was developed as a resource for patients and surrogates after enrollment. Collaboration between investigators, patient partners, and a CIRB can facilitate innovation and implementation of patient-centered, context-appropriate consent strategies.

Reframing Recruitment: Evaluating Framing in Authorization for Research Contact Programs.

BACKGROUND: The changing clinical research recruitment landscape involves practical challenges but introduces opportunities. Researchers can now identify large numbers of eligible patients through electronic health record review and can directly contact those who have authorized contact. Applying behavioral science-driven strategies to design and frame communication could affect patients' willingness to authorize contact and their understanding of these programs. The ethical and practical implications of various strategies warrant empirical evaluation. METHODS: We conducted an online survey (n = 1070) using a nationally-representative sample. Participants were asked to imagine being asked for authorization for research contact in clinic. They were randomly assigned to view one of three flyers: #1-neutral text flyer; #2-a positive text flyer; or #3-positive graphics-based flyer. Primary outcomes included likelihood of enrollment and comprehension of the program. Chi-Square tests and regression analyses were used to examine whether those who saw the positive flyers were more likely to enroll and had increased comprehension. RESULTS: Compared to the neutral flyer, individuals who received the positive text flyer were numerically more likely to enroll, but this was not statistically significant (24.2% v. 19.0%, p = 0.11). Individuals who received the positive graphics flyer were more likely to enroll (28.7% v. 19.0%, p = 0.002). After adjustment, individuals assigned to both novel flyers had increased odds of being likely to enroll (OR = 1.55 95%CI [1.04, 2.31] and OR = 1.95 95%CI [1.31, 2.91]). Flyer type did not affect overall comprehension (p = 0.21), and greater likelihood of enrollment was observed only in individuals with better comprehension. CONCLUSIONS: This study demonstrated that employing behavioral science-driven communication strategies for authorization for research contact had an effect on likelihood of hypothetical enrollment but did not significantly affect comprehension. Strategies using simple, positive language and visual tools may be effective and ethically appropriate. Further studies should explore how these and other approaches can help to optimize research recruitment.

Public attitudes toward an authorization for contact program for clinical research.

We conducted an online experimental survey to evaluate attitudes toward an authorization for contact (AFC) program allowing researchers to contact patients about studies based on electronic record review. A total of 1070 participants were randomly assigned to 1 of 3 flyers varying in design and framing. Participants were asked to select concerns about and reasons for signing up for AFC. Logistic regression and latent class analysis were conducted. The most commonly selected concerns included needing more information (43%), privacy (40%), and needing more time to think (28%). A minority were not interested in participating in research (16%) and did not want to be bothered (15%). Latent class analysis identified clusters with specific concerns about privacy, lack of interest in research, and not wanting to be bothered. A novel flyer with simple and positive framing was associated with lower odds of both not wanting to be bothered (P = .01) and not being interested in research (P = .01). Many concerns about AFC programs appear nonspecific. Addressing privacy, lack of interest in research, and not wanting to be bothered warrant further study as ways to enhance recruitment.

Framing Benefits in Decision Aids: Effects of Varying Contextualizing Statements on Decisions About Sacubitril-Valsartan for Heart Failure.

Background. Presenting numeric data alone may result in patients underappreciating clinically significant benefits. Contextualizing statements to counter this may raise concern about absence of neutrality. These issues arose during construction of a decision aid for sacubitril-valsartan, a heart failure medication associated with a ∼3% absolute reduction in 2-year mortality that carries high out-of-pocket cost. A contextualizing statement framing this as a "pretty big benefit" was incorporated. The impact of statements like this within decision aids is unknown. Objective. This online Qualtrics survey sought to deepen understanding of benefit framing by testing the impact of varying contextualizing statements within a decision aid for sacubitril-valsartan. Design. Participants were randomly assigned to receive one of six abbreviated versions of a decision aid for sacubitril-valsartan that varied only by contextualizing statement (ranging from strongly neutral to strongly positive and using relative and absolute risk reductions). Participants were asked to answer questions regarding the likelihood of taking the medication at a cost of $50/month and their perception of the drug's benefits. Results. A total of 1873 participants who were demographically similar to the heart failure population completed the survey. Fifty-four percent were willing to take sacubitril-valsartan at $50/month. Each of the five experimental contextualizing statements was compared with the baseline version; no significant differences were observed in reported likelihood of taking sacubitril-valsartan. After controlling for demographics and covariates, group assignment did not predict likelihood of taking the medication. Higher income, better self-reported health status, and younger age were associated with increased likelihood of taking sacubitril-valsartan. Limitations. This study used a hypothetical scenario and evaluated one method of delivering contextualizing statements. Conclusions. Contextualizing statements as tested within this decision aid did not affect decision making.

