FDA Approvals of Oncology Drugs for Tissue-Agnostic Indications.

BACKGROUND: The development of molecularly targeted oncology drugs for tissue-agnostic indications represents a new paradigm, but marketing authorization may carry additional risks due to uncertainties about extrapolating drug safety and efficacy, and biomarker test accuracy, to unstudied tumor types. OBJECTIVE: To determine tumor types represented and method of mutation identification in trials supporting the US Food and Drug Administration (FDA) approvals of tissue-agnostic drugs, and to describe post-marketing requirements and commitments (PMRs/PMCs) issued for studies to evaluate additional tumor types and to validate companion diagnostic devices. METHODS: For each tissue-agnostic drug approval identified via the FDA's Hematology/Oncology Approvals and Safety Notifications website, prescribing information, approval packages, and letters were retrieved from the Drugs@FDA website. Characteristics of approvals, details of supporting trials, and PMRs/PMCs for clinical trials and diagnostic tests were extracted. RESULTS: Six drugs were approved for seven tissue-agnostic indications between 2017 and 2022, with 9-15 different tumor types represented in trials supporting approvals. Only one approval prospectively utilized a commercial assay to identify the molecular alteration of interest in tumor samples. All seven approvals were issued PMRs for trials with additional tumor types, and six of seven were issued PMCs for studies to support labeling for companion diagnostic devices. CONCLUSION: The number of patients and cancer subtypes in trials supporting tissue-agnostic oncology drug approvals varied by mutation. Most drug approvals did not have concurrent approval of a diagnostic test. Post-marketing studies play a critical role in confirming clinical benefit and ensuring companion diagnostic device performance across a broader range of tumor types.

The use of real-world evidence to support FDA post-approval study requirements for oncology drugs.

BACKGROUND: The 21st Century Cures Act of 2016 included provisions for the Food and Drug Administration (FDA) to evaluate the potential for real-world evidence (RWE) to support or fulfill post-approval study requirements. This study reviewed post-marketing requirement (PMR) and post-marketing commitment (PMC) obligations for oncology drugs approved by the FDA post-Cures Act to identify those with RWE components. METHODS: Approval letters issued by the FDA between 2017-2020 for oncology drugs were systematically analyzed for PMRs or PMCs with requests for RWE. For each PMR/PMC identified, the characteristics of the approvals, the PMRs/PMCs, and the RWE requested were reviewed. RESULTS: Of 189 oncology drug approvals with 456 associated PMRs/PMCs, a total of 15 PMRs/PMCs specified RWE. Compared with all oncology drug approvals, the 14 approvals with PMRs/PMCs requesting RWE were more frequently accelerated approvals, for new therapies, with orphan indications. All 15 PMRs/PMCs requested real-world safety data, with 3 also requesting real-world effectiveness data. RWE requested included post-marketing safety reports, prospective observational studies, expanded access study data, and registry data. CONCLUSION: As a greater proportion of safety and efficacy data generation for oncology drugs shifts to the post-marketing setting, RWE has the potential to become an integral component of PMR/PMC fulfillment.

The RACE for children act at one year: progress in pediatric development of molecularly targeted oncology drugs.

BACKGROUND: The Research to Accelerate Cures and Equity (RACE) for Children Act of 2017 authorized the Food and Drug Administration (FDA) to require pediatric clinical trials for new oncology drugs with relevant molecular targets. This study reviewed oncology drug approvals within the first year after the new legislation came into effect, to evaluate the impact on development of molecularly targeted oncology drugs for pediatric cancers. RESEARCH DESIGN AND METHODS: For new oncology drugs approved by the FDA between 08/18/2020 and 08/18/2021, drug approval packages, letters, and prescribing information were reviewed for the submission and approval dates, indication, and molecular target of the drug, and post-marketing requirements that included pediatric clinical trials. RESULTS: Within the 1-year period, 17 new oncology drugs were approved, but only 5 had been submitted after 08/18/2020. Three of the 5 (60.0%) had requirements for pediatric trials under the RACE Act. None of the 12 submitted prior to 08/18/2020 had pediatric trial requirements, but 10 (83.3%) had molecular targets that would have made them candidates under the RACE Act. CONCLUSIONS: Early evidence suggests that the RACE Act was effective at closing the loopholes of previous legislation and creating new opportunities for innovation in developing therapies for childhood cancers.

