Clinical Trials Of Cardiovascular Disease Research Articles

Derivation of an Annualized Claims-Based Major Adverse Cardiovascular Event Estimator in Type 2 Diabetes

BackgroundMajor adverse cardiovascular events (MACE) are a leading cause of morbidity and mortality among adults with type 2 diabetes. Currently, available MACE prediction models have important limitations, including reliance on data that may not be routinely available, narrow focus on primary prevention, limited patient populations, and longtime horizons for risk prediction. ObjectivesThe purpose of this study was to derive and internally validate a claims-based prediction model for 1-year risk of MACE in type 2 diabetes. MethodsUsing medical and pharmacy claims for adults with type 2 diabetes enrolled in commercial, Medicare Advantage, and Medicare fee-for-service plans between 2014 and 2021, we derived and internally validated the annualized claims-based MACE estimator (ACME) model to predict the risk of MACE (nonfatal acute myocardial infarction, nonfatal stroke, and all-cause mortality). The Cox proportional hazards model was composed of 30 covariates, including patient age, sex, comorbidities, and medications. ResultsThe study cohort comprised 6,623,526 adults with type 2 diabetes, mean age 68.1 ± 10.6 years, 49.8% women, and 73.0% Non-Hispanic White. ACME had a concordance index of 0.74 (validation index range: 0.739-0.741). The predicted 1-year risk of the study cohort ranged from 0.4% to 99.9%, with a median risk of 3.4% (IQR: 2.3%-6.5%). ConclusionsACME was derived in a large usual care population, relies on routinely available data, and estimates short-term MACE risk. It can support population risk stratification at the health system and payer levels, participant identification for decentralized clinical trials of cardiovascular disease, and risk-stratified observational studies using real-world data.

A female acronym is not enough: underrepresentation of women in cardiovascular trials

Abstract Introduction Cardiovascular disease is the leading cause of death for women worldwide. Yet, women are often underrepresented in clinical trials of cardiovascular disease compared to population prevalence. Reasons for underrepresentation are multifactorial, and often attributed to trial criteria. Yet, women may also decide not to participate for more subconscious reasons, such as the perception of the trial acronym. Trial acronyms are used in patient communication and are often chosen to have a certain meaning, which can be perceived as gendered. We hypothesize that masculine trial names are associated with underrepresentation of women in clinical trials. Purpose To investigate if the perceived gender of the trial acronym, and other study characteristics affect the representation of women in cardiovascular clinical trials. Methods We performed a systematic search of ClinicalTrials.gov to collect information on randomized clinical trials testing drug interventions for cardiovascular disease. We extracted trial characteristics and acronyms from primary outcome publications. We conducted a survey among 148 cardiovascular patients (both women and men) recruited via an online patient forum and asked them whether they perceived trial acronyms names as more masculine, feminine or neutral. We defined female underrepresentation as those trials where the proportion of included women divided by the proportion of women in the disease population was below 0.8. We analyzed female underrepresentation and study setting, participant characteristics, and female first and last authorship. Results We identified 148 eligible clinical trials of which 29.9% of participants were women. Women were underrepresented in 61.5% of trials (Figure 1). Only 45.3% of publications reported sex-stratified results. The proportion of trials in which women were underrepresented increased between 1992 and 2022 from 48.3% to 70.5%. A total of 148 patients (67.6% women, mean age 61 y) evaluated the trial acronyms for their perceived gender. The majority (70.9%) of trial names was perceived as neutral, 17.6% as masculine and 11.5% as feminine. Female representation was not associated with the perceived gender of the trial name (OR 0.92, 95% CI 0.63 – 1.35) (Figure 2A). Trials had a higher odds of female underrepresentation if they recruited at an in-patient setting (OR 2.47, 95% CI 1.14 – 5.58), or if their participants were in the second-highest age group between 64.0 and 66.3 years (OR 3.93, 95% CI 1.25 – 14.18). Trials had lower odds of female underrepresentation if the last author was a woman (OR 0.10, 95% CI 0.01 – 0.49). Conclusion Female representation in cardiovascular clinical trials remains poor but is not depending on the perceived gender of the trial acronym. Female representation varies with recruitment type, participant age and last author gender, which are important starting points to improve participation rates of women.

