Effects of an Intervention to Improve Evidence-Based Care for People With Diabetes and Cardiovascular Disease Across Sex, Race, and Ethnicity Subgroups: Insights From the COORDINATE-Diabetes Trial.

BACKGROUND: Results from the COORDINATE-Diabetes trial (Coordinating Cardiology Clinics Randomized Trial of Interventions to Improve Outcomes - Diabetes) demonstrated that a multifaceted, clinic-based intervention increased prescription of evidence-based medical therapies to participants with type 2 diabetes and atherosclerotic cardiovascular disease. This secondary analysis assessed whether intervention success was consistent across sex, race, and ethnicity. METHODS: COORDINATE-Diabetes, a cluster randomized trial, recruited participants from 43 US cardiology clinics (20 randomized to intervention and 23 randomized to usual care). The primary outcome was the proportion of participants prescribed all 3 groups of evidence-based therapy (high-intensity statin, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and sodium-glucose cotransporter-2 inhibitor or glucagon-like peptide 1 receptor agonist) at last trial assessment (6 to 12 months). In this prespecified analysis, mixed-effects logistic regression models were used to assess the outcome by self-reported sex, race, and ethnicity in the intervention and usual care groups, with adjustment for baseline characteristics, medications, comorbidities, and site location. RESULTS: Among 1045 participants with type 2 diabetes and atherosclerotic cardiovascular disease, the median age was 70 years, 32% were female, 16% were Black, and 9% were Hispanic. At the last trial assessment, there was an absolute increase in the proportion of participants prescribed all 3 groups of evidence-based therapy in women (36% versus 15%), Black participants (41% versus 18%), and Hispanic participants (46% versus 18%) with the intervention compared with usual care, with consistent benefit across sex (male versus female; Pinteraction=0.44), race (Black versus White; Pinteraction=0.59), and ethnicity (Hispanic versus Non-Hispanic; Pinteraction= 0.78). CONCLUSIONS: The COORDINATE-Diabetes intervention successfully improved delivery of evidence-based care, regardless of sex, race, or ethnicity. Widespread dissemination of this intervention could improve equitable health care quality, particularly among women and minority communities who are frequently underrepresented in clinical trials. REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03936660.

Obicetrapib on top of maximally tolerated lipid-modifying therapies in participants with or at high risk for atherosclerotic cardiovascular disease: rationale and designs of BROADWAY and BROOKLYN.

BACKGROUND: Obicetrapib, a novel, selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), LDL particles, apolipoprotein (Apo) B, and lipoprotein(a) [Lp(a)] and increases high-density lipoprotein cholesterol (HDL-C) when added to statins with or without ezetimibe. By substantially reducing LDL-C, obicetrapib has the potential to lower atherogenic lipoproteins in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) whose LDL-C levels remain high despite treatment with available maximally tolerated lipid-modifying therapies, addressing an unmet medical need in a patient population at high risk for cardiovascular events. METHODS AND RESULTS: BROADWAY (NCT05142722) and BROOKLYN (NCT05425745) are ongoing placebo-controlled, double-blind, randomized Phase III trials designed to examine the efficacy, safety, and tolerability of obicetrapib as an adjunct to dietary intervention and maximally tolerated lipid-modifying therapies in participants with a history of ASCVD and/or underlying HeFH whose LDL-C is not adequately controlled. The primary efficacy endpoint was the percent change in LDL-C from baseline to day 84. Other endpoints included changes in Apo B, non-HDL-C, HDL-C, Apo A1, Lp(a), and triglycerides in addition to parameters evaluating safety, tolerability, and pharmacokinetics. BROADWAY also included an adjudicated assessment of major adverse cardiovascular events, measurements of glucose homeostasis, and an ambulatory blood pressure monitoring substudy. A total of 2,532 participants were randomized in BROADWAY and 354 in BROOKLYN to receive obicetrapib 10 mg or placebo (2:1) for 365 days with follow-up through 35 days after the last dose. Results from both trials are anticipated in 2024. CONCLUSION: These trials will provide safety and efficacy data to support the potential use of obicetrapib among patients with ASCVD or HeFH with elevated LDL-C for whom existing therapies are not sufficiently effective or well-tolerated.

