Cardiovascular Trials Research Articles

Beyond the classic major cardiovascular event outcome for cardiovascular trials.

Beyond the classic major cardiovascular event outcome for cardiovascular trials.

Participation of transgender and gender diverse persons in cardiovascular clinical trials

Study objectiveTransgender persons face increased risk in developing cardiovascular diseases due to administration of hormonal therapy used for gender expression, or due to the presence of other risk factors, such as minority stress and difficulty to have full access to health care. Even though the need for gender diversity in research has been identified, the number of clinical trials including transgender persons remains low. The aim of this study was to highlight gaps in inclusion of transgender individuals in cardiovascular clinical research. Design, settingA search in the pubmed.com database, as well as in the clinicaltrials.gov repository, was performed with search terms regarding transgender persons and cardiovascular diseases. Main outcome measure(s)The inclusion of transgender persons in cardiovascular clinical trials was evaluated. Results and conclusionsThis study revealed that there is only a small number of cardiovascular clinical trials including or studying transgender persons. This finding demonstrates the overall lack of clinical trials regarding cardiovascular health in transgender individuals and is indicative of their under-representation in clinical research.

How to interpret subgroup analyses in cardiovascular trials?

Clinical trials provide the best evidence on the effect of a treatment, but they evaluate this effect on the total population of the study as if the effect of the randomized treatment was identical in all possible subgroups of patients (young, elderly, male, female, etc.). Subgroup analyses are an important tool to evaluate the presence of any diversity of the treatment effect concerning specific patient characteristics, if there are practical questions about who to treat and when, or if there are doubts about the benefit/risk profile of a therapy in a specific subpopulation. Subgroup analyses should be defined a priori, biologically plausible, and limited to few clinically important questions. Subgroup analyses have greater relevance in the context of studies that have demonstrated an overall significant difference between treatments. In the case of neutral or negative studies, any significant analyses between subgroups should be considered as essentially exploratory. Post-hoc subgroup analyses should be treated with great caution and considered more credible as the results are consistent with other studies. If significant heterogeneity is expected in specific subgroups of patients when planning a trial, they should have sufficient statistical power to detect the difference in the effect. In this review, we propose a critical approach for interpreting subgroup analyses in cardiovascular trials.

†Cardiovascular Trials Over the Last 15 years: Analysis of the Characteristics and Trends of ClinicalTrials.gov Listings from 2008 to 2022

†Cardiovascular Trials Over the Last 15 years: Analysis of the Characteristics and Trends of ClinicalTrials.gov Listings from 2008 to 2022

Improving diversity in cardiac surgery clinical trials with ROMA:Women as an exemplar.

To describe methods to improve representation of women in cardiac surgery clinical trials. Cardiovascular disease risk among women is high. Historically, women have been excluded from cardiac surgery trials, in part due to restrictive inclusion criteria. Surgical outcomes, specifically after coronary artery bypass grafting, are consistently worse among female patients, and these outcomes have not improved over the last decade. Addressing treatment effects and clinical benefit among women requires accurate representation in cardiovascular surgery trials. ROMA:Women, is the first cardiac surgery trial to focus solely on women, with the goal of addressing underrepresentation. Through utilizing specific strategies, ROMA:Women is a promising first step in advancing health equity. Strategies to ensure effective recruitment and representation among women in cardiac surgery clinical trials, such as tailored eligibility criteria and comprehensive strategies to improve communication and increase trust, are two of many potential approaches to address the structural barriers to female representation in cardiac surgery clinical trials. To date, ROMA:Women is an example of a trial that has shown extraordinary preliminary success enrolling women. Designing trials exclusively for women is one strategy to improve the diversity of clinical trial participation.

Application of the Win Ratio Method in the ENGAGE AF-TIMI 48 Trial Comparing Edoxaban With Warfarin in Patients With Atrial Fibrillation.