Impact of Augmented Intelligence on Utilization of Palliative Care Services in a Real-World Oncology Setting.

PURPOSE: For patients with advanced cancer, timely referral to palliative care (PC) services can ensure that end-of-life care aligns with their preferences and goals. Overestimation of life expectancy may result in underutilization of PC services, counterproductive treatment measures, and reduced quality of life for patients. We assessed the impact of a commercially available augmented intelligence (AI) tool to predict 30-day mortality risk on PC service utilization in a real-world setting. METHODS: Patients within a large hematology-oncology practice were scored weekly between June 2018 and October 2019 with an AI tool to generate insights into short-term mortality risk. Patients identified by the tool as being at high or medium risk were assessed for a supportive care visit and further referred as appropriate. Average monthly rates of PC and hospice referrals were calculated 5 months predeployment and 17 months postdeployment of the tool in the practice. RESULTS: The mean rate of PC consults increased from 17.3 to 29.1 per 1,000 patients per month (PPM) pre- and postdeployment, whereas the mean rate of hospice referrals increased from 0.2 to 1.6 per 1,000 PPM. Eliminating the first 6 months following deployment to account for user learning curve, the mean rate of PC consults nearly doubled over baseline to 33.0 and hospice referrals increased 12-fold to 2.4 PPM. CONCLUSION: Deployment of an AI tool at a hematology-oncology practice was found to be feasible for identifying patients at high or medium risk for short-term mortality. Insights generated by the tool drove clinical practice changes, resulting in significant increases in PC and hospice referrals.

Impact of social determinants of health on cancer care: a survey of community oncologists.

OBJECTIVE: Cancer survival rates have improved over the past few decades, yet socioeconomic disparities persist. Social determinants of health (SDOH) have consistently been shown to correlate with health outcomes. The objective of this study was to characterise oncologists' perceptions of the impact of SDOH on their patients, and their opinions on how these effects could be remediated. DESIGN: Cross-sectional survey of physicians. SETTING: Web-based survey completed prior to live meetings held between February and April 2020. PARTICIPANTS: Oncologists/haematologists from across the USA. EXPOSURE: Clinical practice in a community-based or hospital-based setting. MAIN OUTCOME AND MEASURE: Physician responses regarding how SDOH affected their patients, which factors represented the most significant barriers to optimal health outcomes and how the impact of SDOH could be mitigated through assistance programmes. RESULTS: Of the 165 physicians who completed the survey, 93% agreed that SDOH had a significant impact on their patients' health outcomes. Financial security/lack of insurance and access to transportation were identified most often as the greatest barriers for their patients (83% and 58%, respectively). Eighty-one per cent of physicians indicated that they and their staff had limited time to spend assisting patients with social needs, and 76% reported that assistance programmes were not readily accessible. Government organisations, hospitals, non-profit organisations and commercial payers were selected by 50% or more of oncologists surveyed as who should be responsible for delivering assistance programmes to patients with social needs; 42% indicated that pharmaceutical manufacturers should also be responsible. CONCLUSION: Our survey found that most oncologists were aware of the impact of SDOH on their patients but were constrained in their time to assist patients with social needs. The physicians in our study identified a need for more accessible assistance programmes and greater involvement from all stakeholders in addressing SDOH to improve health outcomes.

Augmented intelligence to predict 30-day mortality in patients with cancer.