Remote Follow-up in a Heart Failure Pragmatic Trial: Insights From the CONNECT-HF.

BACKGROUND: Randomized controlled trials typically require study-specific visits, which can burden participants and sites. Remote follow-up, such as centralized call centers for participant-reported or site-reported, holds promise for reducing costs and enhancing the pragmatism of trials. In this secondary analysis of the CONNECT-HF (Care Optimization Through Patient and Hospital Engagement For HF) trial, we aimed to evaluate the completeness and validity of the remote follow-up process. METHODS AND RESULTS: The CONNECT-HF trial evaluated the effect of a post-discharge quality-improvement intervention for heart failure compared to usual care for up to 1 year. Suspected events were reported either by participants or by health care proxies through a centralized call center or by sites through medical-record queries. When potential hospitalization events were suspected, additional medical records were collected and adjudicated. Among 5942 potential hospitalizations, 18% were only participant-reported, 28% were reported by both participants and sites, and 50% were only site-reported. Concordance rates between the participant/site reports and adjudication for hospitalization were high: 87% participant-reported, 86% both, and 86% site-reported. Rates of adjudicated heart failure hospitalization events among adjudicated all-cause hospitalization were lower but also consistent: 45% participant-reported, 50% both, and 50% site-reported. CONCLUSIONS: Participant-only and site-only reports missed a substantial number of hospitalization events. We observed similar concordance between participant/site reports and adjudication for hospitalizations. Combining participant-reported and site-reported outcomes data is important to capture and validate hospitalizations effectively in pragmatic heart failure trials.

How Will Our Practice Change After the CLEAR Outcomes Trial?

PURPOSE OF REVIEW: Bempedoic acid is a novel therapeutic agent that is designed to reduce levels of low-density lipoprotein cholesterol (LDL-C). The purpose of this review is to provide the background for development of bempedoic acid, findings from clinical trials and to discuss clinical implications. RECENT FINDINGS: Bempedoic acid inhibits ATP citrate lyase within the liver and reduces cholesterol synthesis, with the potential to avoid muscle symptoms experienced by patients treated with statins. Early clinical studies demonstrated that administration of bempedoic acid resulted in lowering of LDL-C by 20-30% as monotherapy and by 40-50% when combined with ezetimibe, in addition to lowering of high sensitivity C-reactive protein by 20-30%. The CLEAR Outcomes trial of high cardiovascular risk patients, with elevated LDL-C levels and either unable or unwilling to take statins demonstrated that bempedoic acid reduced the rate of major adverse cardiovascular events. A greater incidence of elevation of hepatic transaminase and creatinine, gout, and cholelithiasis were consistently observed in bempedoic acid-treated patients. Bempedoic acid presents an additional therapeutic option to achieve more effective lowering of LDL-C levels and reduction in cardiovascular risk.

Patterns of 12-Month Post-Myocardial Infarction Medication Use According to Revascularisation Strategy: Analysis of 15,339 Admissions in Victoria, Australia.

