Comparison of interleukin-6 and high-sensitivity C-reactive protein for cardiovascular risk assessment: Findings from the MESA study.

BACKGROUND AND AIMS: Inflammation is a risk factor for major adverse cardiovascular events (MACE). Elevated levels of both high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL6) have been associated with MACE. However, few studies have compared IL6 to hsCRP for cardiovascular risk assessment. Using the MESA (Multi-Ethnic Study of Atherosclerosis) study cohort, we aim to compare IL6 to hsCRP. METHODS: We divided IL6 and hsCRP by their median values and created 4 groups i.e., low-low, high-low, low-high and high-high. The median follow-up was 14 years. RESULTS: 6614 (97 %) participants had complete baseline IL6 and hsCRP data. The correlation between hsCRP and IL6 was modest (Rho = 0.53). IL6 ≥1.2 pg/mL (median) was present in 3309 participants, and hsCRP ≥1.9 mg/L (median) was present in 3339 participants. Compared to participants with low IL6 and low hsCRP, those with high IL6 and high hsCRP were older (64 vs. 60 years), more frequently women (63 % vs. 45 %), and with more cardiovascular co-morbidities. hsCRP outcome associations lost statistical significance when adjusting for IL6: MACE HR (95 %CI) 1.06 (0.93-1.20), p =0.39, whereas IL6 associations remained significant after adjusting for hsCRP: HR (95 %CI) 1.44 (1.25-1.64), p <0.001. The C-index of Framingham score for did not improve with hsCRP but improved with IL6. Compared to participants with low IL6 and low hsCRP, those with high IL6, regardless of hsCRP, experienced an increased risk of MACE, heart failure and mortality. CONCLUSIONS: In a diverse and asymptomatic population, IL6 showed a stronger association with atherosclerotic, heart failure and fatal outcomes than hsCRP.

Circulating miR-133a-3p defines a low-risk subphenotype in patients with heart failure and central sleep apnea: a decision tree machine learning approach.

BACKGROUND: Patients with heart failure with reduced ejection fraction (HFrEF) and central sleep apnea (CSA) are at a very high risk of fatal outcomes. OBJECTIVE: To test whether the circulating miRNome provides additional information for risk stratification on top of clinical predictors in patients with HFrEF and CSA. METHODS: The study included patients with HFrEF and CSA from the SERVE-HF trial. A three-step protocol was applied: microRNA (miRNA) screening (n = 20), technical validation (n = 60), and biological validation (n = 587). The primary outcome was either death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening of heart failure, whatever occurred first. MiRNA quantification was performed in plasma samples using miRNA sequencing and RT-qPCR. RESULTS: Circulating miR-133a-3p levels were inversely associated with the primary study outcome. Nonetheless, miR-133a-3p did not improve a previously established clinical prognostic model in terms of discrimination or reclassification. A customized regression tree model constructed using the Classification and Regression Tree (CART) algorithm identified eight patient subphenotypes with specific risk patterns based on clinical and molecular characteristics. MiR-133a-3p entered the regression tree defining the group at the lowest risk; patients with log(NT-proBNP) ≤ 6 pg/mL (miR-133a-3p levels above 1.5 arbitrary units). The overall predictive capacity of suffering the event was highly stable over the follow-up (from 0.735 to 0.767). CONCLUSIONS: The combination of clinical information, circulating miRNAs, and decision tree learning allows the identification of specific risk subphenotypes in patients with HFrEF and CSA.

Pharmaco-disparities in heart failure: a survey of the affordability of guideline recommended therapy in 10 countries.