Aim: An augmented intelligence tool to predict short-term mortality risk among patients with cancer could help identify those in need of actionable interventions or palliative care services. Patients & methods: An algorithm to predict 30-day mortality risk was developed using socioeconomic and clinical data from patients in a large community hematology/oncology practice. Patients were scored weekly; algorithm performance was assessed using dates of death in patients' electronic health records. Results: For patients scored as highest risk for 30-day mortality, the event rate was 4.9% (vs 0.7% in patients scored as low risk; a 7.4-times greater risk). Conclusion: The development and validation of a decision tool to accurately identify patients with cancer who are at risk for short-term mortality is feasible.

Expanded Access and Right To Try Requests: The Community Oncologist's Experience.

PURPOSE: For patients with cancer who have exhausted approved treatment options and for whom appropriate clinical trials are not available, access to investigational drugs through the US Food and Drug Administration's Expanded Access (EA) program has been an alternative since the program's inception more than 30 years ago. In 2018, federal Right To Try legislation was passed in the United States, creating a second pathway-one that bypasses the US Food and Drug Administration-to obtain unapproved drugs outside of clinical trials. The use of the two programs by community medical oncologists and hematologist-oncologists has not been studied. METHODS: Between October 2019 and February 2020, community oncologists-hematologists from across the United States completed web-based surveys about EA and Right To Try pathways for accessing unapproved drugs for their patients. Physicians were asked about their utilization of, and perceptions of, the two programs. RESULTS: Of the 238 physicians who completed the survey, 46% indicated that they had attempted to gain access to an investigational drug for a patient using the EA program, whereas 14% reported attempting to use Right To Try pathway to obtain an unapproved drug for a patient. Eighty-nine percent of those who tried to use the EA program reported success in obtaining the investigational drug versus 73% of those who attempted to use the Right To Try pathway. CONCLUSION: Our survey found that most community oncologists-hematologists were aware of both the EA and Right To Try pathways, but there is room for improvement in understanding and utilization of the programs.

Comparison of Solid Tumor Treatment Response Observed in Clinical Practice With Response Reported in Clinical Trials.

Importance: In clinical trials supporting the regulatory approval of oncology drugs, solid tumor response is assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Calculation of RECIST-based responses requires sequential, timed imaging data, which presents challenges to the method's application in real-world evidence research. Objective: To evaluate the feasibility and validity of a novel real-world RECIST method in assessing tumor burden associated with therapy for a large heterogeneous patient population undergoing treatment in routine clinical practice. Design, Setting, and Participants: This cohort study used physician-abstracted data pooled from retrospective, multisite electronic health record (EHR) review studies of patients treated with anticancer drugs at US oncology practices from 2014 through 2017. Included patients were receiving first-line treatment for thyroid cancer, breast cancer, or metastatic melanoma. Data were analyzed from March through August 2020. Exposures: Undergoing treatment with immunotherapy or targeted therapy. Main Outcomes and Measures: Tumor response was classified according to RECIST guidelines (ie, change in sum diameter of target lesions) post hoc with measurements derived from imaging scans and reports. Results: Among 1308 completed electronic case report forms, 956 forms (73.1%) had adequate data to classify real-world RECIST response. The greatest difference between physician-recorded responses and real-world RECIST-based responses was found in the proportion of complete responses: 118 responses (12.3%) vs 46 responses (4.8%) (P < .001). Among 609 patients in the metastatic melanoma population, complete responses were reported in 112 physician-recorded responses (18.4%) vs 44 real-world RECIST-based responses (7.2%) (P < .001), compared with 11 of 247 responses (4.5%) to 31 of 192 responses (16.1%) across pivotal trials of the same melanoma therapies. Conclusions and Relevance: These findings suggest that comparing tumor lesion sizes and categorizing treatment response according to RECIST guidelines may be feasible using real-world data. This study found that physician-recorded assessments were associated with overestimation of treatment response, with the largest overestimation among complete responses. Real-world RECIST-based assessments were associated with better approximations of tumor response reported in clinical trials compared with those reported in EHRs.

Real-world adverse events associated with CAR T-cell therapy among adults age ≥ 65 years.

