Implementation Science to Achieve Equity in Heart Failure Care: A Scientific Statement From the American Heart Association.

Guideline-directed medical therapies and guideline-directed nonpharmacological therapies improve quality of life and survival in patients with heart failure (HF), but eligible patients, particularly women and individuals from underrepresented racial and ethnic groups, are often not treated with these therapies. Implementation science uses evidence-based theories and frameworks to identify strategies that facilitate uptake of evidence to improve health. In this scientific statement, we provide an overview of implementation trials in HF, assess their use of conceptual frameworks and health equity principles, and provide pragmatic guidance for equity in HF. Overall, behavioral nudges, multidisciplinary care, and digital health strategies increased uptake of therapies in HF effectively but did not include equity goals. Few HF studies focused on achieving equity in HF by engaging stakeholders, quantifying barriers and facilitators to HF therapies, developing strategies for equity informed by theory or frameworks, evaluating implementation measures for equity, and titrating strategies for equity. Among these HF equity studies, feasibility was established in using various educational strategies to promote organizational change and equitable care. A couple include ongoing randomized controlled pragmatic trials for HF equity. There is great need for additional HF implementation trials designed to promote delivery of equitable guideline-directed therapy.

Sex Disparities in Longitudinal Use and Intensification of Guideline-Directed Medical Therapy Among Patients With Newly Diagnosed Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Guideline-directed medical therapies (GDMTs) are the mainstay of treatment for heart failure with reduced ejection fraction (HFrEF), but they are underused. Whether sex differences exist in the initiation and intensification of GDMT for newly diagnosed HFrEF is not well established. METHODS: Patients with incident HFrEF were identified from the 2016 to 2020 Optum deidentified Clinformatics Data Mart Database, which is derived from a database of administrative health claims for members of large commercial and Medicare Advantage health plans. The primary outcome was the use of optimal GDMT within 12 months of HFrEF diagnosis. Consistent with the guideline recommendations during the time period of the study, optimal GDMT was defined as ≥50% of the target dose of evidence-based beta-blocker plus ≥50% of the target dose of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, or any dose of angiotensin receptor neprilysin inhibitor plus any dose of mineralocorticoid receptor antagonist. The probability of achieving optimal GDMT on follow-up and predictors of optimal GDMT were evaluated with time-to-event analysis with adjusted Cox proportional hazard models. RESULTS: The study cohort included 63 759 patients (mean age, 71.3 years; 15.2% non-Hispanic Black race; 56.6% male). Optimal GDMT use was achieved by 6.2% of patients at 12 months after diagnosis. Female (compared with male) patients with HFrEF had lower use across every GDMT class and lower use of optimal GDMT at each time point at follow-up. In an adjusted Cox model, female sex was associated with a 23% lower probability of achieving optimal GDMT after diagnosis (hazard ratio [HR], 0.77 [95% CI, 0.71-0.83]; P<0.001). The sex disparities in GDMT use after HFrEF diagnosis were most pronounced among patients with commercial insurance (females compared with males; HR, 0.66 [95% CI, 0.58-0.76]) compared with Medicare (HR, 0.85 [95% CI, 0.77-0.92]); Pinteraction sex×insurance status=0.005) and for younger patients (age <65 years: HR, 0.65 [95% CI, 0.58-0.74]) compared with older patients (age ≥65 years: HR, 87 [95% CI, 80-96]) Pinteraction sex×age=0.009). CONCLUSIONS: Overall use of optimal GDMT after HFrEF diagnosis was low, with significantly lower use among female (compared with male) patients. These findings highlight the need for implementation efforts directed at improving GDMT initiation and titration.

2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association.

BACKGROUND: The American Heart Association (AHA), in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, nutrition, sleep, and obesity) and health factors (cholesterol, blood pressure, glucose control, and metabolic syndrome) that contribute to cardiovascular health. The AHA Heart Disease and Stroke Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, brain health, complications of pregnancy, kidney disease, congenital heart disease, rhythm disorders, sudden cardiac arrest, subclinical atherosclerosis, coronary heart disease, cardiomyopathy, heart failure, valvular disease, venous thromboembolism, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS: The AHA, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States and globally to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2024 AHA Statistical Update is the product of a full year's worth of effort in 2023 by dedicated volunteer clinicians and scientists, committed government professionals, and AHA staff members. The AHA strives to further understand and help heal health problems inflicted by structural racism, a public health crisis that can significantly damage physical and mental health and perpetuate disparities in access to health care, education, income, housing, and several other factors vital to healthy lives. This year's edition includes additional global data, as well as data on the monitoring and benefits of cardiovascular health in the population, with an enhanced focus on health equity across several key domains. RESULTS: Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS: The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

In adults with ATTR cardiac amyloidosis, patisiran reduced decline in functional capacity at 12 mo.