AIMS: Heart failure with reduced ejection fraction (HFrEF) is treatable but guideline-directed medical therapy (GDMT) may not be affordable or accessible to people living with the disease. METHODS AND RESULTS: In this cross-sectional survey, we investigated the price, affordability, and accessibility of four pivotal classes of HFrEF GDMT: angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB) or angiotensin-neprilysin inhibitors (ARNI); beta-blockers; mineralocorticoid receptor antagonists (MRA); and sodium glucose co-transporter 2 inhibitors (SGLT2i). We sampled online or community pharmacies in 10 countries across a range of World Bank income groups, assessing mean 30 day retail prescription prices, affordability relative to gross national income per capita per month, and accessibility. We reported median price ratios relative to the International Reference Standard. We performed a literature review to evaluate accessibility to GDMT classes through publicly funded drug programmes in each country. HFrEF GDMT prices, both absolute and relative to the international reference, were highest in the United States and lowest in Pakistan and Bangladesh. The most expensive drug was the ARNI, sacubitril/valsartan, with a mean (standard deviation, SD) 30 day price ranging from $11.06 (0.81) in Pakistan to $611.50 (3.54) in United States. The least expensive drug was the MRA, spironolactone, with a mean (SD) 30 day price ranging from $0.18 (0.00) in Pakistan to $12.32 (0.00) in England. Affordability (SD) of quadruple therapy-ARNI, beta-blockers, MRA, and SGLT2i-was best in high-income and worst in low-income countries, ranging from 1.49 (0.00)% of gross national income per capita per month in England to 232.47 (31.47)% in Uganda. Publicly funded drug programmes offset costs for eligible patients, but ARNI and SGLT2i were inaccessible through these programmes in low- and middle-income countries. Price, affordability, and access were substantially improved in all countries by substituting ARNI for ACEi/ARB. CONCLUSIONS: There was marked variation between countries in the retail price of HFrEF GDMT. Despite higher prices in high-income countries, GDMT was more accessible and affordable than in low- and middle-income countries. Publicly funded drug programmes in lower income countries increased affordability but limited access to newer HFrEF GDMT classes. Pharmaco-disparities must be addressed to improve HFrEF outcomes globally.

Prevalence and management of hyperkalemia in chronic kidney disease and heart failure patients in the Gulf Cooperation Council (GCC).

Hyperkalemia is a frequent complication in patients with chronic kidney disease (CKD) or heart failure (HF) and associated with neuromuscular manifestations, changes in the electrocardiogram, and increased risk of mortality. While data on the prevalence and management of hyperkalemia in the gulf region are scarce, risk factors such as preference for potassium-rich foods (e.g., dates and dried fruits/vegetables), periods of intense fasting (e.g., Ramadan), and diabetes (an ancestor of CKD and HF) are common. Therefore, a panel of nephrologists and cardiologists from countries of the Gulf Cooperation Council (GCC) convened to collate and review available data on the prevalence, regional drivers, and current practice in the management of hyperkalemia in the region. Eventually, this review provides consensus recommendations on a balanced utilization of dietary and pharmacological options including new potassium binders for achieving and sustainably maintaining desirable serum potassium levels in countries of the GCC region. Alignment with regional habits and practice was a key aspect to facilitate the uptake of the recommendations into physicians' practice and patients' lives.

How can we optimise health technology assessment and reimbursement decisions to accelerate access to new cardiovascular medicines?

Regulatory approvals of, and subsequent access to, innovative cardiovascular medications have declined. How much of this decline relates to the final step of gaining reimbursement for new treatments is unknown. Payers and health technology assessment (HTA) bodies look beyond efficacy and safety to assess whether a new drug improves patient outcomes, quality of life, or satisfaction at a cost that is affordable compared to existing treatments. HTA bodies work within a limited healthcare budget, and this is one of the reasons why only half of newly approved drugs are accepted for reimbursement, or receive restricted or "optimised" recommendations from HTA bodies. All stakeholders have the common goal of facilitating access to safe, effective, and affordable treatments to appropriate patients. An important strategy to expedite this is providing optimal data. This is demonstrably facilitated by early (and ongoing) discussions between all stakeholders. Many countries have formal programmes to provide collaborative regulatory and HTA advice to developers. Other strategies include aligning regulatory and HTA processes, increasing use of real-world evidence, formally defining the decision-making process, and educating stakeholders on the criteria for positive decision making. Industry should focus on developing treatments for unmet medical needs, seek early engagement with HTA and regulatory bodies, improve methodologies for optimal price setting, develop internal systems to collaborate with national and international stakeholders, and conduct post-approval studies. Patient involvement in all stages of development, including HTA, is critical to capture the lived experience and priorities of those whose lives will be impacted by new treatment approvals.

Biomarker-based assessment of collagen cross-linking identifies patients at risk of heart failure more likely to benefit from spironolactone effects on left atrial remodelling. Insights from the HOMAGE clinical trial.