AIM: Clinical guidelines recommend secondary prevention medications following myocardial infarction (MI) regardless of revascularisation strategy. Studies suggest that there is variation in post-MI medication use following percutaneous coronary intervention (PCI) and coronary artery bypass grafts (CABG). We investigated initial dispensing and 12-month patterns of medication use according to revascularisation strategy following non-ST-elevation MI (NSTEMI). METHOD: We included all public and private hospital admissions for NSTEMI for patients aged ≥30 years in Victoria, Australia, between July 2012 and June 2017. We investigated initial dispensing of P2Y12 inhibitors (P2Y12i), statins (total and high intensity), angiotensin-converting-enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB), and beta blockers within 60 days after discharge. Twelve-month post-MI medication use was estimated as the proportion of days covered (PDC) over a 12-month period from the date of hospital discharge. Analyses were performed using adjusted regression models, stratified by revascularisation strategy. RESULTS: There were 15,399 admissions for NSTEMI: 11,754 with PCI and 3,645 with CABG. Following adjustments, predicted probability of initial dispensing in the PCI and CABG groups, respectively, was 0.94 (95% confidence interval 0.93-0.95) vs 0.17 (0.13-0.21) for P2Y12i; 0.69 (0.66-0.71) vs 0.42 (0.37-0.48) for ACEi/ARB; 0.59 (0.57-0.62) vs 0.69 (0.64-0.74) for beta blockers; 0.89 (0.87-0.91) vs 0.89 (0.85-0.92) for statins; and 0.60 (0.57-0.62) vs 0.69 (0.63-0.73) for high intensity statins. The 12-month PDC in the PCI and CABG groups, respectively, was 0.82 (0.80-0.83) vs 0.12 (0.09-0.15) for P2Y12i; 0.62 (0.60-0.65) vs 0.43 (0.39-0.48) for ACEi/ARB; 0.53 (0.51-0.55) vs 0.632 (0.58-0.66) for beta blockers; 0.79 (0.78-0.81) vs 0.78 (0.74-0.81) for statins; and 0.49 (0.47-0.51) vs 0.55 (0.50-0.59) for high intensity statins. CONCLUSIONS: Post-discharge dispensing of secondary prevention medications differed with respect to revascularisation strategy from 2012 to 2017, despite clear evidence of benefit during this period. Interventions may be needed to address possible clinician and patient uncertainty about the benefits of secondary prevention medications, regardless of revascularisation strategy.

Managing hypercholesterolaemia.

Hypercholesterolaemia is one of the most common conditions treated by clinicians in Australia. Low-density lipoprotein cholesterol (LDL-C) plays a causal role in the development and progression of atherosclerosis and cardiovascular disease. Every 1 mmol/L reduction in LDL-C concentration is associated with a 21 to 25% reduction in the relative risk of prospective atherosclerotic cardiovascular events, and emerging evidence suggests this benefit increases over time. Absolute cardiovascular risk assessment identifies patients likely to derive the most benefit from lowering LDL-C concentration, and helps determine the intensity of their treatment regimens and targets. Optimal management of LDL-C may require combination treatment with multiple classes of drugs.

Comparing the Classification of Percutaneous Coronary Interventions Using the 2012 and 2017 Appropriate Use Criteria: Insights From 245,196 Patients in the NCDR CathPCI Registry.

BACKGROUND: Appropriate use criteria (AUC) have been developed to promote the rational use of percutaneous coronary intervention (PCI) among clinicians and to provide benchmarking feedback to hospitals. The original AUC were published in 2012 and subsequently updated in 2017 to reflect emerging, contemporary evidence however the degree to which the updated guidance re-classifies PCI appropriateness is unknown. METHODS: Elective PCI cases from March 1, 2018 until June 30, 2021 were identified from within the NCDR CathPCI database. PCI cases were classified as 'appropriate,' 'uncertain' or 'inappropriate' under 2012 AUC and 'appropriate,' 'may be appropriate' or 'rarely appropriate' under 2017 AUC; those with missing data elements were termed 'not mappable.' Groups that 'remained appropriate' (appropriate in both 2012 and 2017), 'became non-appropriate' ('appropriate' in 2012 but became either 'may be appropriate' or 'rarely appropriate in 2017) and 'became appropriate' ('appropriate' in 2017 but were 'uncertain' or 'inappropriate' in 2012) were descriptively compared. Concordance was assessed by calculation of Cohen's Kappa. RESULTS: A total of 245,196 patients underwent elective PCI across 1669 centers. By 2012 AUC, 44% were classified 'appropriate,' 28% were 'uncertain' and 16% were 'inappropriate' compared with 2017 AUC which considered 34% 'appropriate', 56% may be 'appropriate' and 4% 'rarely appropriate'. Overall fair agreement was observed with a Kappa statistic of 0.40 (95%CI 0.396-0.403). Compared with PCI that 'remained appropriate' under the 2017 AUC, PCI that 'became non-appropriate' in 2017 were more likely to be asymptomatic, less likely to be on anti-anginals and less likely to have complex lesions. Compared with PCI that 'became non-appropriate', PCI that 'became appropriate' had a higher proportion of atypical and non-anginal symptoms and were less likely to have had positive functional tests. Procedural related outcomes were similar across all groups. A total of 29 429 PCI (12.0%) were not mappable by 2012 AUC while 16 077 (6.6%) were not mappable by 2017 AUC. CONCLUSIONS: In this contemporary analysis of patients undergoing PCI in the United States, only fair agreement between the 2012 and updated 2017 AUC was observed. While some of this reflects the intention of the updated guidance, the large proportion that were considered 'maybe appropriate' or who 'became non-appropriate' reflect the difficulties of documenting and implementing contemporary AUC guidance.