Show Me the Money: Patients' Perspectives on a Decision Aid for Sacubitril/Valsartan Addressing Out-of-Pocket Cost.

BACKGROUND: Out-of-pocket medication costs for patients who have heart failure with reduced ejection fraction may be an important part of shared decision-making, but cost has generally been excluded from clinical discussions. This study reports patients' perspectives on a decision aid for sacubitril/valsartan that explicitly addresses out-of-pocket costs. METHODS: Structured, in-depth interviews were conducted with 20 patients with heart failure with reduced ejection fraction from 2 medical centers to elicit their views on a publicly available decision aid for sacubitril/valsartan that explicitly incorporates considerations related to out-of-pocket costs. Qualitative descriptive analysis was conducted. RESULTS: Key themes identified were general enthusiasm for decision aids for medication decisions, openness on the part of patients to incorporation of cost into decision-making and the decision aid, requests for greater specificity regarding patient-specific cost, and challenges communicating evidence of benefit in a way that allows patients to make cost-benefit analyses for themselves. Patients also raised questions regarding logistical challenges of incorporating a decision aid into the normal clinical and decision-making workflow. CONCLUSIONS: Patients were receptive to the inclusion of out-of-pocket cost as relevant in a decision aid for sacubitril/valsartan. Key challenges to effective integration of cost in these decisions include developing mechanisms for acquiring reliable patient-specific cost estimates and addressing patients' difficulties (and sometimes skepticism) applying trial evidence to their own situation. In addition, implementation strategies are important to develop to facilitate decision aid integration for routine medical decisions into clinic workflow.

Placental transfer of 125 iodinated humanized immunoglobulin G2Δa in the cynomolgus monkey.

Antibody-like biopharmaceuticals cross the placenta by utilizing existing transport pathways (e.g., FcRn receptor). There are limited data evaluating this transfer during organogenesis in any species. Understanding placental transfer of antibody-like biopharmaceuticals can help to predict risk of developmental toxicity across species, including humans. To complement previously published placental transfer data in the rat with humanized IgGΔ2 (hIgG2), the timing and magnitude of transfer in the cynomolgus monkey and embryo/fetal biodistribution of maternally administered 125 I-radiolabeled hIgG2 was quantified on gestation days (GD) 35, 40, 50, 70, and 140 using gamma counting and whole body autoradiography 24 hr following intravenous injection. Chorioallantoic placental tissues were collected at all time points for Western Blot analysis with anti-FcRn antibody. Maternally administered 125 I-hIgG2 was found in embryo/fetal tissues at all time points, including organogenesis. Embryo/fetal plasma 125 I-hIgG2 concentration increased during gestation, but only slightly up to GD 70 in embryo/fetal tissues, with hIgG2 tissue concentrations generally similar between GD70 and 140. The embryo/fetal:maternal 125 I-hIgG2 plasma concentration ratio was approximately 2.3 fold higher on GD 140, in comparison to ratios on GD 40. Importantly, placental FcRn protein expression was confirmed at all timepoints. These data demonstrate placental transfer of hIgG2 in a nonhuman primate model, and at levels comparable to the rat model, raising the potential for adverse developmental outcomes by direct antibody binding to biological targets.

Role of conjugative elements in the evolution of the multidrug-resistant pandemic clone Streptococcus pneumoniaeSpain23F ST81.