1234-P: Derivation of a Claims-Computable Major Adverse Cardiovascular Event Estimator (ACME) in Adults with Type 2 Diabetes

Major adverse cardiovascular events (MACE) are a major cause of morbidity and mortality among adults with type 2 diabetes. Currently available risk prediction models estimate long-term risk (typically 10-year) and require clinical data not routinely available in real-world data sources, which limit their use on population level. Using de-identified claims data from OptumLabs® Data Warehouse for enrollees in private and Medicare Advantage health plans linked to 100% sample of Medicare fee-for-service beneficiaries between 2014 and 2021, we derived ACME to estimate annualized risk of non-fatal myocardial infarction, non-fatal stroke, or all-cause mortality in patients with type 2 diabetes aged ≥21 years (N=6,623,526). The Cox proportional hazards model, combined with an estimate of the baseline hazard using the Nelson-Aalen estimator to allow conditional survival predictions, included 28 covariates available in claims (age, sex, cardiovascular comorbidities, and cardiovascular medications). The study population had mean age 68.1 (SD, 10.6) years, 49.8% were women, and 73.0% were non-Hispanic White. ACME’s concordance index was 0.74 (se = 0.0002) and it performed comparably in all racial and ethnic groups. Strongest predictors of MACE were acute myocardial infarction and stroke within the past 3 months, heart failure hospitalization within the past year, and end-stage kidney disease. Overall, 4.2% of patients were predicted to have low (<1%) annualized MACE risk, 62.8% were predicted to have moderate (≥1 to <5%) annualized risk, and 33.0% were predicted to have high (≥5%) annualized risk. Other thresholds can be chosen for individualized applications. ACME can support population risk stratification and health management efforts at the health system and payer levels, participant identification for decentralized pragmatic clinical trials of cardiovascular disease and its prevention, and risk-stratified observational studies using real-world data. Disclosure R.G.Mccoy: Consultant; Emmi. G.Umpierrez: Research Support; Abbott, Dexcom, Inc., Baxter. R.J.Galindo: Consultant; Novo Nordisk, Eli Lilly and Company, Sanofi, Pfizer Inc., Bayer Inc., WW (Weight Watchers), Research Support; Novo Nordisk, Eli Lilly and Company, Dexcom, Inc. J.Brito: None. M.Mickelson: None. E.Polley: None. K.Swarna: None. Y.Deng: None. J.Herrin: Consultant; Johnson & Johnson Medical Devices Companies. J.Ross: Research Support; Johnson & Johnson. D.M.Kent: Research Support; W.L. Gore. B.Borah: Consultant; Boehringer Ingelheim Inc., Exact Sciences. W.Crown: Consultant; Janssen Scientific Affairs, LLC, UnitedHealth Group, Viatris Inc. V.M.Montori: None. Funding Patient-Centered Outcomes Research Institute (DB-2020C2-20306)

Female Recruitment Into Cardiovascular Disease Trials

Female Recruitment Into Cardiovascular Disease Trials

The participation of Arab women in randomised clinical trials for cardiovascular diseases.