SOURCE CITATION: Maurer MS, Kale P, Fontana M, et al; APOLLO-B Trial Investigators. Patisiran treatment in patients with transthyretin cardiac amyloidosis. N Engl J Med. 2023;389:1553-1565. 37888916.

SGLT2 inhibitors improved health status in Black and White patients with HF regardless of race.

SOURCE CITATION: Gupta K, Spertus JA, Birmingham M, et al. Racial differences in quality of life in patients with heart failure treated with sodium-glucose cotransporter 2 inhibitors: a patient-level meta-analysis of the CHIEF-HF, DEFINE-HF, and PRESERVED-HF trials. Circulation. 2023;148:220-228. 37191040.

In adults with HF, opioids do not reduce refractory breathlessness (low-certainty evidence).

SOURCE CITATION: Gaertner J, Fusi-Schmidhauser T, Stock S, et al. Effect of opioids for breathlessness in heart failure: a systematic review and meta-analysis. Heart. 2023;109:1064-1071.36878671.

Worth Their Weight? An Update on New and Emerging Pharmacologic Agents for Obesity and Their Potential Role for Persons with Cardiac Conditions.

PURPOSE OF REVIEW: Obesity is associated with cardiovascular (CV) conditions, including but not limited to atherosclerotic disease, heart failure, and atrial fibrillation. Despite this, the impact of intentional weight loss on CV outcomes for persons with obesity and established CV conditions remains poorly studied. New and emerging pharmacologic therapies for weight loss primarily targeting the incretin/nutrient sensing axes induce substantial and sustained weight loss. The glucagon-like-peptide 1 receptor agonists (GLP-1 RA) liraglutide and semaglutide have US FDA approval for the treatment of obesity, and the application for an obesity indication for the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide is presently under FDA review. Extensive phase II and IIIa randomized controlled trials are underway evaluating permutations of combined GLP-1 RA, GIP receptor agonist, GIP receptor antagonist, and glucagon receptor agonists. Clinical outcome trials of these therapies in persons with obesity at high risk of established CV conditions should make it possible to estimate the role of intentional weight loss in managing CV risk via these medications. RECENT FINDINGS: High-dose once weekly injectable semaglutide (2.4 mg/week) use among persons with obesity and heart failure with preserved ejection fraction was effective at both reducing weight and improving health status; exercise capacity was also improved. Ongoing CV outcome trials of oral semaglutide and once weekly injectable tirzepatide will help to establish the role of these therapies among persons with other CV conditions. In addition to these two therapies targeting a CV claim or indication, many other new therapeutics for weight loss, as reviewed, are currently in development. The impact of pharmacologic-induced weight loss on CV conditions for persons with obesity and established CV conditions is currently under investigation for multiple agents. These therapies may offer new avenues to manage CV risk in persons with obesity and with established or at high risk for CV disease.

Putting More Weight on Obesity Trials in Heart Failure.

PURPOSE OF REVIEW: To review ongoing and planned clinical trials of weight loss among individuals with or at high risk of heart failure. RECENT FINDINGS: Intentional weight loss via semaglutide among persons with heart failure and preserved ejection fraction and obesity significantly improves weight loss and health status as assessed by the KCCQ-CSS score and is associated with improvements in 6-min walk test. Ongoing and planned trials will explore the role of intentional weight loss with treatments such as semaglutide or tirzepatide for individuals with heart failure across the entire ejection fraction spectrum.

Rapid, accurate publication and dissemination of clinical trial results: benefits and challenges.