Coordinating Cardiology clinics randomized trial of interventions to improve outcomes (COORDINATE) - Diabetes: rationale and design.

Several medications that are proven to reduce cardiovascular events exist for individuals with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease, however they are substantially underused in clinical practice. Clinician, patient, and system-level barriers all contribute to these gaps in care; yet, there is a paucity of high quality, rigorous studies evaluating the role of interventions to increase utilization. The COORDINATE-Diabetes trial randomized 42 cardiology clinics across the United States to either a multifaceted, site-specific intervention focused on evidence-based care for patients with T2DM or standard of care. The multifaceted intervention comprised the development of an interdisciplinary care pathway for each clinic, audit-and-feedback tools and educational outreach, in addition to patient-facing tools. The primary outcome is the proportion of individuals with T2DM prescribed three key classes of evidence-based medications (high-intensity statin, angiotensin converting enzyme inhibitor or angiotensin receptor blocker, and either a sodium/glucose cotransporter-2 inhibitor (SGLT-2i) inhibitor or glucagon-like peptide 1 receptor agonist (GLP-1RA) and will be assessed at least 6 months after participant enrollment. COORDINATE-Diabetes aims to identify strategies that improve the implementation and adoption of evidence-based therapies.

Impact of PCSK9 inhibitors on coronary atheroma phenotype following myocardial infarction: insights from intravascular imaging.

PURPOSE OF REVIEW: The aim of this study was to review the impact of combination lipid lowering with statins and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors on coronary atherosclerosis using serial intravascular imaging. RECENT FINDINGS: Early studies using intravascular ultrasound established the ability of increasingly intensive lipid lowering to both slow progression and ultimately promote regression of coronary disease. More recent clinical trials that have employed serial imaging with optical coherence tomography have permitted the ability to evaluate the impact of intensive lipid lowering on compositional features associated with plaque vulnerability. In particular, the combination of intensive statin and PCSK9 inhibitor therapy promotes plaque stability in patients following an acute coronary syndrome. SUMMARY: More intensive lipid lowering using the combination of statins and PCSK9 inhibitors promote plaque regression in addition to promoting calcification, fibrous cap thickening and reductions in plaque lipid. These plaque-stabilizing effects underscore the benefits of combination therapy on cardiovascular events and highlight the importance of combination lipid-lowering therapy.

Coordinated Care to Optimize Cardiovascular Preventive Therapies in Type 2 Diabetes: A Randomized Clinical Trial.