AIMS: The HOMAGE randomized trial found that spironolactone reduced left atrial volume index (LAVI), E:A ratio, and a marker of collagen type I synthesis (procollagen type I C-terminal propeptide) in patients at risk of heart failure (HF). Previous trials showed that patients with HF, preserved ejection fraction and low serum collagen type I C-terminal telopeptide to matrix metalloproteinase-1 ratio (CITP:MMP-1), associated with high collagen cross-linking, had less improvement in diastolic function with spironolactone. We evaluated the interaction between serum CITP:MMP-1 and spironolactone on cardiac function in the HOMAGE trial. METHODS AND RESULTS: Patients at risk of HF were randomized to spironolactone (n = 260) or not (n = 255). Blood sampling and echocardiography were done at baseline, one and nine months. CITP:MMP-1 was used as an indirect measure of collagen cross-linking. Higher baseline CITP:MMP-1 (i.e. lower collagen cross-linking) was associated with greater reductions in LAVI with spironolactone at both one (p = 0.003) and nine (p = 0.01) months, but no interaction was observed for E:A ratio. Spironolactone reduced LAVI after one and nine months only for those patients in the third tertile of CITP:MMP-1 (estimated lowest collagen cross-linking) [mean differencesspiro/control : -1.77 (95% confidence interval, CI -2.94 to -0.59) and -2.52 (95% CI -4.46 to -0.58) mL/m2 ; interaction pacross-tertiles  = 0.005; interaction pthird tertile  = 0.008] with a similar trend for N-terminal pro-B-type natriuretic peptide which was consistently reduced by spironolactone only in the lowest collagen cross-linking tertile [mean differencesspiro/control : -0.47 (95% CI -0.66 to -0.28) and -0.31 (95% CI -0.59 to -0.04) ng/L; interaction pacross-tertiles  = 0.09; interaction pthird tertile < 0.001]. CONCLUSIONS: These findings suggest that, for patients at risk of HF, the effects of spironolactone on left atrial remodelling may be more prominent in patients with less collagen cross-linking (indirectly assessed by serum CITP:MMP-1).

Kidney function assessment and endpoint ascertainment in clinical trials.

Heterogeneity in the reporting of kidney function, kidney outcomes, and definitions for kidney endpoints in clinical trials makes it challenging to compare results and gauge incremental benefit of interventions across trials. We conducted a systematic review of the ascertainment of baseline kidney variables, reporting of kidney endpoints, and definitions used to characterize these endpoints in type 2 diabetes mellitus (T2DM), kidney, and heart failure (HF) trials. Medline, Scopus, and ClinicalTrials.gov were searched from January 2014 through January 2021 for large (>1000 participants) T2DM, HF, and kidney disease trials and their secondary analyses. Trial publication and supplementary appendices were searched to abstract relevant data. Thirty-three trials (16 T2DM; 10 HF; 7 kidney diseases) were included. Thirteen trials did not include patients with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 and for trials that did, representation of this cohort ranged from 0.1% to 15%. Reporting of baseline kidney function and albuminuria remained low, especially in HF trials. Variability was observed in the definition of chronic kidney disease, sustained decline in eGFR, end-stage kidney disease, kidney death, and kidney composite endpoint across trials. eGFR slope was reported in less than half trials, with differences observed in statistical models, definition of acute or chronic slope, and follow-up duration across trials. Significant heterogeneity in reporting of kidney function and kidney outcomes in large T2DM, kidney, and HF trials underscores the need for future stakeholders to draft a consensus solution. Detailed profiling of patients at baseline, accrual of more patients with advanced kidney disease, and standardization of definitions in trials may improve the ability to compare the results across trials.

Non-adherence to heart failure medications predicts clinical outcomes: assessment in a single spot urine sample by liquid chromatography-tandem mass spectrometry (results of a prospective multicentre study).

AIMS: Liquid chromatography-mass spectrometry (LC-MS/MS) is an objective new technique to assess non-adherence to medications. We used this method to study the prevalence, predictors and outcomes of non-adherence in patients with heart failure with reduced left ventricular ejection fraction (HFrEF). METHODS AND RESULTS: This study included 1296 patients with HFrEF from BIOSTAT-CHF, a study that aimed to optimise guideline-recommended therapies. Angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, ß-blockers and loop diuretics were measured in a single spot urine sample at 9 months using LC-MS/MS. The relationship between medication non-adherence and the composite endpoint of all-cause death or heart failure hospitalisation, over a median follow-up of 21 months, was evaluated. Non-adherence to at least one prescribed medication was observed in 45.9% of patients. The strongest predictor of non-adherence was non-adherence to any of the other medication classes (P < 0.0005). Regional differences within Europe were observed. On multivariable analyses, non-adherence to ACEi/ARBs and ß-blockers was associated with an increased risk of the composite endpoint [hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.09-1.95, P = 0.008 and HR 1.48, 95% CI 1.12-1.96, P = 0.006, respectively). Non-adherence to ß-blockers was also associated with an increased risk of death (HR 2.48, 95% CI 1.67-3.68, P < 0.0005). Patients who were non-adherent to loop diuretics were healthier and had a decreased risk of the composite endpoint (HR 0.69, 95% CI 0.51-0.93, P = 0.014). Non-adherence to mineralocorticoid receptor antagonists was not related to any clinical outcome. CONCLUSION: Non-adherence to medications, assessed by a single urine test, is common and predicts clinical outcomes in patients with HFrEF.