Women's enrolment in randomised clinical trials (RCTs) raises the attention of medical personnel and evidence-based medicine researchers to achieve the highest possible quality and transparency of conducted studies. This study aims to demonstrate various patterns and relationships of women's enrolment in cardiovascular RCTs conducted in Arab countries. Three databases (PubMed, Web of Science and Scopus) were accessed and searched for randomised clinical trials investigating cardiovascular diseases in Arab countries. Studies were screened, data were extracted and risk of bias of included studies was assessed independently by two sets of authors. The female to male ratio and the participation prevalence ratio (PPR) were calculated for each trial and the association of them with different variables were analysed. Of the 9071 patients enrolled in the 71 included RCTs, 38.02% were women. Various factors such as age of participants, publication year, therapeutic class, clinical indication, prevention type, and location of trial showed a significant association with the level of women enrolment in cardiovascular randomised clinical trials in Arab countries (P-value <.05). The median female to male ratio of all the trials was 0.55. The median female: male ratio varied by clinical indications (2.33 for valvular heart diseases vs 0.5 for stroke), intervention type (0.46 for surgical procedures vs 0.52 for drugs), prevention type (0.79 for secondary prevention, 0.74 for primary prevention and 0.52 for tertiary prevention), sample size (0.48 for Q1 vs 0.85 for Q2) and by age groups (0.98 for ages ≤50years old vs 0.47 for 56-60years old). Women were overrepresented in valvular heart disease trials (PPR = 1.37), and underrepresented in coronary artery disease, stroke and atrial fibrillation trials (PPR = 0.6, 0.63, and 0.71, respectively). As a result of the huge importance of RCTs in the medical field, and to reduce biases arising from inaccurate representation of different study populations, women's enrolment in Arab cardiovascular trials should be pre-planned and based on the percentage of women among the studied disease population.

Obstructive sleep apnea and atrial fibrillation: we need to go step by step.

Citation:Sanchez-de-la-Torre M, Lee C-H, Barbe F. Obstructive sleep apnea and atrial fibrillation: we need to go step by step. J Clin Sleep Med. 2021;17(5):869–870.

Randomized clinical trials of cardiovascular disease in obstructive sleep apnea: understanding and overcoming bias.

Randomized clinical trials of cardiovascular disease in obstructive sleep apnea: understanding and overcoming bias.

A systematic review of subgroup analyses in randomised clinical trials in cardiovascular disease.

Background:Subgroup analyses are frequently used to assess heterogeneity of treatment effects in randomised clinical trials. Inconsistent, improper and incomplete implementation, reporting and interpretation have been identified as ongoing challenges. Further, subgroup analyses were frequently criticised because of unreliable or potentially misleading results. More recently, recommendations and guidelines have been provided to improve the reporting of data in this regard.Methods:This systematic review was based on a literature search within the digital archives of three selected medical journals, The New England Journal of Medicine, The Lancet and Circulation. We reviewed articles of randomised clinical trials in the domain of cardiovascular disease which were published in 2015 and 2016. We screened and evaluated the selected articles for the mode of implementation and reporting of subgroup analyses.Results:We were able to identify a total of 130 eligible publications of randomised clinical trials. In 89/130 (68%) articles, results of at least one subgroup analysis were presented. This was dependent on the considered journal (p < 0.001), the number of included patients (p < 0.001) and the lack of statistical significance of a trial’s primary analysis (p < 0.001). The number of reported subgroup analyses ranged from 1 to 101 (median = 13). We were able to comprehend the specification time of reported subgroup analyses for 71/89 (80%) articles, with 55/89 (62%) articles presenting exclusively pre-specified analyses. This information was not always traceable on the basis of provided trial protocols and often did not include the pre-definition of cut-off values for the categorization of subgroups. The use of interaction tests was reported in 84/89 (94%) articles, with 36/89 (40%) articles reporting heterogeneity of the treatment effect for at least one primary or secondary trial outcome. Subgroup analyses were reported more frequently for larger randomised clinical trials, and if primary analyses did not reach statistical significance. Information about the implementation of subgroup analyses was reported most consistently for articles from The New England Journal of Medicine, since it was also traceable on the basis of provided trial protocols. We were able to comprehend whether subgroup analyses were pre-specified in a majority of the reviewed publications. Even though results of multiple subgroup analyses were reported for most published trials, a corresponding adjustment for multiple testing was rarely considered.Conclusion:Compared to previous reviews in this context, we observed improvements in the reporting of subgroup analyses of cardiovascular randomised clinical trials. Nonetheless, critical shortcomings, such as inconsistent reporting of the implementation and insufficient pre-specification, persist.

Randomized clinical trials of cardiovascular disease in obstructive sleep apnea: understanding and overcoming bias.