Large-scale clinical trials are essential in cardiology and require rapid, accurate publication, and dissemination. Whereas conference presentations, press releases, and social media disseminate information quickly and often receive considerable coverage by mainstream and healthcare media, they lack detail, may emphasize selected data, and can be open to misinterpretation. Preprint servers speed access to research manuscripts while awaiting acceptance for publication by a journal, but these articles are not formally peer-reviewed and sometimes overstate the findings. Publication of trial results in a major journal is very demanding but the use of existing checklists can help accelerate the process. In case of rejection, procedures such as easing formatting requirements and possibly carrying over peer-review to other journals could speed resubmission. Secondary publications can help maximize benefits from clinical trials; publications of secondary endpoints and subgroup analyses further define treatment effects and the patient populations most likely to benefit. These rely on data access, and although data sharing is becoming more common, many challenges remain. Beyond publication in medical journals, there is a need for wider knowledge dissemination to maximize impact on clinical practice. This might be facilitated through plain language summary publications. Social media, websites, mainstream news outlets, and other publications, although not peer-reviewed, are important sources of medical information for both the public and for clinicians. This underscores the importance of ensuring that the information is understandable, accessible, balanced, and trustworthy. This report is based on discussions held on December 2021, at the 18th Global Cardiovascular Clinical Trialists meeting, involving a panel of editors of some of the top medical journals, as well as members of the lay press, industry, and clinical trialists.

Improving representativeness in trials: a call to action from the Global Cardiovascular Clinical Trialists Forum.

Participants enrolled in cardiovascular disease (CVD) randomized controlled trials are not often representative of the population living with the disease. Older adults, children, women, Black, Indigenous and People of Color, and people living in low- and middle-income countries are typically under-enrolled in trials relative to disease distribution. Treatment effect estimates of CVD therapies have been largely derived from trial evidence generated in White men without complex comorbidities, limiting the generalizability of evidence. This review highlights barriers and facilitators of trial enrollment, temporal trends, and the rationale for representativeness. It proposes strategies to increase representativeness in CVD trials, including trial designs that minimize the research burden on participants, inclusive recruitment practices and eligibility criteria, diversification of clinical trial leadership, and research capacity-building in under-represented regions. Implementation of such strategies could generate better and more generalizable evidence to reduce knowledge gaps and position the cardiovascular trial enterprise as a vehicle to counter existing healthcare inequalities.

Endpoint adjudication in cardiovascular clinical trials.

Endpoint adjudication (EA) is a common feature of contemporary randomized controlled trials (RCTs) in cardiovascular medicine. Endpoint adjudication refers to a process wherein a group of expert reviewers, known as the clinical endpoint committee (CEC), verify potential endpoints identified by site investigators. Events that are determined by the CEC to meet pre-specified trial definitions are then utilized for analysis. The rationale behind the use of EA is that it may lessen the potential misclassification of clinical events, thereby reducing statistical noise and bias. However, it has been questioned whether this is universally true, especially given that EA significantly increases the time, effort, and resources required to conduct a trial. Herein, we compare the summary estimates obtained using adjudicated vs. non-adjudicated site designated endpoints in major cardiovascular RCTs in which both were reported. Based on these data, we lay out a framework to determine which trials may warrant EA and where it may be redundant. The value of EA is likely greater when cardiovascular trials have nuanced primary endpoints, endpoint definitions that align poorly with practice, sub-optimal data completeness, greater operator variability, and lack of blinding. EA may not be needed if the primary endpoint is all-cause death or all-cause hospitalization. In contrast, EA is likely merited for more nuanced endpoints such as myocardial infarction, bleeding, worsening heart failure as an outpatient, unstable angina, or transient ischaemic attack. A risk-based approach to adjudication can potentially allow compromise between costs and accuracy. This would involve adjudication of a small proportion of events, with further adjudication done if inconsistencies are detected.

Leveraging electronic health records to streamline the conduct of cardiovascular clinical trials.