The Future of Meat: Health Impact Assessment with Randomized Evidence.

Massive animal farming for meat production poses major problems in terms of resource use, environmental impact, and biodiversity. Furthermore, excessive meat consumption has been associated with multiple deleterious health consequences. However, more and better-designed randomized trials are needed to increase the level of evidence on the health impacts of meat. Novel meat alternatives, such as plant- and cell-based meat, are much less impactful to the environment and might replace traditional animal meat in the future, but, despite promising early data, the health consequences of these novel products need further study. This manuscript focuses on the health impacts of meat over 3 main sections: 1) overview of the evidence highlighting the association of meat consumption with health; 2) novel alternatives to meat, including plant-based and cell-based alternatives; and 3) examine the rationale for randomized studies to evaluate the effects of the novel meat alternatives compared with the standard animal meat.

Income level and inequality as complement to geographical differences in cardiovascular trials.

BACKGROUND: Analyses of country or regional differences in cardiovascular (CV) trials are based on geographical subgroup analyses. However, apart from map location and related racial, ethnic, and genetic variations, identified differences may also depend on social structure and provision and access to health care, for which country income and income inequality are indicators. The aim of the study was to examine the association between country per capita income and income inequality and prognosis in patients with heart failure or an acute coronary syndrome in 3 international trials (EMPHASIS-HF, EPHESUS, and EXAMINE). METHODS: Countries were classified into high income or low-middle income (LMICs) and into low, middle, or high inequality using the Gini index. The main outcome measures were all-cause and CV death. RESULTS: Patients from LMICs and countries with higher inequality were younger, were less often white, had fewer comorbid conditions, and were less often treated with guideline-recommended therapies, including devices. These patients had higher adjusted mortality rates (+15% to +70%) compared with patients from high-income countries and countries with less inequality. Patients from countries with the combination of greater inequality and low-middle income had particularly high mortality rates (+80% to +190%) compared with those that did not have both characteristics. Living in a country that is poor and has inequality had more impact on death rates than any comorbidity. These findings were reproduced in 3 trials. CONCLUSIONS: Patients from LMICs and countries with greater inequality had the highest mortality rates. The prognostic impact of income and inequality is substantial and should be considered when looking into subgroup differences in CV trials.

Assessment of Tunisian acceptance to participate in a Clinical Trial.

"CT" clinical trials are medical research studies to determine whether different treatments are effective and safe. Some trials involve patients and other trials involve healthy volunteers. This survey aims to assess CT knowledge and the acceptance to participate to CT of Tunisian citizen. The study involved 260 participants in three groups: healthy people (n = 133), physicians (n = 57) and patients (n = 70). The analysis shows that, even if ignorance and lack of will can be universally common, one of the major shortcomings in Tunisia is the lack of communication on CTs, their benefits and the transparency of the Tunisian regulatory framework. The culture of CT and training on Clinical Research is missing as well. The results are encouraging, and suggest that Tunisians are reasonably aware of CTs and have a positive intention to participate.

Income Inequality and Outcomes in Heart Failure: A Global Between-Country Analysis.