Three recent randomized control trials (RCTs) found that treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) did not reduce rates of future cardiovascular events. This article discusses the biases in these RCTs that may explain their negative results, and how to overcome these biases in future studies. First, sample selection bias affected each RCT. The subjects recruited were not patients typically presenting for treatment of OSA. In particular, subjects with excessive sleepiness were excluded due to ethical concerns. As recent data indicate that the excessively sleepy OSA subtype has increased cardiovascular risk, subjects most likely to benefit from treatment were excluded. Second, RCTs had low adherence to therapy. Reported adherence is lower than found clinically, suggesting it is in part related to selection bias. Each RCT showed a CPAP benefit consistent with epidemiological studies when restricting to adherent patients, but was underpowered. Future studies need to include sleepy individuals and maximize adherence. Since it is unethical and impractical to randomize very sleepy subjects to no therapy, alternative designs are required. Observational designs using propensity scores, which are accepted by FDA for studies of medical devices, provide an opportunity. The design needs to ensure covariate balance, including measures assessing healthy user and healthy adherer biases, between regular users of CPAP and non-users. Sensitivity analyses can evaluate the robustness of results to unmeasured confounding, thereby improving confidence in conclusions. Thus, these designs can robustly assess the cardiovascular benefit of CPAP in real-world patients, overcoming biases in RCTs.

The Roles of Nanoparticles in Stem Cell-Based Therapy for Cardiovascular Disease.

Cardiovascular disease (CVD) is currently one of the primary causes of mortality and morbidity worldwide. Nanoparticles (NPs) are playing increasingly important roles in regulating stem cell behavior because of their special features, including shape, size, aspect ratio, surface charge, and surface area. In terms of cardiac disease, NPs can facilitate gene delivery in stem cells, track the stem cells in vivo for long-term monitoring, and enhance retention after their transplantation. The advantages of applying NPs in peripheral vascular disease treatments include facilitating stem cell therapy, mimicking the extracellular matrix environment, and utilizing a safe non-viral gene delivery tool. However, the main limitation of NPs is toxicity, which is related to their size, shape, aspect ratio, and surface charge. Currently, there have been many animal models proving NPs’ potential in treating CVD, but no extensive applications of stem-cell therapy using NPs are available in clinical practice. In conclusion, NPs might have significant potential uses in clinical trials of CVD in the future, thereby meeting the changing needs of individual patients worldwide.

Role of serum amyloid A in atherosclerosis.

Acute phase serum amyloid A (SAA) is persistently elevated in chronic inflammatory conditions, and elevated levels predict cardiovascular risk in humans. More recently, murine studies have demonstrated that over-expression of SAA increases and deficiency/suppression of SAA attenuates atherosclerosis. Thus, beyond being a biomarker, SAA appears to play a causal role in atherogenesis. The purpose of this review is to summarize the data supporting SAA as a key player in atherosclerosis development. A number of pro-inflammatory and pro-atherogenic activities have been ascribed to SAA. However, the literature is conflicted, as recombinant SAA, and/or lipid-free SAA, used in many of the earlier studies, do not reflect the activity of native human or murine SAA, which exists largely lipid-associated. Recent literatures demonstrate that SAA activates the NLRP3 inflammasome, alters vascular function, affects HDL function, and increases thrombosis. Importantly, SAA activity appears to be regulated by its lipid association, and HDL may serve to sequester and limit SAA activity. SAA has many pro-inflammatory and pro-atherogenic activities, is clearly demonstrated to affect atherosclerosis development, and may be a candidate target for clinical trials in cardiovascular diseases.