Conventional randomized controlled trials (RCTs) can be expensive, time intensive, and complex to conduct. Trial recruitment, participation, and data collection can burden participants and research personnel. In the past two decades, there have been rapid technological advances and an exponential growth in digitized healthcare data. Embedding RCTs, including cardiovascular outcome trials, into electronic health record systems or registries may streamline screening, consent, randomization, follow-up visits, and outcome adjudication. Moreover, wearable sensors (i.e. health and fitness trackers) provide an opportunity to collect data on cardiovascular health and risk factors in unprecedented detail and scale, while growing internet connectivity supports the collection of patient-reported outcomes. There is a pressing need to develop robust mechanisms that facilitate data capture from diverse databases and guidance to standardize data definitions. Importantly, the data collection infrastructure should be reusable to support multiple cardiovascular RCTs over time. Systems, processes, and policies will need to have sufficient flexibility to allow interoperability between different sources of data acquisition. Clinical research guidelines, ethics oversight, and regulatory requirements also need to evolve. This review highlights recent progress towards the use of routinely generated data to conduct RCTs and discusses potential solutions for ongoing barriers. There is a particular focus on methods to utilize routinely generated data for trials while complying with regional data protection laws. The discussion is supported with examples of cardiovascular outcome trials that have successfully leveraged the electronic health record, web-enabled devices or administrative databases to conduct randomized trials.

Evidence-Based Medical Therapy in Patients With Heart Failure With Reduced Ejection Fraction and Chronic Kidney Disease.

Chronic kidney disease (CKD) as identified by a reduced estimated glomerular filtration rate (eGFR) is a common comorbidity in patients with heart failure with reduced ejection fraction (HFrEF). The presence of CKD is associated with more severe heart failure, and CKD itself is a strong independent risk factor of poor cardiovascular outcome. Furthermore, the presence of CKD often influences the decision to start, uptitrate, or discontinue possible life-saving HFrEF therapies. Because pivotal HFrEF randomized clinical trials have historically excluded patients with stage 4 and 5 CKD (eGFR <30 mL/min/1.73 m2), information on the efficacy and tolerability of HFrEF therapies in these patients is limited. However, more recent HFrEF trials with novel classes of drugs included patients with more severe CKD. In this review on medical therapy in patients with HFrEF and CKD, we show that for both all-cause mortality and the combined end point of cardiovascular death or heart failure hospitalization, most drug classes are safe and effective up to CKD stage 3B (eGFR minimum 30 mL/min/1.73 m2). For more severe CKD (stage 4), there is evidence of safety and efficacy of sodium glucose cotransporter 2 inhibitors, and to a lesser extent, angiotensin-converting enzyme inhibitors, vericiguat, digoxin and omecamtiv mecarbil, although this evidence is restricted to improvement of cardiovascular death/heart failure hospitalization. Data are lacking on the safety and efficacy for any HFrEF therapies in CKD stage 5 (eGFR < 15 mL/min/1.73 m2 or dialysis) for either end point. Last, although an initial decline in eGFR is observed on initiation of several HFrEF drug classes (angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers/mineralocorticoid receptor antagonists/angiotensin receptor blocker neprilysin inhibitors/sodium glucose cotransporter 2 inhibitors), renal function often stabilizes over time, and the drugs maintain their clinical efficacy. A decline in eGFR in the context of a stable or improving clinical condition should therefore not be cause for concern and should not lead to discontinuation of life-saving HFrEF therapies.

Inconsistent Outcome Reporting in Heart Failure Randomized Controlled Trials.

BACKGROUND: Randomized controlled trials (RCTs) may report outcomes different from those prespecified on trial-registration websites, protocols and statistical analysis plans (SAPs). This study sought to investigate the prevalence and characteristics of heart failure (HF) RCTs that report outcomes different from those prespecified. METHODS AND RESULTS: MEDLINE via PubMed was searched to include phase II-IV HF RCTs in 9 high-impact journals from 2010 to 2020. Outcomes reported in trial publications were compared with prespecified outcomes in protocols, registration websites and SAPs. We used the χ2 or Fisher exact test to analyze correlations between trial characteristics and inconsistencies. Among 216 trials, 32 inconsistencies were observed in 28 trials (13.0%). Among 32 inconsistencies, 2 (6.3%) pertained to omission of prespecified primary outcomes, 4 (12.5%) to omission of prespecified secondary outcomes, 2 (6.3%) to changing prespecified primary outcomes to secondary outcomes, and 2 (6.3%) to changing prespecified secondary outcomes to primary outcomes. Of the inconsistencies, 3 (9.4%) pertained to addition of new primary outcomes, 17 (53.1%) to addition of new secondary outcomes, and 2 (6.3%,) to changes in the timing of assessment of primary outcomes. The majority of the inconsistencies favored statistically significant findings; 78 (36.1%) were registered retrospectively. Single-center recruitment was associated with outcome inconsistencies (ß = -0.14; 95% CI, -0.22 - -0.01; P = 0.035). CONCLUSIONS: More than 1 in 10 trials reported outcomes inconsistent with those specified in trial registration websites, SAPs and protocols. An action plan is warranted to minimize selective reporting and improve transparency.