OBJECTIVES: This study examined the relationship between income inequality and heart failure outcomes. BACKGROUND: The income inequality hypothesis postulates that population health is influenced by income distribution within a society, with greater inequality associated with worse outcomes. METHODS: This study analyzed heart failure outcomes in 2 large trials conducted in 54 countries. Countries were divided by tertiles of Gini coefficients (where 0% represented absolute income equality and 100% represented absolute income inequality), and heart failure outcomes were adjusted for standard prognostic variables, country per capita income, education index, hospital bed density, and health worker density. RESULTS: Of the 15,126 patients studied, 5,320 patients lived in Gini coefficient tertile 1 countries (coefficient: <33%), 6,124 patients lived in tertile 2 countries (33% to 41%), and 3,772 patients lived in tertile 3 countries (>41%). Patients in tertile 3 were younger than tertile 1 patients, were more often women, and had less comorbidity and several indicators of less severe heart failure, yet the tertile 3-to-1 hazard ratios (HRs) for the primary composite outcome of cardiovascular death or heart failure hospitalization were 1.57 (95% confidence interval [CI]: 1.38 to 1.79) and 1.48 for all-cause death (95% CI: 1.29 to 1.71) after adjustment for recognized prognostic variables. After additional adjustments were made for per capita income, education index, hospital bed density, and health worker density, these HRs were 1.46 (95% CI: 1.25 to 1.70) and 1.30 (95% CI: 1.10 to 1.53), respectively. CONCLUSIONS: Greater income inequality was associated with worse heart failure outcomes, with an impact similar to those of major comorbidities. Better understanding of the societal and personal bases of these findings may suggest approaches to improve heart failure outcomes.

Association with outcomes and response to treatment of trimethylamine N-oxide in heart failure: results from BIOSTAT-CHF.

AIMS: Association of elevated circulating levels of trimethylamine N-oxide (TMAO) with adverse outcomes in patients with heart failure (HF) has been described. However, response of TMAO levels to treatment and medications has not been investigated. Therefore, we investigated whether TMAO levels are responsive to guideline-recommended treatment and medications, and further reflect changes in outcomes. METHODS AND RESULTS: TMAO levels were investigated in the systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF), which addressed response to guideline-recommended pharmacological treatment. TMAO levels in 2234 patients with new-onset or progressively worsening HF showed strong associations with adverse events (mortality and/or rehospitalisation) at 1, 2 and 3 years [hazard ratio (HR) 1.37-1.51, P ≤ 0.019). Analysis of 972 patients with plasma available at both enrolment and follow-up visit showed reductions of B-type natriuretic peptide (BNP) levels with guideline-based treatment (P < 0.001), but not for TMAO levels. Moreover, patients with higher TMAO levels than median before and after treatment showed increased association with adverse outcomes [HR 2.21, 95% confidence interval (CI) 1.43-3.43, P < 0.001] compared to patients with lower than median levels either before or after treatment (HR 1.13, 95% CI 0.63-2.04, P = 0.684 and HR 1.14, 95% CI 0.64-2.03, P = 0.662, respectively). CONCLUSION: TMAO levels were associated with adverse outcomes (mortality and/or rehospitalisation) in BIOSTAT-CHF, and did not respond to guideline-based pharmacological treatment in contrast to BNP levels which did as expected. Lower TMAO levels were associated with favourable outcome regardless of treatment.

Relationship Between Enrolling Country Income Level and Patient Profile, Protocol Completion, and Trial End Points.

BACKGROUND: Globalization of clinical trials fosters inclusion of higher and lower income countries, but the influence of enrolling country income level on heart failure trial performance is unclear. This study sought to evaluate associations between enrolling country income level, acute heart failure patient profile, protocol completion, and trial end points. METHODS AND RESULTS: The ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial included 7141 patients with acute heart failure from 30 countries. Country income data in gross national income per capita in current US dollars from the year 2007 (ie, the year trial enrollment began) were abstracted from the World Bank. Patients were grouped by enrolling country income level (ie, high [>$11 455], upper middle [$3706-$11 455], lower middle [$936-$3705], and low [<$936]). Income data were available for 29 (97%) countries (N=7064). There were 3996 (57%), 1518 (21%), and 1550 (22%) patients from high-income, upper-middle-income, and lower-middle-income countries, respectively. There were no patients from low-income countries. Patients from lower-middle-income countries tended to be younger with fewer comorbidities and lower utilization of guideline-directed therapies. Rates of adverse events (13.8%) and protocol noncompletion (4.9%) during 180-day follow-up were highest among high-income countries (all P <0.01). After adjustment for race, geographic region, and clinical characteristics, compared with lower-middle-income countries, enrollment from higher income countries was associated with increased 30-day mortality or rehospitalization (high income: odds ratio, 1.70; 95% CI, 1.02-2.85; upper-middle-income: odds ratio, 2.16; 95% CI, 1.23-3.81), driven by higher rates of rehospitalization. Mortality was similar at 30 and 180 days. The association between higher country income and the 30-day composite end point was similar across geographic regions, with exception of Latin America ( P for interaction, 0.03). CONCLUSIONS: In this global acute heart failure trial, patients from higher income countries had lower rates of protocol completion, higher rates of adverse events, and similar mortality rates. After adjustment for race, geographic region, and clinical factors, enrollment from a higher income country was associated with worse clinical outcomes, driven by higher rates of rehospitalization. Variation in enrolling country income level may influence study end points and trial performance independent of geographic region. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00475852.