Major Randomized Clinical Trials in Cardiovascular Disease Prevention Presented at the 2019 American College of Cardiology Annual Scientific Session

At the 2019 American College of Cardiology annual scientific sessions, major randomized clinical trials in cardiovascular disease (CVD) prevention were presented. The CLEAR Wisdom trial examined the safety and efficacy of adding bempedoic acid to maximally tolerated statin for reducing low-density lipoprotein cholesterol. Post hoc analyses from the REDUCE-IT trial evaluated the efficacy of icosapent ethyl for lowering risk of total (first time and recurrent) CVD events. A sub-analysis of ODYSSEY OUTCOMES examined the effect of alirocumab on lipoprotein(a) lowering for reducing CVD risk. The CREOLE trial compared three different combination antihypertensive therapies for blood pressure lowering among black individuals in sub-Saharan Africa. The INFINITY trial examined the effect of intensive blood pressure control on progression of brain white matter changes and various components of mobility and cognitive function. Lastly, post hoc analyses from DECLARE-TIMI 58 evaluated the efficacy of dapagliflozin among patients with type 2 diabetes mellitus and heart failure or peripheral artery disease. These trials hold future promise for novel agents aimed at reducing CVD burden among high-risk patients who continue to experience CVD events despite treatment with currently available guideline-directed therapy.

Abstract 136: Enrollment of Black Individuals in Cardiovascular Clinical Trials: A Meta-Analysis

Objectives: Lack of racial and ethnic diversity in clinical trials (CT) limits the generalizability of results to individuals who have unique cultural, environmental and physiological factors that affect outcomes. Consequently, the NIH and FDA issued directives to include historically underrepresented racial and ethnic groups in research studies. We sought to determine the enrollment of black relative to non-black populations in cardiovascular clinical trials and whether racial enrollment varied across trial characteristics. Methods: Clinical trials were identified using PubMed, Embase, and Cochrane. Between 2000-2018, studies were included if they were English language, CT of cardiovascular disease or risk factors and race/ethnicity were reported. Trial characteristics were extracted from the primary manuscript or clinical trials.gov and included: study area, funding source, intervention type, location, sample size, and distribution of female participants. Summary statistics for each study included percentage of blacks enrolled with 95% CI. Meta-analysis of the proportion of black enrollment across relevant CT was conducted to analyze overall estimates of the effect compared to non-black enrollment using an inverse variance weighted random effects model. Additional meta-analyses compared candidate variables that could influence the likelihood of black enrollment. All analyses were performed with SAS version 9.4 (SAS Institute Inc., Cary NC). Results: We identified 2501 trials, 85 met inclusion criteria, comprising a total of 159,791 patients: 25,720 black and 134,071 non-black. The percentage of blacks 38.2% (95%CI: 33.0%-43.6%) enrolled was significantly less than non-blacks 61.8% (95%CI: 56.4%-67%). Enrollment differed significantly across study type with peripheral vascular disease enrolling the largest 59.9% (95%CI: 47.3%-71.4%) and cerebrovascular disease the least 25.1% (16.1%-37%). Industry only studies accounted for 41% (35 of 85) of total trials and were less likely 30.3% (95%CI: 22.7%-39.1%), than NIH 40.9% (95%CI: 34%-48.1%), joint NIH/Industry 46.8% (95%CI: 33.3%-60.7%), and non-NIH/Industry 76.6% (95%CI: 38.7%-94.4%) funded studies to enroll black patients. Pharmacotherapy studies 29.3% (23.3%-36.1%) enrolled fewer black patients than behavioral 43.8% (36.9%-51%) and device/other 48.2% (37.5%-59.1%) studies. Black enrollment decreased for non-US based studies, and as a function of decreasing female sex enrollment and increasing sample sizes of studies. Conclusion: CTs of cardiovascular disease and risk factors were significantly less likely to enroll blacks when compared to non-black patients. Trial characteristics such as study area, funding source, intervention type, study site location, sample size, female percentage, and mean age had statistically significant impacts on black patient accrual in cardiovascular CTs.

Cardiovascular Disease and the Female Disadvantage.

