Reduced left ventricular contractility, increased diastolic operant stiffness and high energetic expenditure in patients with severe aortic regurgitation without indication for surgery.

OBJECTIVES: Recent mortality studies showed worse prognosis in patients (ARNS) with severe aortic regurgitation and preserved ejection fraction (EF) not fulfilling the criteria of current guidelines for surgery. The aim of our study was to analyse left ventricular (LV) systolic and diastolic function and mechanical energetics to find haemodynamic explanations for the reduced prognosis of these patients and to seek a new concept for surgery. METHODS: Global longitudinal strain (GLS) and echo-based single-beat pressure-volume analyses were performed in patients with ARNS (LV end-diastolic diameter <70 mm, EF >50%, GLS > -19% n = 41), with indication for surgery (ARS; n = 19) and in mild hypertensive controls (C; n = 20). Additionally, end-systolic elastance (LV contractility), stroke work and total energy (pressure-volume area) were calculated. RESULTS: ARNS demonstrated significantly depressed LV contractility versus C: end-systolic elastance (1.58 ± 0.7 vs 2.54 ± 0.8 mmHg/ml; P < 0.001), despite identical EF (EF: 59 ± 6% vs 59 ± 7%). Accordingly, GLS was decreased [-15.7 ± 2.7% (n = 31) vs -21.2 ± 2.4%; P < 0.001], end-diastolic volume (236 ± 90 vs 136 ± 30 ml; P < 0.001) and diastolic operant stiffness were markedly enlarged, as were pressure-volume area and stroke work, indicating waste of energy. The correlation of GLS versus end-systolic elastance was good (r = -0.66; P < 0.001). ARNS and ARS patients demonstrated similar haemodynamic disorders, whereas only GLS was worse in ARS. CONCLUSIONS: ARNS patients almost matched the ARS patients in their haemodynamic and energetic deterioration, thereby explaining poor prognosis reported in literature. GLS has been shown to be a reliable surrogate for LV contractility, possibly overestimating contractility due to exhausted preload reserve in aortic regurgitation patients. GLS may outperform conventional echo parameters to predict more precisely the timing of surgery.

Relationship of Body Mass Index With Outcomes After Transcatheter Aortic Valve Replacement: Results From the National Cardiovascular Data-STS/ACC TVT Registry.

OBJECTIVE: To investigate the relationship of body mass index (BMI) with short- and long-term outcomes after transcatheter aortic valve replacement (TAVR). PATIENTS AND METHODS: The relationship between BMI and baseline characteristics and procedural characteristics was assessed for 31,929 patients who underwent TAVR between November 1, 2011, and March 31, 2015, from the STS/ACC TVT Registry. Registry data on 20,429 patients were linked to the Centers for Medicare and Medicaid Services to assess the association of BMI with 30-day and 1-year mortality using multivariable Cox proportional hazards models. The effect of BMI on mortality was also assessed with BMI as a continuous variable. Restricted cubic regression splines were used to model the effect of BMI and to determine appropriate cut points of BMI. RESULTS: Among 31,929 patients, 806 (2.5%) were underweight (BMI, <18.5 kg/m2), 10,755 (33.7%) had normal weight (BMI, 18.5- 24.9 kg/m2), 10,691 (33.5%) were overweight (BMI, 25.0-29.9 kg/m2), 5582 (17.5%) had class I obesity (BMI, 30.0-34.9 kg/m2), 2363 (7.4%) had class II obesity (BMI, 35.0-39.9 kg/m2), and 1732 (5.4%) had class III obesity (BMI, ≥40 kg/m2). Patients in various BMI categories were different in most baseline and procedural characteristics. On multivariable analysis, compared with normal-weight patients, underweight patients had higher mortality at 30 days and at 1 year after TAVR (hazard ratio [HR], 1.35; 95% CI, 1.02-1.78 and HR, 1.41; 95% CI, 1.17-1.69, respectively), whereas overweight patients and those with class I and II obesity had a decreased risk of mortality at 1 year (HR, 0.88; 95% CI, 0.81-0.95, HR, 0.80; 95% CI, 0.72-0.89, and HR, 0.84; 95% CI, 0.72-0.98, respectively). For BMI of 30 kg/m2 or less, each 1-kg/m2 increase was associated with a 2% and 4% decrease in the risk of 30-day and 1-year mortality, respectively; for BMI greater than 30 kg/m2, a 1-kg/m2 increase was associated with a 3% increased risk of 30-day mortality but not with 1-year mortality. CONCLUSION: Results of this large registry study evaluating the relationship of BMI and outcomes after TAVR support the existence of an obesity paradox among patients with severe aortic stenosis undergoing TAVR.