Cardiovascular trials often use a composite end point and a time-to-first event model. We sought to compare edoxaban versus warfarin using the win ratio, which offers data complementary to time-to-first event analysis, emphasizing the most severe clinical events. ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind, randomized trial in which patients with atrial fibrillation were assigned 1:1:1 to a higher dose edoxaban regimen (60/30 mg daily), a lower dose edoxaban regimen (30/15 mg daily), or warfarin. In an exploratory analysis, we analyzed the trial outcomes using an unmatched win ratio approach. The win ratio for each edoxaban regimen was the total number of edoxaban wins divided by the number of warfarin wins for the following ranked clinical outcomes: 1: death; 2: hemorrhagic stroke; 3: ischemic stroke/systemic embolic event/epidural or subdural bleeding; 4: noncerebral International Society on Thrombosis and Haemostasis major bleeding; and 5: cardiovascular hospitalization. 21 105 patients were randomized to higher dose edoxaban regimen (N=7035), lower dose edoxaban regimen (N=7034), or warfarin (N=7046), yielding >49 million pairs for each treatment comparison. The median age was 72 years, 38% were women, and 59% had prior vitamin K antagonist use. The win ratio was 1.11 (95% CI, 1.05-1.18) for higher dose edoxaban regimen versus warfarin and 1.11 (95% CI, 1.05-1.18) for lower dose edoxaban regimen versus warfarin. The favorable impacts of edoxaban on death (34% of wins) and cardiovascular hospitalization (41% of wins) were the major contributors to the win ratio. Results consistently favored edoxaban in subgroups based on creatine clearance and dose reduction at baseline, with heightened benefit among those without prior vitamin K antagonist use. In a win ratio analysis of the ENGAGE AF-TIMI 48 trial, both dose regimens of edoxaban were superior to warfarin for the net clinical outcome incorporating ischemic and bleeding events. As the win ratio emphasizes the most severe clinical events, this analysis supports the superiority of edoxaban over warfarin in patients with atrial fibrillation. URL: https://www.clinicaltrials.gov; Unique identifier: NCT00781391.

Estimated Glomerular Filtration Rate Slope as an Endpoint in Cardiovascular Trials.

End stage kidney disease can be a slow process and it may be challenging to achieve required follow-up for sufficient events. Therefore, a surrogate kidney endpoint, such as estimated glomerular filtration rate (eGFR) slope maybe attractive to assess the kidney in cardiovascular trials, especially heart failure (HF). eGFR slope can generate informative results in a shorter follow-up period, has decreased risk of type-2 error, and is less sensitive to eGFR shifts compared with other surrogate kidney endpoints (eGFR decline≥40% or doubling creatinine). However, eGFR slope has its limitations with acute effects, heterogeneity in slope calculation/reporting, and deviations from linearity. eGFR slope is a kidney endpoint which may be well-suited for HF trials. Cross-collaborated guideline recommendations are needed to optimize the use of eGFR slope as a kidney endpoint in patients with HF.

Patient-reported outcomes in atrial fibrillation clinical trials: trends, utilisation, and implications