Importance: Evidence-based therapies to reduce atherosclerotic cardiovascular disease risk in adults with type 2 diabetes are underused in clinical practice. Objective: To assess the effect of a coordinated, multifaceted intervention of assessment, education, and feedback vs usual care on the proportion of adults with type 2 diabetes and atherosclerotic cardiovascular disease prescribed all 3 groups of recommended, evidence-based therapies (high-intensity statins, angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs], and sodium-glucose cotransporter 2 [SGLT2] inhibitors and/or glucagon-like peptide 1 receptor agonists [GLP-1RAs]). Design, Setting, and Participants: Cluster randomized clinical trial with 43 US cardiology clinics recruiting participants from July 2019 through May 2022 and follow-up through December 2022. The participants were adults with type 2 diabetes and atherosclerotic cardiovascular disease not already taking all 3 groups of evidence-based therapies. Interventions: Assessing local barriers, developing care pathways, coordinating care, educating clinicians, reporting data back to the clinics, and providing tools for participants (n = 459) vs usual care per practice guidelines (n = 590). Main Outcomes and Measures: The primary outcome was the proportion of participants prescribed all 3 groups of recommended therapies at 6 to 12 months after enrollment. The secondary outcomes included changes in atherosclerotic cardiovascular disease risk factors and a composite outcome of all-cause death or hospitalization for myocardial infarction, stroke, decompensated heart failure, or urgent revascularization (the trial was not powered to show these differences). Results: Of 1049 participants enrolled (459 at 20 intervention clinics and 590 at 23 usual care clinics), the median age was 70 years and there were 338 women (32.2%), 173 Black participants (16.5%), and 90 Hispanic participants (8.6%). At the last follow-up visit (12 months for 97.3% of participants), those in the intervention group were more likely to be prescribed all 3 therapies (173/457 [37.9%]) vs the usual care group (85/588 [14.5%]), which is a difference of 23.4% (adjusted odds ratio [OR], 4.38 [95% CI, 2.49 to 7.71]; P < .001) and were more likely to be prescribed each of the 3 therapies (change from baseline in high-intensity statins from 66.5% to 70.7% for intervention vs from 58.2% to 56.8% for usual care [adjusted OR, 1.73; 95% CI, 1.06-2.83]; ACEIs or ARBs: from 75.1% to 81.4% for intervention vs from 69.6% to 68.4% for usual care [adjusted OR, 1.82; 95% CI, 1.14-2.91]; SGLT2 inhibitors and/or GLP-1RAs: from 12.3% to 60.4% for intervention vs from 14.5% to 35.5% for usual care [adjusted OR, 3.11; 95% CI, 2.08-4.64]). The intervention was not associated with changes in atherosclerotic cardiovascular disease risk factors. The composite secondary outcome occurred in 23 of 457 participants (5%) in the intervention group vs 40 of 588 participants (6.8%) in the usual care group (adjusted hazard ratio, 0.79 [95% CI, 0.46 to 1.33]). Conclusions and Relevance: A coordinated, multifaceted intervention increased prescription of 3 groups of evidence-based therapies in adults with type 2 diabetes and atherosclerotic cardiovascular disease. Trial Registration: ClinicalTrials.gov Identifier: NCT03936660.

Atherosclerotic Cardiovascular Events in Cancer Patients Treated With Immune Checkpoint Inhibitors: A Retrospective Cohort Study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are effective therapies for numerous cancers, but have been associated with atherosclerotic cardiovascular disease (ASCVD). This study aimed to identify predictors for ASCVD events among cancer patients treated with ICIs and the cardiovascular risk factor (CVRF) control of those who developed ASCVD. METHOD: A single-centre retrospective study of 366 cancer patients who received ICIs from 2018 to 2020 was performed. Demographic, baseline CVRF, cancer history, and ICI regimen data were obtained from medical records. The primary end point of ASCVD events was defined as myocardial infarction, coronary revascularisation, ischaemic stroke, or acute limb ischaemia. Cox proportional multivariable modelling and competing risks analysis were performed to assess ASCVD predictors. Descriptive analysis was performed to describe CVRF management among those who developed ASCVD events. RESULTS: Over a median follow-up of 3.4 years (2.8-4.3), 26 patients (7.1%) experienced 27 ASCVD events (seven myocardial infarction, one coronary revascularisation, 13 ischaemic stroke, and six acute limb ischaemia events). There were 226 (61.8%) cancer-related deaths and no cardiac deaths. History of ASCVD before ICI initiation was independently associated with ASCVD events on traditional Cox modelling (hazard ratio [HR] 4.00; 95% confidence interval [CI] 1.79-8.91; p<0.01) and competing risks analysis (HR 4.23; 95% CI 1.87-9.60; p<0.01). A total of 17 patients developed ASCVD events after ICI cessation (median 1.4 years). Among those with ASCVD events, 12 had prior ASCVD, 16 had hypertension, nine had hypercholesterolaemia, and four had diabetes, and nine were actively smoking. Variable prescription of cardiovascular preventative therapies was noted. CONCLUSIONS: History of ASCVD was associated with subsequent ASCVD events among patients treated with ICIs, which could occur even after active treatment was stopped. Identification and aggressive management of modifiable CVRFs should be considered throughout cancer survivorship in patients who received ICI treatment.

Pop-up screening nested within routine community activities unmasks an addressed cardiovascular risk: A pilot study (Gippsland Healthy Heart Study).