INTRODUCTION: Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for relapsed or refractory large B-cell lymphoma (LBCL) with the Food and Drug Administration (FDA) approvals of axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tis-cel). Although the incidence of LBCL is highest among patients age ≥ 65, clinical trials supporting approval of these 2 products primarily enrolled younger patients. Safety data for axi-cel and tis-cel in older patients is limited. METHODS: In this analysis, we queried the FDA Adverse Events Reporting System (FAERS) database for cases associated with axi-cel or tis-cel from the FDA approval dates for the LBCL indication for each product through December 31, 2019, and compared adverse events (AEs) reported for cases involving patients aged <65 and ≥ 65. RESULTS: A total of 804 cases were retrieved, with 333 (41%) involving patients age ≥ 65. Cytokine release syndrome (CRS) was the most common AE reported in both age groups. Cases involving older patients had a significantly higher proportion of neurological AEs, including CAR T-cell-related encephalopathy syndrome (8% vs. 4%, p = 0.03). Some individual clinical features of CRS were significantly more common among younger age group cases, including pyrexia (33% vs. 23%, p < 0.01), tachycardia (10% vs. 5%, p < 0.01), and thrombocytopenia (4% vs. 2%, p = 0.03). DISCUSSION: In this age-based analysis of FAERS reports for patients treated with axi-cel or tis-cel, we identified differences in patterns of AEs experienced. This large-scale post-marketing study complements clinical trial safety data and may help inform clinicians' decision making when treating adult patients with CAR-T cell therapy.

Use of Real-World Evidence to Support FDA Approval of Oncology Drugs.

OBJECTIVES: Real-world evidence (RWE) has gained increased attention in recent years as a complement to traditional clinical trials. The use of RWE to establish the efficacy of oncology drugs for Food and Drug Administration (FDA) approval has not been described. In this paper, we review 5 recent examples where RWE was submitted in support of the FDA approvals of original or supplementary indications for oncology drugs. METHODS: To identify cases where RWE was used, we reviewed drug approval packages available at Drugs@FDA for oncology drugs approved between 2017 and 2019. Five cases were selected to present a broad overview of different types of RWE, different circumstances under which RWE has been used for regulatory approvals, and how FDA evaluated the data in each case. The type of RWE submitted, the indication, limitations identified by FDA reviewers, and the outcome of the submission are discussed. RESULTS: RWE, particularly historical controls for rare or orphan indications, has been used to support both original and supplementary oncology drug approvals. Types of RWE included data from electronic health records, claims, post-marketing safety reports, retrospective medical record reviews, and expanded access studies. Small sample sizes, data quality, and methodological issues were among concerns cited by FDA reviewers. CONCLUSION: By bridging the gap between the constraints of the trial setting and the realities of clinical practice, RWE can add value to a regulatory submission. These early examples provide insight into how regulators evaluated RWE submitted as evidence of efficacy for oncology drugs.

Neurological adverse events following CAR T-cell therapy: a real-world analysis.

Aim: To characterize real-world neurological adverse events (AEs) associated with chimeric antigen receptor T-cell therapies in patients with refractory/relapsed large B-cell lymphomas. Materials & methods: Postmarketing case reports from the US FDA AEs reporting system involving axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) for large B-cell lymphomas were analyzed. Results: Of 804 AE cases identified (637 axi-cel, 167 tisa-cel), 428 (67%) of axi-cel cases and 43 (26%) of tisa-cel cases reported neurological AEs. Compared with cases without neurological AEs, significant associations were observed between neurological AEs and use of axi-cel, age ≥65 years, and the outcome of hospitalization. Conclusion: Neurological AEs were common with chimeric antigen receptor T-cell therapy in the real world and largely reflected those reported in clinical trials.

The safety and effectiveness of adenosine diphosphate receptor inhibitor pretreatment among acute myocardial infarction patients treated with percutaneous coronary intervention in community practice: Insights from the TRANSLATE-ACS study.