Abstract Background/Introduction Atrial fibrillation (AF) is the most prevalent clinical arrhythmia, and it is associated with diverse and consequential adverse outcomes that significantly impact the quality of life (QoL) experienced by patients. The evaluation and quantification of QoL have become an important aspect of assessing AF patients, with patient-reported outcomes (PROs) increasingly used in cardiovascular clinical trials. However, there is no consensus on which PROs are most suitable to report, and there is a limited understanding of their prevalence in AF clinical trials. Purpose This study aims to characterise the utilisation of PROs in AF clinical trials. We distinguish between AF-specific and AF-agnostic PROs, with the goal of understanding the evolving role of PROs and emphasising the significance of precise measurement of patient QoL in AF research. Methods We queried the ClinicalTrials.gov database for all available clinical trials that focused on AF as the primary condition from inception to August 1, 2023. This search yielded 3,208 clinical trials, encompassing a total of 65,545,864 participants. We filtered and manually reviewed each clinical trial for their use of PROs within the "outcomes measures" field and divided the results between AF-specific and AF-agnostic PROs. We displayed these findings over time (Figure) and conducted a linear regression analysis for each PRO. Results Of the 3,208 AF clinical trials, 569 (17.7%) reported using at least one PRO, with 178 (5.5%) using AF-specific PROs. There was a statistically significant increase in the use of PROs between 2000 and 2023 (8 vs. 518; P < 0.001; R2= 0.959). This finding held for both AF-specific PROs between 2000 and 2023 (0 vs. 79; P < 0.001; R2=0.930) and AF-agnostic PROs between 2000 and 2023 (8 vs. 360; P < 0.001; R2=0.969). The Atrial Fibrillation Effect on Quality-of-life (AFEQT) was the most used AF-specific PRO, utilized 130 times, with its usage increasing between 2000 and 2023 (0 vs. 61; P = 0.003; R2= 0.888). The EQ-5D was the most frequently used AF-agnostic PRO, employed 131 times. Conclusion The study reveals a significant increase in the use of PROs in AF clinical trials over time. While most trials use AF-agnostic PROs for measuring QoL, several AF-specific PROs, especially AFEQT, have gained wide adoption. These findings underscore the importance of patient-centred outcomes and suggest the increasing emphasis on PROs in AF research. However, significant heterogeneity remains in the choice of PROs, with limited utilisation of validated, AF-specific measures. Future research should focus on understanding the distinct strengths and limitations of AF-specific PROs compared to AF-agnostic ones and promoting their appropriate integration into AF clinical trials to improve patient-centred care for AF patients.Figure

#615 Generalisability of cardiovascular RCTs to patients with chronic kidney disease in clinical practice: a comparison between RCTs and real-world data

Abstract Background and Aims Randomised controlled trials (RCTs) often apply stringent eligibility criteria, which could limit the external applicability of RCTs to patients in routine clinical practice. This is specifically troublesome in the setting of chronic kidney disease (CKD) given that kidney disease is commonly used as an ineligibility criterion in RCTs. In this pilot study we estimated the eligibility of patients with CKD in routine clinical practice in five major cardiovascular outcome trials - CREDENCE, DAPA-CKD, CIBIS II, CIBIS III, and AUGUSTUS - and described reasons for ineligibility. Method We included patients with CKD (defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or an urinary albumin creatinine ratio (UACR) >3 mg/mmol present for >3 months) from the Utrecht Patient Oriented Database (UPOD) who visited a cardiovascular outpatient clinic in the University Medical Centre Utrecht between 2012 and 2019. The eligibility criteria were extracted from the selected RCTs and consequently modelled on the patients from UPOD. The percentage of eligible patients and reasons for ineligibility were described descriptively. The percentage of eligible patients for CIBIS II and CIBIS III were only calculated for patients with heart failure, and for the AUGUSTUS trial for patients with coronary artery disease as patients with these conditions were targeted. Patients could not fulfil multiple inclusion criteria and or meet multiple exclusion criteria or both. Results In total, 9005 UPOD patients with CKD were included. Patients had a mean age of 65 ± 14 years, 42% was female, mean eGFR was 49 ± 17, 1741 (19%) had a history of atherosclerotic cardiovascular disease, and 765 (8%) of heart failure. Overall, 0.05% of patients would be eligible for the DAPA-CKD trial and 0% for the CREDENCE trial. Of included patients with heart failure, 2% would have been eligible for CIBIS II and 3% for CIBIS III. Of included patients with coronary artery disease, 2% would have been eligible for the AUGUSTUS trial. Main reasons for ineligibility for DAPA-CKD were not fulfilling the inclusion criteria for UACR (52%), eGFR (20%), or the prescription of RAAS-inhibitors (arb) (49%) or meeting the exclusion criteria for primary kidney disease (PRD, 6%), or a kidney transplant (15%), or other comorbidities. Similarly, patients were often ineligible for the CREDENCE trial because they did not fulfill the inclusion criteria for UACR (48%), eGFR (18%), HbA1c (35%), or prescription of a RAAS-inhibitor (43%) or met one of the exclusion criteria for PRD (29%), cardiovascular disease (23%), or prescription of a mineralocorticoid receptor antagonist (10%). For CIBIS II, main reasons for ineligibility were not fulfilling the inclusion criteria for left-ventricular ejection fraction (LVEF, 50%) or prescription of an ace-inhibitor (42%) or diuretic (33%) or meeting the exclusion criteria of coronary artery disease (17%) or prescription of a calcium-channel blocker (16%). For CIBIS III, patients were also ineligible because they were not fulfilling the inclusion criteria for age (46%), LVEF (46%), or prescription of diuretics (31%) or met the exclusion criteria for serum creatinine (9%) or prescription of an angiotension receptor blocker (14%). Lastly, for the AUGUSTUS trial, patients were mainly ineligible due to not fulfilling the inclusion criteria of atrial fibrillation (79%) or percutaneous coronary interventions (PCI, 91%) or meeting the eGFR exclusion criteria (14%). Conclusion Based on this pilot study, less than 3% of patients with CKD in routine clinical practice would be eligible to participate in cardiovascular RCTs. Patients were often ineligible because they did not fulfil the inclusion criteria and a substantial number of patients was ineligible due to kidney disease. The low eligibility rate of patients with CKD in cardiovascular trials could limit the generalisability of results to patients with CKD treated in practice. To improve generalisability, RCTs in patients with CKD should aim to include more patients who reflect the patients with CKD treated in practice.