OBJECTIVE: To evaluate the benefits of a pop-up health screening for cardiovascular risk factors (CVRF) in the Gippsland region, and to assess the acceptability of the screening and to determine whether such a process results in attendance at a general practitioner (GP). PARTICIPANTS: Overall, 454 participants over the age of 18 who were residents of the Gippsland region were enrolled. METHODS: This is a community-based, observational, prospective cohort study using pop-up screening sites at six retail locations or workplaces, where participants' blood pressure, body weight and lipid profile were measured. The primary outcome was to assess the proportion of participants with at least one unaddressed CVRF (hypertension [blood pressure >140/90 mmHg], overweight and obesity [body mass index >25 kg/m2 ] or hypercholesterolaemia [low-density lipoprotein cholesterol >2.5 mmol/L]). Email surveys were performed after 4 weeks of follow-up. RESULTS: Overall, 85.8% (95% confidence interval [CI], 82.1%-88.8%) of participants had at least one unaddressed CVRF. Among the 54 participants who responded to the email survey, 50 participants (92.6% [95% CI, 81.3%-97.6%]) found the screening approach acceptable, and 31 (57.4% [95% CI, 43.3%-70.5%]) considered a discussion with the GP. CONCLUSIONS: This study supported the feasibility and effectiveness of pop-up screening to detect CVRF in rural communities.

Can we revive CETP-inhibitors for the prevention of cardiovascular disease?

PURPOSE OF REVIEW: To review recent developments in the field of cholesteryl ester transfer protein (CETP) inhibition from clinical trials and genomic analyses which have the potential to impact future clinical programs. RECENT FINDINGS: CETP plays an important role in remodelling of lipoproteins. A large body of evidence suggests that the presence of low CETP activity should have favourable effects on lipid profiles and cardiovascular risk. However, a number of clinical development programs of pharmacological CETP inhibitors have been disappointing with reports of toxicity and clinical futility. These findings have led many to consider abandoning CETP inhibition as a potential strategy for cardiovascular prevention. However, recent observations from genomic analyses and post hoc observations of prior clinical trials have given greater insights into the potential relationship between CETP inhibition and cardiovascular risk. This has highlighted the importance of lowering levels of atherogenic lipoproteins. SUMMARY: These findings provide a pathway for ongoing clinical development of CETP inhibitors, where the potential to play an important role in the prevention of cardiovascular disease may still be possible. The lessons learned and pathway forward for new CETP inhibitors will be reviewed.

Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Prostate Cancer: The Primary Results of the PRONOUNCE Randomized Trial.

BACKGROUND: The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease remains controversial. METHODS: In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant atherosclerotic cardiovascular disease were randomly assigned 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (composite of death, myocardial infarction, or stroke) through 12 months. RESULTS: Because of slower-than-projected enrollment and fewer-than-projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From May 3, 2016, to April 16, 2020, a total of 545 patients from 113 sites across 12 countries were randomly selected. Baseline characteristics were balanced between study groups. The median age was 73 years, 49.8% had localized prostate cancer; 26.3% had locally advanced disease, and 20.4% had metastatic disease. A major adverse cardiovascular event occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) patients assigned to leuprolide (hazard ratio, 1.28 [95% CI, 0.59-2.79]; P=0.53). CONCLUSIONS: PRONOUNCE (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease) is the first, international, randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely because of the smaller than planned number of participants and events, and no difference in major adverse cardiovascular events at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02663908.

Late Outcomes of the RAPID-TnT Randomized Controlled Trial: 0/1-Hour High-Sensitivity Troponin T Protocol in Suspected ACS.