OBJECTIVES: To understand the optimal timing of adenosine diphosphate (ADP) receptor inhibitor pretreatment prior to percutaneous coronary intervention (PCI) among acute myocardial infarction (MI) patients. BACKGROUND: The role of ADP receptor inhibitor pretreatment in this population is unclear. METHODS: A total of 9,251 ADP receptor inhibitor-naïve MI patients undergoing PCI at 229 TRANSLATE-ACS sites were evaluated. Adjusted risks of in-hospital major adverse cardiovascular events (MACE) and major bleeding were compared among patients with and without pretreatment using inverse probability-weighted propensity adjustment. RESULTS: Of 9,251 patients treated with either prasugrel or clopidogrel during the index MI hospitalization, 4,056 (44%) received pretreatment (ST-segment elevation MI [STEMI] 54.9%, non-STEMI 45.1%); pretreatment was used more commonly among those receiving clopidogrel than prasugrel (52% vs. 20%, P < 0.0001). MACE risks were not significantly different between patients with and without pretreatment (clopidogrel 2.1% vs. 2.2%, adjusted hazard ratio [HR] 1.00, 95% confidence interval [CI] 0.70-1.43; prasugrel 2.1% vs. 2.3%, adjusted odds ratio [OR] 0.82, 95% CI 0.42-1.60). No differences in major bleeding were observed among those receiving versus not receiving pretreatment (clopidogrel 3.1% vs. 3.5%, adjusted HR 0.94, 95% CI 0.65-1.36; prasugrel 2.5% vs. 2.7%, adjusted OR 0.93, 95% CI 0.42-2.02); results were similar when stratified by MI type. CONCLUSIONS: ADP receptor inhibitor pretreatment (44%) is commonly used among acute MI patients undergoing PCI in contemporary practice, but no significant differences were found in in-hospital MACE and/or bleeding risks between patients receiving versus not receiving pretreatment, regardless of ADP receptor inhibitor type.

Multivessel Versus Culprit Vessel-Only Percutaneous Coronary Intervention Among Patients With Acute Myocardial Infarction: Insights From the TRANSLATE-ACS Observational Study.

BACKGROUND: Among patients with acute myocardial infarction (MI) who have multivessel disease, it is unclear if multivessel percutaneous coronary intervention (PCI) improves clinical and quality-of-life outcomes compared with culprit-only intervention. We sought to compare clinical and quality-of-life outcomes between multivessel and culprit-only PCI. METHODS AND RESULTS: Among 6061 patients with acute MI who have multivessel disease in the TRANSLATE-ACS (Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) study, we used inverse probability-weighted propensity adjustment to study the associations between multivessel and culprit-only intervention during the index PCI and major adverse cardiovascular events, unplanned all-cause readmission, and angina frequency at 6 weeks and 1 year. Multivessel PCI was performed in 1208 (20%) of patients with MI who had multivessel disease. Relative to the culprit-only intervention, patients receiving multivessel PCI were similarly aged and more likely to be seen with non-ST-segment elevation MI or cardiogenic shock. At 6 weeks, the initial multivessel PCI strategy was associated with lower major adverse cardiovascular events and unplanned readmission risks, whereas angina frequency was not significantly different between multivessel and culprit-only PCI. At 1 year, major adverse cardiovascular event risk was persistently lower in the multivessel PCI group (adjusted hazard ratio, 0.84; 95% confidence interval, 0.72-0.99), whereas long-term readmission risk (adjusted hazard ratio, 0.94; 95% confidence interval, 0.84-1.04) and angina frequency were similar between groups (adjusted odds ratio, 1.01; 95% confidence interval, 0.82-1.24). Similar associations were seen when patients with ST-segment elevation MI and non-ST-segment elevation MI were examined separately. CONCLUSIONS: Among patients with acute MI who have multivessel disease, multivessel PCI was associated with lower risk of all-cause readmission at 6 weeks and lower risk of major adverse cardiovascular events at 6 weeks and 1 year. However, similar short- and long-term angina frequencies were noted.