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.

Financial impact of ivabradine on reducing heart failure penalties under the Hospital Readmission Reduction Program.

OBJECTIVE: The introduction of the Hospital Readmission Reduction Program (HRRP) has led to renewed interest in developing strategies to reduce 30 day readmissions among patients with heart failure (HF). In this study, a model was developed to investigate whether the addition of ivabradine to a standard-of-care (SoC) treatment regimen for patients with HF would reduce HRRP penalties incurred by a hypothetical hospital with excess 30 day readmissions. RESEARCH DESIGN: A model using a Monte Carlo simulation framework was developed. Model inputs included national hospital characteristics, hospital-specific characteristics, and the ivabradine treatment effect as quantified by a post hoc analysis of the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT). RESULTS: The model computed an 83% reduction in HF readmission penalty payments in a hypothetical hospital with a readmission rate of 22.95% (excess readmission ratio = 1.056 over the national average readmission rate of 21.73%), translating into net savings of $44,016. A sensitivity analysis indicated that the readmission penalty is affected by the specific characteristics of the hospital, including the readmission rate, size of the ivabradine-eligible population, and ivabradine utilization. CONCLUSIONS: The results of this study indicate that the addition of ivabradine to an SoC treatment regimen for patients with HF may lead to a reduction in the penalties incurred by hospitals under the HRRP. This highlights the role ivabradine can play as part of a wider effort to optimize the care of patients with HF.

Budget Impact of Adding Ivabradine to Standard of Care in Patients with Chronic Systolic Heart Failure in the United States.

BACKGROUND: Heart failure (HF) costs $21 billion annually in direct health care costs, 80% of which is directly attributable to hospitalizations. The SHIFT clinical study demonstrated that ivabradine plus standard of care (SoC) reduced HF-related and all-cause hospitalizations compared with SoC alone. OBJECTIVE: To estimate the budget impact of ivabradine from a U.S. commercial payer perspective. METHODS: A budget impact model estimated the per-member-per month (PMPM) impact of introducing ivabradine to existing formularies by comparing a reference scenario (SoC) and a new drug scenario (ivabradine + SoC) in hypothetical 1 million-member commercial and Medicare Advantage plans. In both scenarios, U.S. claims data were used for the reference cumulative annual rates of hospitalizations (HF, non-HF cardiovascular [CV], and non-CV), and hospitalization rates were adjusted using SHIFT data. The model controlled for mortality risk using SHIFT and U.S. life table data, and hospitalization costs were obtained from U.S. claims data: HF-related = $37,507; non-HF CV = $28,951; and non-CV = $17,904. The annualized wholesale acquisition cost of ivabradine was $4,500, with baseline use for this new drug at 2%, increasing 2% per year. RESULTS: Based on the approved U.S. indication, approximately 2,000 commercially insured patients from a 1 million-member commercial plan were eligible to receive ivabradine. Ivabradine resulted in a PMPM cost savings of $0.01 and $0.04 in years 1 and 3 of the core model, respectively. After including the acquisition price for ivabradine, the model showed a decrease in total costs in the commercial ($991,256 and $474,499, respectively) and Medicare populations ($13,849,262 and $4,280,291, respectively) in year 1. This decrease was driven by ivabradine's reduction in hospitalization rates. For the core model, the estimated pharmacy-only PMPM in year 1 was $0.01 for the commercial population and $0.24 for the Medicare Advantage population. CONCLUSIONS: Adding ivabradine to SoC led to lower average annual treatment costs. The negative PMPM budget impact indicates that ivabradine is an affordable option for U.S. payers. DISCLOSURES: This study was funded by Amgen. Patel is employed by Amgen; Kielhorn was employed by Amgen at the time of the study but is no longer affiliated with Amgen. Borer, Böhm, Ford, and Komajda have received scientific support, consultative fees, and/or speakers honoraria from Servier and Amgen in connection with SHIFT, the trial underlying this analysis. Borer also has received consultative fees from Celladon, Pfizer, ARMGO, Cardiorentis, Novartis, and Takeda USA. Kansal, Dorman, Krotneva, and Zheng are employees of Evidera, which was hired to assist with this study. Tavazzi has received research grants and consultation fees from Servier in connection with this study and has had advisory board memberships with Boston Scientific, Servier, Cardiorentis, Medtronic, St. Jude Medical, and CVie Therapeutics. Study concept and design were contributed by Dorman and Keilhorn, along with the other authors. Tavazzi, Komajda, Ford, BÖhm, and Borer oversaw collection of the data. Tavazzi, Komajda, Ford, BÖhm, and Borer (along with Karl Swedberg) formed the Executive Committee of SHIFT, the trial underlying this analysis. The manuscript was written by Kansal, along with the other authors, and revised by Borer and Patel, with assistance from the other authors.