Age-standardised rates of cardiovascular disease (CVD) are substantially higher in men than women. This explains why CVD has traditionally been seen as a “man’s problem”. However, CVD is the leading cause of death in women, worldwide, and is one of the most common causes of disability-adjusted life-years lost. In general, this is under-recognised and, in several ways, women are disadvantaged in terms of CVD. Both in primary and secondary prevention, there is evidence that women are undertreated, compared to men. Women often experience heart disease in a different way compared to men, and lack of recognition of this has been shown to have adverse consequences. Female patients of male cardiac physicians have been found to have worse outcomes than their male counterparts, with no such gender differential for female cardiologists. Clinical trials in CVD primarily recruit male patients, yet, it is well recognised that some drugs act differently in women and men. Diabetes and smoking, and perhaps other risk factors, confer a greater proportional excess cardiovascular risk to women than to men, whilst adverse pregnancies and factors concerned with the female reproductive cycle give women added vulnerability to CVD. However, women’s health research is skewed towards mother and child health, an area where, arguably, the greatest public health gains have already been made, and breast cancer. Hence there is a need to redefine what is meant by “women’s health” to encompass the whole lifecycle, with a stronger emphasis on CVD and other non-communicable diseases. Sex-specific analyses of research data should be the norm, whenever feasible.

Research Participation of a Professional Organization in Clinical Trials: The Association of Black cardiologists Clinical Trial Investigator Identification Project

IntroductionBlack individuals continue to be underrepresented in clinical trials despite efforts by the National Institutes of Health and the Federal Drug Administration to increase their enrollment. Health care providers play a critical role in the recruitment of patients into clinical trials, as they have established relationships and are uniquely positioned to make referrals for participation. While prior initiatives have focused on training black physicians to conduct clinical research, we sought to determine the potential of utilizing a professional organization as a resource to identify established investigators to champion recruitment of underrepresented racial and ethnic populations. The Association of Black Cardiologists (ABC) is a non-profit organization with a mission to eliminate racial and ethnic disparities in cardiovascular disease and may provide a conduit for recruiting investigators. The purpose of this study was to examine the feasibility of using the ABC membership to identify investigators with an established track record in clinical trials. Methods/ResultsUtilizing a roster of ABC members, we searched Scopus to quantify ABC member publications from 1999 to 2015 and identify members who have been active in clinical trials. Within the membership of 2037 individuals, we identified 794 with peer-reviewed publications, and 109 who co-authored manuscripts involving randomized clinical trials. The manuscripts largely focused on hypertension and heart failure, conditions that have a disproportionately greater affect on black individuals. ConclusionMembers of the ABC have varied amounts of research productivity. We identified a group of experienced investigators to engage in efforts aimed at recruiting/enrolling underrepresented racial and ethnic populations in clinical trials of cardiovascular disease.

Multifunctional Role of Chymase in Acute and Chronic Tissue Injury and Remodeling.

Chymase is the most efficient Ang II (angiotensin II)-forming enzyme in the human body and has been implicated in a wide variety of human diseases that also implicate its many other protease actions. Largely thought to be the product of mast cells, the identification of other cellular sources including cardiac fibroblasts and vascular endothelial cells demonstrates a more widely dispersed production and distribution system in various tissues. Furthermore, newly emerging evidence for its intracellular presence in cardiomyocytes and smooth muscle cells opens an entirely new compartment of chymase-mediated actions that were previously thought to be limited to the extracellular space. This review illustrates how these multiple chymase-mediated mechanisms of action can explain the residual risk in clinical trials of cardiovascular disease using conventional renin-angiotensin system blockade.

Trends in Consent for Clinical Trials in Cardiovascular Disease.

BackgroundCardiovascular clinical trials depend on patient enrollment. Enrollment rates appear inadequate, but little is known about how frequently patients accept or decline offers of enrollment. The objective of this study was to assess trends and predictors of patient acceptance of offers to enroll in clinical trials for cardiovascular disease.Methods and ResultsWe utilized an established database containing all randomized, controlled trials (n=1224) in cardiovascular disease published between 2001 and 2012 in the 8 highest‐impact general medical and cardiology journals. Studies were eligible if the number of patients approached and number of patients declining enrollment could be ascertained from published materials. All studies were screened for eligibility. Each eligible study was reviewed by 3 co‐authors. All discrepancies were resolved by the group. The main outcome was acceptance rate, defined as the number of patients enrolled divided by the number patients who were eligible and approached. Only 21.7% (n=266) of studies provided information sufficient to assess patient enrollment and refusals. The median acceptance rate across trials was 83.2%. Significant predictors of higher enrollment included: enrollment in the acute setting (P=0.031); geographical region (P<0.001 for group); and trial sponsorship (P=0.006 for group).ConclusionsRates of reporting data sufficient to calculate acceptance rates are low. This compromises the ability to identify drivers of low enrollment and assess trial generalizability. However, the high rates of acceptance observed suggest that factors other than patients’ decisions may be the primary drivers of declining rates of trial enrollment.