Association of measured platelet reactivity with changes in P2Y12 receptor inhibitor therapy and outcomes after myocardial infarction: Insights into routine clinical practice from the TReatment with ADP receptor iNhibitorS: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) study.

BACKGROUND: Little is known about the use of platelet function testing to guide choice of P2Y12 receptor inhibitor therapy in routine clinical practice. METHODS: We studied 671 myocardial infarction (MI) patients treated with percutaneous coronary intervention in the TRANSLATE-ACS Registry who had VerifyNow platelet function testing performed while on clopidogrel treatment during their index hospitalization (April 2010-October 2012). RESULTS: High platelet reactivity (>208 platelet reactivity units [PRU]) was present in 261 (38.9%) patients. Clopidogrel was switched in-hospital to prasugrel in 80 (30.7%) patients with high platelet reactivity and 18 (4.4%) patients with therapeutic platelet reactivity (≤208 PRU). Among high platelet reactivity patients, switch to prasugrel was associated with lower major adverse cardiovascular events (death, MI, stroke, or unplanned revascularization) at 1year (10.0% vs 22.7%, P=.02; adjusted odds ratio [OR] 0.39, 95% CI 0.18-0.85, P=.02) and no significant difference in Bleeding Academic Research Consortium type 2 or higher bleeding (23.8% vs 22.1%, P=.77; adjusted OR 0.91, 95% CI 0.48-1.7, P=.77) compared with patients continued on clopidogrel. No significant differences in major adverse cardiovascular event (22.2% vs 12.8%, P=.25; adjusted OR 1.8, 95% CI 0.47-7.3, P=.38) or bleeding (22.2% vs 19.4%, P=.77; adjusted OR 1.3, 95% CI 0.27-6.8, P=.72) were observed among therapeutic platelet reactivity patients between switching and continuation on clopidogrel. CONCLUSIONS: Only one-third of percutaneous coronary intervention-treated MI patients with high on-clopidogrel platelet reactivity were switched to a more potent P2Y12 receptor inhibitor. Intensification of antiplatelet therapy was associated with lower risk of ischemic events at 1year among HPR patients.

Switching of adenosine diphosphate receptor inhibitor after hospital discharge among myocardial infarction patients: Insights from the Treatment with Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) observational study.

The reasons for postdischarge adenosine diphosphate receptor inhibitor (ADPri) switching among patients with myocardial infarction (MI) are unclear. We sought to describe the incidence and patterns of postdischarge ADPri switching among patients with acute MI treated with percutaneous coronary intervention. METHODS: We used TRANSLATE-ACS (2010-2012) data to assess postdischarge ADPri switching among 8,672 MI patients discharged after percutaneous coronary intervention who remained on ADPri therapy 1 year post-MI. We examined patient-reported reasons for switching, GUSTO moderate or severe bleeding, major adverse cardiovascular events (MACEs), and definite stent thrombosis events around the time of the switch. RESULTS: Among patients still on ADPri therapy 1 year post-MI, 663 (7.6%) switched ADPri during that year. Switching occurred at a median of 50 days postdischarge and most frequently in patients discharged on ticagrelor (64/226; 28.3%), followed by prasugrel (383/2,489; 15.4%) and clopidogrel (216/5,957; 3.6%) (P < .001). Among patients discharged on prasugrel, 97.3% of switches were to clopidogrel and 87.5% of ticagrelor switches were to clopidogrel; both of these groups most often cited cost as a reason for switching (43.6% and 39.1%, respectively), whereas 60.7% who switched from clopidogrel cited physician decision as a reason. In the 7 days preceding the switch from clopidogrel, 40 (18.5%) had a MACE and 12 (5.6%) had a definite stent thrombosis event, whereas that from prasugrel or ticagrelor, a GUSTO moderate or severe bleeding event occurred in 1 (0.3%) and 0 patients, respectively. CONCLUSIONS: Postdischarge ADPri switching occurred infrequently within the first year post-MI and uncommonly was associated with MACEs or bleeding events.