Italian Association of Hospital Cardiologists Position Paper 'Gender discrepancy: time to implement gender-based clinical management'.

It has been well assessed that women have been widely under-represented in cardiovascular clinical trials. Moreover, a significant discrepancy in pharmacological and interventional strategies has been reported. Therefore, poor outcomes and more significant mortality have been shown in many diseases. Pharmacokinetic and pharmacodynamic differences in drug metabolism have also been described so that effectiveness could be different according to sex. However, awareness about the gender gap remains too scarce. Consequently, gender-specific guidelines are lacking, and the need for a sex-specific approach has become more evident in the last few years. This paper aims to evaluate different therapeutic approaches to managing the most common women's diseases.

Accuracy of Event Rate and Effect Size Estimation in Major Cardiovascular Trials

For the design of a randomized clinical trial (RCT), estimation of the expected event rate and effect size of an intervention is needed to calculate the sample size. Overestimation may lead to an underpowered trial. To evaluate the accuracy of published estimates of event rate and effect size in contemporary cardiovascular RCTs. A systematic search was conducted in MEDLINE for multicenter cardiovascular RCTs associated with MeSH (Medical Subject Headings) terms for cardiovascular diseases published in the New England Journal of Medicine, JAMA, or the Lancet between January 1, 2010, and December 31, 2019. Identified trials underwent abstract review; eligible trials then underwent full review, and those with insufficiently reported data were excluded. Data were extracted from the original publication or the study protocol, and a random-effects model was used for data pooling. This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. The primary outcome was the accuracy of event rate and effect size estimation. Accuracy was determined by comparing the observed event rate in the control group and the effect size with their hypothesized values. Linear regression was used to determine the association between estimation accuracy and trial characteristics. Of the 873 RCTs identified, 374 underwent full review and 30 were subsequently excluded, resulting in 344 trials for analysis. The median observed event rate was 9.0% (IQR, 4.3% to 21.4%), which was significantly lower than the estimated event rate of 11.0% (IQR, 6.0% to 25.0%) with a median deviation of -12.3% (95% CI, -16.4% to -5.6%; P < .001). More than half of the trials (196 [61.1%]) overestimated the expected event rate. Accuracy of event rate estimation was associated with a higher likelihood of refuting the null hypothesis (0.13 [95% CI, 0.01 to 0.25]; P = .03). The median observed effect size in superiority trials was 0.91 (IQR, 0.74 to 0.99), which was significantly lower than the estimated effect size of 0.72 (IQR, 0.60 to 0.80), indicating a median overestimation of 23.1% (95% CI, 17.9% to 28.3%). A total of 216 trials (82.1%) overestimated the effect size. In this systematic review of contemporary cardiovascular RCTs, event rates of the primary end point and effect sizes of an intervention were frequently overestimated. This overestimation may have contributed to the inability to adequately test the trial hypothesis.