In HF with mitral regurgitation, adding transcatheter mitral valve repair to medical therapy improved renal outcomes at 2 y.

SOURCE CITATION: Beohar N, Ailawadi G, Kotinkaduwa LN, et al. Impact of baseline renal dysfunction on cardiac outcomes and end-stage renal disease in heart failure patients with mitral regurgitation: the COAPT trial. Eur Heart J. 2022;43:1639-48. 35134897.

In HFpEF, the benefit of empagliflozin on a composite of CV death or HF hospitalization at 26 mo did not vary by diabetes status.

SOURCE CITATION: Filippatos G, Butler J, Farmakis D, et al. Empagliflozin for heart failure with preserved left ventricular ejection fraction with and without diabetes. Circulation. 2022;146:676-86. 35762322.

Patient-Reported Outcome Measures in Cardiovascular Disease: An Evidence Map of the Psychometric Properties of Health Status Instruments.

BACKGROUND: Patient-reported outcomes (PROs) are important measures of treatment effect and can be used to inform the approval of cardiovascular drugs and devices by the U.S. Food and Drug Administration (FDA). PURPOSE: To catalogue the health status patient-reported outcome measures (PROMs) validated in cardiovascular diseases (CVDs), describe their psychometric properties, and assess adherence with both FDA recommendations and the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) framework. DATA SOURCES: MEDLINE, EMBASE, CINAHL, and Allied and Complementary Medicine Database from inception to August 2022. STUDY SELECTION: Studies that developed and/or validated health status PROMs in CVD populations. DATA EXTRACTION: Two study authors extracted data on CVD type, PROM psychometric properties, and adherence to FDA recommendations. The risk of bias informing the development or validation of PROMs was assessed using the COSMIN framework. DATA SYNTHESIS: Fifty health status PROMs (described in 83 studies) were identified, of which 45 were disease specific and 5 were generic. Eleven (22%) of the 50 PROMs validated in CVDs had minimally important differences (MIDs) established, and 8 (16%) reported on the validation of all psychometric properties recommended by the FDA. By COSMIN standards, only 2 PROMs (4%) had all of their psychometric properties rated as sufficient in quality, and 32 PROMs (64%) had less than 50% of psychometric properties rated as sufficient. LIMITATION: The quality of reporting varied across included studies. CONCLUSION: Of 50 PROMs validated in CVDs, only a small minority reported on the validation of all FDA-recommended psychometric properties, had psychometric properties rated as sufficient by COSMIN, or had MIDs established. Given the use of PROMs to guide FDA approvals of drugs and devices in CVDs, there is a need for better adherence to quality standards in PROM validation. PRIMARY FUNDING SOURCE: None.

Ethnicity-dependent performance of the Global Registry of Acute Coronary Events risk score for prediction of non-ST-segment elevation myocardial infarction in-hospital mortality: nationwide cohort study.

AIMS: The Global Registry of Acute Coronary Events (GRACE) score was developed to evaluate risk in patients with the acute coronary syndrome with or without ST-segment elevation. Little is known about its performance at predicting in-hospital mortality for ethnic minority patients. METHODS AND RESULTS: We identified 326 160 admissions with non-ST-segment elevation myocardial infarction (NSTEMI) in the Myocardial Infarction National Audit Project (MINAP), 2010-17, including White (n = 299 184) and ethnic minorities (excluding White minorities) (n = 26 976). We calculated the GRACE score for in-hospital mortality and assessed ethnic group baseline characteristics by low, intermediate and high risk. The performance of the GRACE risk score was estimated by discrimination [area under the receiver operating characteristic curve (AUC)] and calibration (calibration plots). Ethnic minorities presented younger and had increased prevalence of cardiometabolic risk factors in all GRACE risk groups. The GRACE risk score for White [AUC 0.87, 95% confidence interval (CI) 0.86-0.87] and ethnic minority (AUC 0.87, 95% CI 0.86-0.88) patients had good discrimination. However, whilst the GRACE risk model was well calibrated in White patients (expected to observed (E : O) in-hospital death rate ratio 0.99; slope 1.00), it overestimated risk in ethnic minority patients (E : O ratio 1.29; slope: 0.94). CONCLUSION: The GRACE risk score provided good discrimination overall for in-hospital mortality, but was not well calibrated and overestimated risk for ethnic minorities with NSTEMI.