Early Cessation of Adenosine Diphosphate Receptor Inhibitors Among Acute Myocardial Infarction Patients Treated With Percutaneous Coronary Intervention: Insights From the TRANSLATE-ACS Study (Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome).

BACKGROUND: Guidelines recommend the use of adenosine diphosphate receptor inhibitor (ADPri) therapy for 1 year postacute myocardial infarction; yet, early cessation of therapy occurs frequently in clinical practice. METHODS AND RESULTS: We examined 11 858 acute myocardial infarction patients treated with percutaneous coronary intervention discharged alive on ADPri therapy from 233 United States TRANSLATE-ACS study (Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) participating hospitals to determine the prevalence of early ADPri cessation (within 1 year), patient-reported reasons for cessation, and associated risk of major adverse cardiovascular events at 1 year. Overall, 2514 (21.2%) of percutaneous coronary intervention-treated patients stopped ADPri by 1 year postmyocardial infarction; the median time from discharge to cessation was 200.5 days (25th, 75th percentiles: 71, 340). Among those with early ADPri cessation, 53.9% received drug-eluting stents and had a median duration of 301 treatment days (25th, 75th percentiles: 137, 353); 33.3% of drug-eluting stent patients stopped treatment within 6 months compared with 64.2% of bare metal stent patients. Those discharged on prasugrel (versus clopidogrel) had a slightly higher likelihood of early ADPri cessation (23.2% versus 21.0%; P=0.03; adjusted hazard ratio, 1.28; 95% confidence interval, 1.17-1.40). Patient-reported reasons for early ADPri cessation included physician-recommended discontinuation (54%), as well as patient self-discontinuation, because of cost (19%), medication side effects (9%), and procedural interruption (10%). Using a time-dependent covariate model, early cessation of ADPri therapy was associated with increased major adverse cardiovascular event (adjusted hazard ratio, 1.40; 95% confidence interval, 1.19-1.65; P<0.0001). CONCLUSIONS: One in 5 percutaneous coronary intervention-treated myocardial infarction patients stopped ADPri treatment within 1 year. Early cessation was associated with increased major adverse cardiovascular event risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01088503.

Factors Associated With Initial Prasugrel Versus Clopidogrel Selection for Patients With Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention: Insights From the Treatment With ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) Study.

BACKGROUND: Few studies have examined how antiplatelet therapies are selected during the routine care of acute myocardial infarction patients, particularly relative to the patient's estimated mortality and bleeding risks. METHODS AND RESULTS: We examined patients presenting with acute myocardial infarction treated with percutaneous coronary intervention at 233 US hospitals in the TRANSLATE-ACS observational study from April 2010 to October 2012. We developed a multivariable logistic regression model to identify factors associated with prasugrel selection. Prasugrel use rates and associated 1-year risk-adjusted major adverse cardiovascular events and Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) moderate/severe bleeding outcomes were also examined in relation to predicted mortality and bleeding using the validated Acute Coronary Treatment and Intervention Outcomes (ACTION) risk prediction scores. Among 11 969 patients, 3123 (26%) received prasugrel at the time of percutaneous coronary intervention. The strongest factors associated with prasugrel use included cardiogenic shock (odds ratio [OR] 1.68, 95% CI 1.25-2.26), drug-eluting stent use (OR 1.45, 95% CI 1.31-1.62), and ST-segment elevation myocardial infarction presentation (OR 1.23, 95% CI 1.12-1.35). Older age (OR 0.57, 95% CI 0.0.53-0.61), dialysis (OR 0.56, 95% CI 0.32-0.96), prior history of stroke/transient ischemic attack (OR 0.52, 95% CI 0.38-0.73), and interhospital transfer (OR 0.50, 95% CI 0.46-0.55) were associated with lowest prasugrel selection. Prasugrel was used less often than clopidogrel in patients at higher predicted bleeding risk (21.9% versus 29.7%, P<0.001). Yet paradoxically, prasugrel was also less likely than clopidogrel to be used in patients with higher predicted mortality risk (21.1% versus 30.2%, P<0.001). Adjusted bleeding and outcomes events were similar among those receiving prasugrel and clopidogrel in the 4 subgroups of patients based on bleeding risk and ischemic benefits. CONCLUSIONS: In community practice, prasugrel use may be driven more by bleeding risk rather than ischemic benefit. This may result in underutilization of higher potency ADP receptor inhibitor among patients more likely to derive ischemic benefit.