Testosterone and the risk of incident atrial fibrillation in older men: further analysis of the ASPREE study

A cardiovascular safety trial of testosterone in men with cardiovascular risk factors or disease found no difference in rates of major adverse cardiovascular events (MACE) or death but noted more atrial fibrillation (AF) events in testosterone-treated men. We investigated the relationship between endogenous testosterone concentrations with risk of developing AF in healthy older men. Post-hoc analysis of 4570 male participants in the ASPirin in Reducing Events in the Elderly (ASPREE) study. Men were aged ≥ 70 years, had no history of cardiovascular disease (including AF), thyroid disease, prostate cancer, dementia, or life-threatening illnesses. Risk of AF was modelled using Cox proportional hazards regression. Median (IQR) age was 73.7 (71.6-77.1) years and median (IQR) follow-up 4.4 (3.3-5.5) years, during which 286 men developed AF (15.3 per 1000 participant-years). Baseline testosterone was higher in men who developed incident AF compared men who did not [17.0 (12.4-21.2) vs 15.7 (12.2-20.0) nmol/L]. There was a non-linear association of baseline testosterone with incident AF. The risk for AF was higher in men with testosterone in quintiles (Q) 4&5 (Q4:Q3, HR=1.91; 95%CI=1.29-2.83 and Q5:Q3HR=1.98; 95%CI=1.33-2.94). Results were similar after excluding men who experienced MACE or heart failure during follow-up. Circulating testosterone concentrations within the high-normal range are independently associated with an increased risk of incident AF amongst healthy older men. This suggests that AF may be an adverse consequence of high-normal total testosterone concentrations. National Institute on Aging and National Cancer Institute at the National Institutes of Health; Australian Government (NHMRC, CSIRO); Monash University; and AlfredHealth.

Strategies for thedelivery of sex-based equity in cardiovascular clinical trials.

Strategies for thedelivery of sex-based equity in cardiovascular clinical trials.

Unexplained Residual Risk In Type 2 Diabetes: How Big Is The Problem?

What is new? Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes (T2D) individuals. Of the major risk factors for CVD, less than 10% of T2D people meet the American Diabetes Association/American Heart Association recommended goals of therapy. The present review examines how much of the absolute cardiovascular (CV) risk in type 2 diabetes patients can be explained by major CV intervention trials. Multiple long-term cardiovascular (CV) intervention trials have examined the effect of specific target-directed therapies on the MACE endpoint. Only one prospective study, STENO-2, has employed a multifactorial intervention comparing intensified versus conventional treatment of modifiable risk factors in T2D patients, and demonstrated a 20% absolute CV risk reduction. If the absolute CV risk reduction in these trials is added to that in the only prospective multifactorial intervention trial (STENO-2), the unexplained CV risk is 44.1%. What are the clinical implications? Potential explanations for the unaccounted-for reduction in absolute CV risk in type 2 diabetes (T2D) patients are discussed. failure to take into account synergistic interactions between major cardiovascular risk factors is responsible for the unexplained CV risk in T2D patients. Simultaneous treatment of all major CV risk factors to recommended AHA/ADA guideline goals is required to achieve the maximum reduction in CV risk.

Abstract P118: Scheduling Recruitment Calls Based on Participant’s Preference Increases Screening Success Among Black Adults