BACKGROUND: High-sensitivity troponin assays are increasingly being adopted to expedite evaluation of patients with suspected acute coronary syndromes. Few direct comparisons have examined whether the enhanced performance of these assays at low concentrations leads to changes in care that improves longer-term outcomes. This study evaluated late outcomes of participants managed under an unmasked 0/1-hour high-sensitivity cardiac troponin T (hs-cTnT) protocol compared with a 0/3-hour masked hs-cTnT protocol. METHODS: We conducted a multicenter prospective patient-level randomized comparison of care informed by unmasked 0/1-hour hs-cTnT protocol (reported to <5 ng/L) versus standard practice masked hs-cTnT testing (reported to ≤29 ng/L) assessed at 0/3 hours and followed participants for 12 months. Participants included were those presenting to metropolitan emergency departments with suspected acute coronary syndromes, without ECG evidence of coronary ischemia. The primary end point was time to all-cause death or myocardial infarction using Cox proportional hazards models adjusted for clustering within hospitals. RESULTS: Between August 2015 and April 2019, we randomized 3378 participants, of whom 108 withdrew, resulting in 12-month follow-up for 3270 participants (masked: 1632; unmasked: 1638). Among these, 2993 (91.5%) had an initial troponin concentration of ≤29 ng/L. Deployment of the 0/1-hour hs-cTnT protocol was associated with reductions in functional testing. Over 12-month follow-up, there was no difference in invasive coronary angiography (0/1-hour unmasked: 232/1638 [14.2%]; 0/3-hour masked: 202/1632 [12.4%]; P=0.13), although an increase was seen among patients with hs-cTnT levels within the masked range (0/1-hour unmasked arm: 168/1507 [11.2%]; 0/3-hour masked arm: 124/1486 [8.3%]; P=0.010). By 12 months, all-cause death and myocardial infarction did not differ between study arms overall (0/1-hour: 82/1638 [5.0%] versus 0/3-hour: 62/1632 [3.8%]; hazard ratio, 1.32 [95% CI, 0.95-1.83]; P=0.10). Among participants with initial troponin T concentrations ≤29 ng/L, unmasked hs-cTnT reporting was associated with an increase in death or myocardial infarction (0/1-hour: 55/1507 [3.7%] versus 0/3-hour: 34/1486 [2.3%]; hazard ratio, 1.60 [95% CI, 1.05-2.46]; P=0.030). CONCLUSIONS: Unmasked hs-cTnT reporting deployed within a 0/1-hour protocol did not reduce ischemic events over 12-month follow-up. Changes in practice associated with the implementation of this protocol may be associated with an increase in death and myocardial infarction among those with newly identified troponin elevations. Registration: URL: https://www.anzctr.org.au; Unique identifier: ACTRN12615001379505.

Incorporating SGLT2i and GLP-1RA for Cardiovascular and Kidney Disease Risk Reduction: Call for Action to the Cardiology Community.

Multiple sodium glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to impart significant cardiovascular and kidney benefits, but are underused in clinical practice. Both SGLT-2i and GLP-1RA were first studied as glucose-lowering drugs, which may have impeded uptake by cardiologists in the wake of proven cardiovascular efficacy. Their significant effect on cardiovascular and kidney outcomes, which are largely independent of glucose-lowering effects, must drive a broader use of these drugs. Cardiologists are 3 times more likely than endocrinologists to see patients with both type 2 diabetes and cardiovascular disease, thus they are ideally positioned to share responsibility for SGLT-2i and GLP-1RA treatment with primary care providers. In order to increase adoption, SGLT-2i and GLP-1RA must be reframed as primarily cardiovascular and kidney disease risk-reducing agents with a side effect of glucose-lowering. Coordinated and multifaceted interventions engaging clinicians, patients, payers, professional societies, and health systems must be implemented to incentivize the adoption of these medications as part of routine cardiovascular and kidney care. Greater use of SGLT-2i and GLP-1RA will improve outcomes for patients with type 2 diabetes at high risk for cardiovascular and kidney disease.

CETP Inhibitors: Should We Continue to Pursue This Pathway?

PURPOSE OF REVIEW: For more than 20 years there has been considerable interest in the development of pharmacological inhibitors of cholesteryl ester transfer protein (CETP) by virtue of their ability to raise levels of high-density lipoprotein cholesterol. This review endeavors to integrate existing data from prior clinical trials with emerging data to understand whether there is a pathway forward to develop CETP inhibitors to prevent cardiovascular disease. RECENT FINDINGS: Large clinical trials have proved disappointing with successive reports of a failure to reduce cardiovascular events. The one clinical development program that did demonstrate a reduction in cardiovascular risk found adipose tissue accumulation and did not proceed for regulatory approval. More recent observations suggest that less CETP activity may prevent cardiovascular events, but due to lipid lowering rather than raising high-density lipoprotein cholesterol. In addition, treatment with CETP inhibitors appears to have a beneficial impact on glycemic control in the setting of diabetes. Advances in the field of CETP inhibition suggest a potentially protective effect on the risk of both cardiovascular disease and diabetes. This has implications for how to best design future clinical development programs and leaves the door open to potentially bring CETP inhibitors to the preventive cardiology clinic.