How Reliable are Patient-Reported Rehospitalizations? Implications for the Design of Future Practical Clinical Studies.

BACKGROUND: Longitudinal clinical investigations often rely on patient reports to screen for postdischarge adverse outcomes events, yet few studies have examined the accuracy of such patient reports. METHODS AND RESULTS: Patients with acute myocardial infarction (MI) in the TRANSLATE-ACS study were asked during structured interviews at 6 weeks, 6 months, and 12 months postdischarge to report any rehospitalizations. The accuracy of patient-reported rehospitalizations within 1 year of postdischarge was determined using claims-based medical bill validation as the reference standard. The cumulative incidence of rehospitalizations was compared when identified by patient report versus medical bills. Patients were categorized by the accuracy in reporting events (accurate, under-, or over- reporters) and characteristics were compared between groups. Among 10 643 MI patients, 4565 (43%) reported 7734 rehospitalizations. The sensitivity and positive predictive value of patient-reported rehospitalizations were low at 67% and 59%, respectively. A higher cumulative incidence of rehospitalization was observed when identified by patient report versus medical bills (43% vs 37%; P<0.001). Overall, 18% of patients over-reported and 10% under-reported the number of hospitalizations. Compared with accurate reporters, under-reporters were more likely to be older, female, African American, unemployed, or a non-high-school graduate, and had greater prevalence of clinical comorbidities such as diabetes and past cardiovascular disease. CONCLUSIONS: The accuracy of patient-reported rehospitalizations was low with patients both under- and over-reporting events. Longitudinal clinical research studies need additional mechanisms beyond patient report to accurately identify rehospitalization events. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT01088503.

Unplanned Inpatient and Observation Rehospitalizations After Acute Myocardial Infarction: Insights From the Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) Study.

BACKGROUND: Previous studies examining early readmission after acute myocardial infarction have focused exclusively on inpatient readmissions. However, from a patient's perspective, any unplanned inpatient or observation rehospitalization after acute myocardial infarction represents a significant event; these unplanned rehospitalizations have not been well characterized. METHODS AND RESULTS: We examined all patients with acute myocardial infarction treated with percutaneous coronary intervention and discharged alive from 233 hospitals in the Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) study from 2010 to 2012. Our primary outcome was unplanned rehospitalizations (inpatient or observation status) within 30 days after discharge. We identified factors associated with unplanned rehospitalizations using multivariable logistic regression. Among 12 312 patients, 1326 (10.8%) had 1483 unplanned rehospitalizations within 30 days of the index event: 1028 (69.3%) were inpatient readmissions, and 455 (30.7%) were observation stays. The majority of unplanned rehospitalizations (72%) were for cardiovascular reasons. Variation in hospital rates of 30-day unplanned rehospitalization ranged from 5.4% to 20.0%, with a median of 10.7%. After multivariable modeling, the factors most strongly associated with unplanned rehospitalization were baseline quality of life and depression, followed by index hospital length of stay. CONCLUSIONS: Early unplanned rehospitalizations are common after acute myocardial infarction, and close to one third were classified as an observation stay. Predischarge and postdischarge assessments of overall, not just cardiovascular, health and strategies to optimize patient functional status may help to reduce unplanned rehospitalizations. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01088503.