First granted example of novel FDA trial design under Expedited Access Pathway for premarket approval: BeAT-HF.

BACKGROUND: The Food and Drug Administration (FDA) initiated the Expedited Access Pathway (EAP) to accelerate approval of novel therapies targeting unmet needs for life-threatening conditions. EAP allows for the possibility of initial FDA approval using intermediate end points with postapproval demonstration of improved outcomes. OBJECTIVE: Describe the EAP process using the BeAT-HF trial as a case study. METHODS: BeAT-HF will examine the safety and effectiveness of baroreflex activation therapy (BAT) in heart failure patients with reduced ejection fraction using an Expedited and Extended Phase design. In the Expedited Phase, BAT plus guideline-directed medical therapy (GDMT) will be compared at 6 months postimplant to GDMT alone using 3 intermediate end points: 6-minute hall walk distance, Minnesota Living with Heart Failure Questionnaire, and N-terminal pro-B-type natriuretic peptide. The rate of heart failure morbidity and cardiovascular mortality will be compared between the arms to evaluate early trending using predictive probability modeling. Sample size of 264 patients randomized 1:1 to BAT + GDMT versus GDMT alone provides 81% power for the Expedited Phase intermediate end points. For the Extended Phase, the heart failure morbidity and cardiovascular mortality end point is based on an expected event rate of 0.4 events/patient/year in the GDMT arm. With an adaptive sample size selection design for robustness to inaccurate assumptions, a sample size of 480-960 randomized patients followed ≥2 years allows detecting a 30% reduction in the primary end point with a power of 97.5%. CONCLUSION: Through a unique collaboration with FDA under the EAP, the BeAT-HF trial design allows for the possibility of approval of BAT, initially for symptom relief and subsequently for outcomes improvement.

Integrative Assessment of Congestion in Heart Failure Throughout the Patient Journey.

Congestion is one of the main predictors of poor patient outcome in patients with heart failure. However, congestion is difficult to assess, especially when symptoms are mild. Although numerous clinical scores, imaging tools, and biological tests are available to assist physicians in ascertaining and quantifying congestion, not all are appropriate for use in all stages of patient management. In recent years, multidisciplinary management in the community has become increasingly important to prevent heart failure hospitalizations. Electronic alert systems and communication platforms are emerging that could be used to facilitate patient home monitoring that identifies congestion from heart failure decompensation at an earlier stage. This paper describes the role of congestion detection methods at key stages of patient care: pre-admission, admission to the emergency department, in-hospital management, and lastly, discharge and continued monitoring in the community. The multidisciplinary working group, which consisted of cardiologists, emergency physicians, and a nephrologist with both clinical and research backgrounds, reviewed the current literature regarding the various scores, tools, and tests to detect and quantify congestion. This paper describes the role of each tool at key stages of patient care and discusses the advantages of telemedicine as a means of providing true integrated patient care.

Role of Payers in the Development of Cardiovascular Therapeutics: Misalignment Between Approval and Reimbursement.

Regulators and payers have contrasting priorities that can lead to divergent decisions and delays in patient access to new treatments. Those involved in coverage decisions have not routinely been integrated in the drug development process. Theoretically, inclusion of payer representatives early in development could help discern discordance among stakeholder priorities; facilitate cooperation to align objectives; foster agreement on the evidence required for approval and reimbursement; improve transparency, accountability, and consistency of payer decision making; and ideally, minimize delays in patient access to new therapies. However, early participation by payers may not provide these expected benefits if payers' decision-making processes are not evidence based or cannot be reliably predicted. This paper describes current interactions among regulatory agencies, payers, sponsors, and investigators and proposes collaboration among all stakeholders earlier in the development process. The premise that a priori discussions might facilitate the delivery of advances in cardiovascular care is a hypothesis worth testing.