Does Cox analysis of a randomized survival study yield a causal treatment effect?

Statistical methods for survival analysis play a central role in the assessment of treatment effects in randomized clinical trials in cardiovascular disease, cancer, and many other fields. The most common approach to analysis involves fitting a Cox regression model including a treatment indicator, and basing inference on the large sample properties of the regression coefficient estimator. Despite the fact that treatment assignment is randomized, the hazard ratio is not a quantity which admits a causal interpretation in the case of unmodelled heterogeneity. This problem arises because the risk sets beyond the first event time are comprised of the subset of individuals who have not previously failed. The balance in the distribution of potential confounders between treatment arms is lost by this implicit conditioning, whether or not censoring is present. Thus while the Cox model may be used as a basis for valid tests of the null hypotheses of no treatment effect if robust variance estimates are used, modeling frameworks more compatible with causal reasoning may be preferrable in general for estimation.

Improving clinical trials for cardiovascular diseases: a position paper from the Cardiovascular Round Table of the European Society of Cardiology.

Cardiovascular disease is the most common cause of mortality and morbidity in the world, but the pharmaceutical industry's willingness to invest in this field has declined because of the many challenges involved with bringing new cardiovascular drugs to market, including late-stage failures, escalating regulatory requirements, bureaucracy of the clinical trial business enterprise, and limited patient access after approval. This contrasts with the remaining burden of cardiovascular disease in Europe and in the world. Thus, clinical cardiovascular research needs to adapt to address the impact of these challenges in order to ensure development of new cardiovascular medicines. The present paper is the outcome of a two-day workshop held by the Cardiovascular Round Table of the European Society of Cardiology. We propose strategies to improve development of effective new cardiovascular therapies. These can include (i) the use of biomarkers to describe patients who will benefit from new therapies more precisely, achieving better human target validation; (ii) targeted, mechanism-based approaches to drug development for defined populations; (iii) the use of information technology to simplify data collection and follow-up in clinical trials; (iv) streamlining adverse event collection and reducing monitoring; (v) extended patent protection or limited rapid approval of new agents to motivate investment in early phase development; and (vi) collecting data needed for health technology assessment continuously throughout the drug development process (before and after approval) to minimize delays in patient access. Collaboration across industry, academia, regulators, and payers will be necessary to enact change and to unlock the existing potential for cardiovascular clinical drug development. A coordinated effort involving academia, regulators, industry, and payors will help to foster better and more effective conduct of clinical cardiovascular trials, supporting earlier availability of innovative therapies and better management of cardiovascular diseases.

Changing of the guard?: Figure 1

This editorial refers to ‘Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: a randomized placebo-controlled trial (MSC-HF trial)’[†][1], by A.B. Mathiasen et al. , on page 1744. Cell therapy continues to hold promise as a future therapeutic modality for patients with heart failure. The first cells to be utilised in clinical trials in cardiovascular disease were autologous bone marrow-derived mononuclear cells (ABMMNCs).1–3 This was likely due to the fact that these cells are readily accessible and can be easily processed and given back to patients as an autologous fresh product in a short amount of time. In the absence of clinical experience, this was a good starting point. Over the next decade, important additional data were obtained with the use of ABMMNCs,4–6 and the initial positive results were tempered by negative results. Nonetheless, after much scrutiny, there seems to be a therapeutic signal, … [1]: #fn-2