Background: Black adults are underrepresented in cardiovascular trials. Competing priorities may limit when they are available to complete trial prescreening requirements. Examining the impact of calling potential participants during their stated preferred time of day could inform strategies to improve recruitment of Black adults in clinical research. Objective: To characterize when Black adults in the Boston area prefer to be called regarding enrollment in two ongoing trials and the association with the number of times a participant was called and/or completion of a phone-based prescreening visit (PSV). Methods: The GoFresh trials are two single-masked, parallel-arm, randomized trials, testing a home-delivered, DASH-patterned grocery intervention on BP among Black adults with and without treated hypertension, residing in Boston-area food deserts. Both trials are identical in recruitment drive, design, assessments, and incentives. Participants’ preferred call time was self-reported via a web-based Qualtrics survey. We logged each time staff called participants, whether they were successfully reached, and if a PSV was completed. Results: Of 2,861 inquiries, 30.1% did not specify a preferred time, 5.8% preferred a call before 9 am, 11.8% preferred a call between 12-1 pm, and 16.3% preferred a call after 4 pm; the remaining 36% fell within working hours. Of the 2,516 attempted calls between August 2022 - July 2023; 1,883 (74.8%) were reached by phone and of those, 1,467 (77.9%) completed a PSV. There was a positive association between preferred call time category and completion of a PSV ( P &lt; 0.0001). There was also a positive association between calling a participant at least once during their preferred call time and reaching that participant ( P = 0.0005). Conclusion: Contacting participants during their preferred call time was associated with completion of a PSV. These data highlight the importance of study teams’ flexibility in outreach time to enhance recruitment of Black adults into cardiovascular clinical trials.

Restricted time win ratio: from estimands to estimation

The win ratio is a novel approach to analyzing prioritized composite endpoints in clinical trials. The win ratio has grown increasingly popular and has been applied in many ongoing cardiovascular clinical trials. Despite the intuitive interpretation of win ratio statistics, the traditionally used win ratio estimands are heavily influenced by the pattern of censoring. Treating missing values or censored data as ties is generally not a reliable way of handling missing values even in the estimation procedure. To avoid this complication, we propose the restricted time win ratio, which is the win ratio at a pre-specified time point τ and can be written in terms of the expectations of potential outcomes. To estimate the proposed estimand, we develop an approximately fully conditional specification algorithm which imputes the missing data of longitudinal and clinical outcomes jointly up to τ . The imputation algorithm can be easily revised to adjust a different hierarchical structure of the sequential comparisons specified by the users. Simulation studies in realistic settings show that the proposed imputation algorithm provides an unbiased and robust estimation of the restricted time win ratio. Finally, real data from a cardiovascular clinical trial are used to illustrate the proposed method.

Not enough known about fenofibrate’s kidney effects in people with Type 2 diabetes

Globally ≈10% of adults have diabetes, with 80% in disadvantaged regions, hence low-cost renoprotective agents are desirable. Fenofibrate demonstrated microvascular benefits in several cardiovascular end-point diabetes trials, but knowledge of effects in late-stage kidney disease is limited. We report new FIELD substudy data and call for further kidney outcomes data.

Representation of Patients With Chronic Kidney Disease in Clinical Trials of Cardiovascular Disease Medications

Patients with chronic kidney disease (CKD) are at high risk for cardiovascular disease, but their systematic underrepresentation in cardiovascular randomized clinical trials (RCTs) limits the generation of appropriate evidence to guide cardiovascular risk management (CVRM). To evaluate the underrepresentation of patients with CKD in cardiovascular RCTs, and to highlight evidence gaps in CVRM medications in this population. A systematic search was conducted in ClinicalTrials.gov from February 2000 through October 2021 for RCTs with full-text publications. If no full-text publications were found in ClinicalTrials.gov, MEDLINE, Embase, and Google Scholar were also searched. Eligible RCTs were those evaluating the effectiveness of antiplatelets, anticoagulants, blood pressure-lowering drugs, glucose-lowering drugs, or cholesterol-lowering drugs in adults with cardiovascular disease or cardiovascular risk factors. Trials with a sample size of fewer than 100 patients were excluded. In total, 1194 RCTs involving 2 207 677 participants (mean [SD] age, 63 [6] years; 1 343 970 males [64%]) were included. Since 2000, the percentage of cardiovascular RCTs excluding patients with CKD has increased from 66% to 79% (74% overall [884 RCTs]). In 864 RCTs (72%), more patients were excluded than anticipated on safety grounds (63% [306] of trials required no dose adjustment, and 79% [561] required dose adjustment). In total, 158 RCTs (13%) reported results for patients with CKD separately (eg, in subgroup analyses). Significant evidence gaps exist in most CVRM interventions for patients with CKD, particularly for those with CKD stages 4 to 5. Twenty-three RCTs (2%) reported results for patients with an estimated glomerular filtration rate less than 30 mL/min/1.73 m2, 15 RCTs (1%) reported for patients receiving dialysis, and 1 RCT (0.1%) reported for recipients of kidney transplant. Results of this systematic review suggest that representation of patients with CKD in cardiovascular RCTs has not improved in the past 2 decades and that these RCTs excluded more patients with CKD than expected on safety grounds. Lack of reporting or underreporting of results for this patient population is associated with evidence gaps in the effectiveness of most CVRM medications in patients with all stages of CKD, particularly CKD stages 4 to 5.