Assessment of cardiovascular risk of new drugs for the treatment of diabetes mellitus: risk assessment vs. risk aversion.

The Food and Drug Administration issued guidance for evaluating the cardiovascular risk of new diabetes mellitus drugs in 2008. Accumulating evidence from several completed trials conducted within this framework raises questions as to whether requiring safety outcome studies for all new diabetes mellitus therapies remains justified. Given the burden of cardiovascular disease in patients with diabetes, the focus should shift towards cardiovascular outcome studies designed to evaluate efficacy (i.e. to determine the efficacy of a drug over placebo or standard care) rather than demonstrating that risk is not increased by a pre-specified safety margin. All stakeholders are responsible for ensuring that new drug approvals occur under conditions of appropriate safety and effectiveness. It is also a shared responsibility to avoid unnecessary hurdles that may compromise access to useful drugs and threaten the sustainability of health systems. It is critical to renew this debate so that stakeholders can collectively determine the optimal approach for developing new drugs to treat type 2 diabetes mellitus.

Cardiovascular drug development: is it dead or just hibernating?

Despite the global burden of cardiovascular disease, investment in cardiovascular drug development has stagnated over the past 2 decades, with relative underinvestment compared with other therapeutic areas. The reasons for this trend are multifactorial, but of primary concern is the high cost of conducting cardiovascular outcome trials in the current regulatory environment that demands a direct assessment of risks and benefits, using clinically-evident cardiovascular endpoints. To work toward consensus on improving the environment for cardiovascular drug development, stakeholders from academia, industry, regulatory bodies, and government agencies convened for a think tank meeting in July 2014 in Washington, DC. This paper summarizes the proceedings of the meeting and aims to delineate the current adverse trends in cardiovascular drug development, understand the key issues that underlie these trends within the context of a recognized need for a rigorous regulatory review process, and provide potential solutions to the problems identified.

Academic perspectives on the United States Food and Drug Administration's guidance for industry on diabetes mellitus.

The United States Food and Drug Administration (FDA) has issued Guidance for Industry, subtitled Diabetes Mellitus-Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. From an academic perspective, these regulatory requirements provide undue emphasis on the results of phase 2 trials not designed to test hypotheses about clinical cardiovascular events. Phase 2 trials should be considered hypothesis formulating either alone or in their meta-analyses. Thus, this FDA guidance for industry does not adequately emphasize the importance and necessity of well designed and conducted phase 3 trials of sufficient size, dose, and duration to test the hypothesis formulated from the meta-analysis of the phase 2 trials. We believe that the guiding principle about benefits and risks of drugs should be that rational decisions for individual patients and the health of the general public should be based on a sufficient totality of evidence. When that totality of evidence is incomplete, it is appropriate to remain uncertain. We believe phase 2 trials should be performed mainly for proof of concept and dose ranging. To detect reliably the most plausible small to moderate effects of drugs, the totality of evidence must include large scale randomized phase 3 trials. These individual trials must be of sufficient size, dose, and duration as well as achieve high adherence and follow-up. They must also achieve enough clinical endpoints to distinguish reliably between the null hypothesis of no effect and the most plausible alternative hypotheses of small benefit or harm.

Cardiovascular safety of drugs not intended for cardiovascular use: need for a new conceptual basis for assessment and approval.

Recently, several drugs for non-cardiovascular diseases have ceased marketing because of cardiovascular risk, highlighting the importance of evaluating the cardiovascular safety of new drugs even if not intended for cardiovascular diseases. Assessing and ensuring acceptable cardiovascular safety of non-cardiovascular drugs is difficult; nonetheless, governmental regulatory agencies are likely to change the requirements for drug safety information. This article explores our recommendations for rethinking current regulatory policies, emphasizing the need for mandatory post-marketing surveillance registries and highlighting the exposures necessary to subserve the need for greater assessment of safety issues.