Cholesteryl Ester Transfer Protein Inhibition Reduces Major Adverse Cardiovascular Events by Lowering Apolipoprotein B Levels.

Cholesteryl ester transfer protein (CETP) facilitates the exchange of cholesteryl esters and triglycerides (TG) between high-density lipoprotein (HDL) particles and TG-rich, apolipoprotein (apo) B-containing particles. Initially, these compounds were developed to raise plasma HDL cholesterol (HDL-C) levels, a mechanism that was previously thought to lower the risk of atherosclerotic cardiovascular disease (ASCVD). More recently, the focus changed and the use of pharmacologic CETP inhibitors to reduce low-density lipoprotein cholesterol (LDL-C), non-HDL-C and apoB concentrations became supported by several lines of evidence from animal models, observational investigations, randomized controlled trials and Mendelian randomization studies. Furthermore, a cardiovascular outcome trial of anacetrapib demonstrated that CETP inhibition significantly reduced the risk of major coronary events in patients with ASCVD in a manner directly proportional to the substantial reduction in LDL-C and apoB. These data have dramatically shifted the attention on CETP away from raising HDL-C instead to lowering apoB-containing lipoproteins, which is relevant since the newest CETP inhibitor, obicetrapib, reduces LDL-C by up to 51% and apoB by up to 30% when taken in combination with a high-intensity statin. An ongoing cardiovascular outcome trial of obicetrapib in patients with ASCVD is expected to provide further evidence of the ability of CETP inhibitors to reduce major adverse cardiovascular events by lowering apoB. The purpose of the present review is to provide an up-to-date understanding of CETP inhibition and its relationship to ASCVD risk reduction.

Sodium-Glucose Cotransporter-2 Inhibitors: Impact on Atherosclerosis and Atherosclerotic Cardiovascular Disease Events.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) improve the risk for heart and kidney failure. However, their effects on major atherosclerotic cardiovascular events (MACE) are less clear. Although outcomes trials of drugs for diabetes were not powered to prove superiority, the totality of trial data yields an estimate of ∼11% relative reduction for MACE (HR 0.89, 95%CI 0.82-0.96) and neutral on stroke (HR 0.92, 95%CI 0.79-1.08). In animal models, SGLT-2i favorably affects plaque size, composition, and inflammatory pathways; human data in this regard are lacking. Ongoing trials are evaluating SGLT-2i efficacy in heart failure, kidney disease, and postmyocardial infarction populations, independent of diabetes status.

An update on emerging drugs for the treatment of hypercholesterolemia.

INTRODUCTION: Elevated levels of low-density lipoprotein (LDL) cholesterol have been unequivocally demonstrated to play a causal role in atherosclerotic cardiovascular disease. The last thirty years have witnessed a generation of clinical trials that have demonstrated a reduction in cardiovascular risk with the use of increasing intensive lipid lowering regimens involving statin therapy in combination with other agents. However, many patients fail to achieve treatment mandated LDL cholesterol goals. This highlights the need to develop additional approaches to lower LDL cholesterol levels. AREAS COVERED: (i) Contemporary data highlighting the atherogenicity of LDL cholesterol and cardiovascular benefits of current lipid lowering therapies. (ii) Importance of statin intolerance and inability to achieve LDL cholesterol goals in driving ongoing cardiovascular risk. (iii) Emergence of new therapeutic agents designed to achieve more effective lowering of LDL cholesterol. EXPERT OPINION: Effective lowering of LDL cholesterol plays a critical role in approaches to the prevention of cardiovascular disease. A greater number of patients will require combinations of agents to achieve optimal lipid control. Accordingly, new agents will be required to provide sufficient choice for patients at high cardiovascular risk.