A short review on CRP synthesis inhibition in cardiovascular disease

C-reactive Protein (CRP) is synthesized in the liver. Synthesis is stimulated via the IL-1ß/IL6 pathway. CRP activates the complement system via C1q and macrophages via Fcγ receptors. Since elevated CRP plasma levels are associated with increased cardiovascular risk, CRP may play a causal role in cardiovascular disease. One approach to transfer these observations into standard medical care would be to generate hepatic CRP synthesis inhibitors and use them in controlled clinical trials. Despite huge pharmacological efforts, the search for CRP synthesis inhibitors proved to be difficult. First, the antisense oligonucleotide RNA technology, although a promising idea, has not yet led to results feasible for clinical practice. Secondly, high throughput screening assays in search for hepatic CRP inhibitors were limited by the fact that primary human hepatocytes do not adequately grow in vitro. Use of genetically engineered hepatoma cells led to the observation that cardiac glycosides are capable of inhibiting CRP synthesis. Because of patent law considerations, however, pharmaceutical companies had limited interest in further pursuing this possible path. Upstream inhibition of IL-1ß and IL-6 by antibodies has shown positive results in cardiovascular clinical trials, but because of side effects none of these antibodies has yet received FDA approval. In contrast, long-term colchicine treatment, though not being a CRP-specific approach, has recently been approved by the FDA. Taken together, there is no compelling evidence until today that hepatic CRP synthesis can specifically, effectively and safely be inhibited in vivo in human medicine. Currently, other avenues appear more promising. Here, we summarize contemporary approaches to inhibit CRP synthesis and potential goals for future clinical trials.

Accuracy of heart failure ascertainment using routinely collected healthcare data: a systematic review and meta-analysis

BackgroundAscertainment of heart failure (HF) hospitalizations in cardiovascular trials is costly and complex, involving processes that could be streamlined by using routinely collected healthcare data (RCD). The utility of coded RCD for HF outcome ascertainment in randomized trials requires assessment. We systematically reviewed studies assessing RCD-based HF outcome ascertainment against “gold standard” (GS) methods to study the feasibility of using such methods in clinical trials.MethodsStudies assessing International Classification of Disease (ICD) coded RCD-based HF outcome ascertainment against GS methods and reporting at least one agreement statistic were identified by searching MEDLINE and Embase from inception to May 2021. Data on study characteristics, details of RCD and GS data sources and definitions, and test statistics were reviewed. Summary sensitivities and specificities for studies ascertaining acute and prevalent HF were estimated using a bivariate random effects meta-analysis. Heterogeneity was evaluated using I2 statistics and hierarchical summary receiver operating characteristic (HSROC) curves.ResultsA total of 58 studies of 48,643 GS-adjudicated HF events were included in this review. Strategies used to improve case identification included the use of broader coding definitions, combining multiple data sources, and using machine learning algorithms to search free text data, but these methods were not always successful and at times reduced specificity in individual studies. Meta-analysis of 17 acute HF studies showed that RCD algorithms have high specificity (96.2%, 95% confidence interval [CI] 91.5–98.3), but lacked sensitivity (63.5%, 95% CI 51.3–74.1) with similar results for 21 prevalent HF studies. There was considerable heterogeneity between studies.ConclusionsRCD can correctly identify HF outcomes but may miss approximately one-third of events. Methods used to improve case identification should also focus on minimizing false positives.