Streptococcus pneumoniae is a human commensal and pathogen able to cause a variety of diseases that annually result in over a million deaths worldwide. The S. pneumoniae(Spain23F) sequence type 81 lineage was among the first recognized pandemic clones and was responsible for almost 40% of penicillin-resistant pneumococcal infections in the United States in the late 1990s. Analysis of the chromosome sequence of a representative strain, and comparison with other available genomes, indicates roles for integrative and conjugative elements in the evolution of pneumococci and, more particularly, the emergence of the multidrug-resistant Spain 23F ST81 lineage. A number of recently acquired loci within the chromosome appear to encode proteins involved in the production of, or immunity to, antimicrobial compounds, which may contribute to the proficiency of this strain at nasopharyngeal colonization. However, further sequencing of other pandemic clones will be required to establish whether there are any general attributes shared by these strains that are responsible for their international success.

Determinants of Patient and Surrogate Experiences With Acute Care Research Consent: A Key Informant Interview Study.

Background Informed consent for acute myocardial infarction and stroke research is challenging. Time for enrollment decisions is limited, patients and family are usually stressed, and being asked to participate in research is often unexpected. Despite these barriers, patients and surrogates have reported a preference for prospective involvement in research decisions and generally positive views of the consent process. It is unknown what drives positive or negative consent experiences. These data are crucial to making consent processes more context appropriate. Methods and Results We conducted a qualitative interview study with 27 patients and surrogates enrolled in acute myocardial infarction and stroke trials in the past 5 years. Purposive sampling from the P-CARE (Patient-Centered Approaches to Research Enrollment) study was based on participant characteristics and responses to initial patient-centered interviews. In-depth interviews used open-ended questions to explore factors influencing consent experiences. Qualitative descriptive analysis was performed utilizing a multilevel coding strategy. Participants identified specific researcher behaviors as important, including expressions of respect, professionalism, and nonpressuring communication. Participants preferred consent conversations focused on risks/benefits and the trial protocol. They had varying views of consent forms and communicated several reasons the form was valuable unrelated to informational content. Participants also valued postenrollment interactions as opportunities to ask questions and learn about the study. Conclusions Barriers to consent in acute myocardial infarction and stroke trials are unavoidable, but participants identified productive ways to demonstrate respect for patients during enrollment conversations. These include key researcher behaviors, concentrating consent discussions on what participants find most important, and structured postenrollment follow-up.

Discussing Out-of-Pocket Costs With Patients: Shared Decision Making for Sacubitril-Valsartan in Heart Failure.

Background "Financial toxicity" is a concern for patients, but little is known about how patients consider out-of-pocket cost in decisions. Sacubitril-valsartan provides a contemporary scenario to understand financial toxicity. It is guideline recommended for heart failure with reduced ejection fraction, yet out-of-pocket costs can be considerable. Methods and Results Structured interviews were conducted with 49 patients with heart failure with reduced ejection fraction at heart failure clinics and inpatient services. Patient opinions of the drug and its value were solicited after description of benefits using graphical displays. Descriptive quantitative analysis of closed-ended responses was conducted, and qualitative descriptive analysis of text data was performed. Of participants, 92% (45/49) said that they would definitely or probably switch to sacubitril-valsartan if their physician recommended it and out-of-pocket cost was $5 more per month than their current medication. Only 43% (21/49) would do so if out-of-pocket cost was $100 more per month ( P<0.001). At least 40% across all income categories would be unlikely to take sacubitril-valsartan at $100 more per month. Participants exhibited heterogeneous approaches to cost in decision making and varied on their use and interpretation of probabilistic information. Few (20%) participants stated physicians had initiated a conversation about cost in the past year. Conclusions Out-of-pocket cost variation reflective of contemporary cost sharing substantially influenced stated willingness to take sacubitril-valsartan, a guideline-recommended therapy with mortality benefit. These findings suggest a need for cost transparency to promote shared decision making. They also demonstrate the complexity of cost discussion and need to study how to incorporate out-of-pocket cost into clinical decisions.