The collateral damage of COVID-19 to cardiovascular services: a meta-analysis.

AIMS: The effect of the COVID-19 pandemic on care and outcomes across non-COVID-19 cardiovascular (CV) diseases is unknown. A systematic review and meta-analysis was performed to quantify the effect and investigate for variation by CV disease, geographic region, country income classification and the time course of the pandemic. METHODS AND RESULTS: From January 2019 to December 2021, Medline and Embase databases were searched for observational studies comparing a pandemic and pre-pandemic period with relation to CV disease hospitalisations, diagnostic and interventional procedures, outpatient consultations, and mortality. Observational data were synthesised by incidence rate ratios (IRR) and risk ratios (RR) for binary outcomes and weighted mean differences for continuous outcomes with 95% confidence intervals. The study was registered with PROSPERO (CRD42021265930). A total of 158 studies, covering 49 countries and 6 continents, were used for quantitative synthesis. Most studies (80%) reported information for high-income countries (HICs). Across all CV disease and geographies there were fewer hospitalisations, diagnostic and interventional procedures, and outpatient consultations during the pandemic. By meta-regression, in low-middle income countries (LMICs) compared to HICs the decline in ST-segment elevation myocardial infarction (STEMI) hospitalisations (RR 0.79, 95% confidence interval [CI] 0.66-0.94) and revascularisation (RR 0.73, 95% CI 0.62-0.87) was more severe. In LMICs, but not HICs, in-hospital mortality increased for STEMI (RR 1.22, 95% CI 1.10-1.37) and heart failure (RR 1.08, 95% CI 1.04-1.12). The magnitude of decline in hospitalisations for CV diseases did not differ between the first and second wave. CONCLUSIONS: There was substantial global collateral CV damage during the COVID-19 pandemic with disparity in severity by country income classification.

Urban-rural disparities in diabetes-related mortality in the USA 1999-2019.

AIMS/HYPOTHESIS: Our study aimed to examine the trends in diabetes-related mortality in urban and rural areas in the USA over the past two decades. METHODS: We examined the trends in diabetes-related mortality (as the underlying or a contributing cause of death) in urban and rural areas in the USA between 1999 and 2019, using the CDC WONDER Multiple Cause of Death database. We estimated the 20 year trends of the age-adjusted mortality rate (AAMR) per 100,000 population in urban vs rural counties. RESULTS: The AAMR of diabetes was higher in rural than urban areas across all subgroups. In urban areas, there was a significant decrease in the AAMR of diabetes as the underlying (-16.7%) and contributing (-13.5%) cause of death (ptrend<0.001), which was not observed in rural areas (+2.6%, +8.9%, respectively). AAMRs of diabetes decreased more significantly in female compared with male individuals, both in rural and urban areas. Among people younger than 55 years old, there was a temporal increase in diabetes-related AAMR (+13.8% to +65.2%). While the diabetes-related AAMRs of American Indian patients decreased in all areas (-19.8% to -40.5%, all ptrend<0.001), diabetes-related AAMRs of Black and White patients decreased significantly in urban (-26.6% to -28.3% and -10.7% to -15.4%, respectively, all ptrend<0.001) but not rural areas (-6.5% to +1.8%, +2.4% to +10.6%, respectively, ptrend NS, NS, NS and <0.001). CONCLUSIONS/INTERPRETATION: The temporal decrease in diabetes-related mortality in the USA has been observed only in urban areas, and mainly among female and older patients. A synchronised effort is needed to improve cardiovascular health indices and healthcare access in rural areas and to decrease diabetes-related mortality.