Research Spotlight

McCullough, P. A., C. M. Ballantyne, S. K. Sanganalmath, G. Langslet, S. J. Baum, P. K. Shah, A. Koren, J. Mandel and M. H. Davidson (2018). “Efficacy and Safety of Alirocumab in High-Risk Patients With Clinical Atherosclerotic Cardiovascular Disease and/or Heterozygous Familial Hypercholesterolemia (from 5 Placebo-Controlled ODYSSEY Trials).” Am J Cardiol 121(8): 940-948.

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Patients with previous atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) are at high risk of future cardiovascular events. Despite maximally tolerated doses of statins, many patients still have elevated low-density lipoprotein cholesterol (LDL-C) levels. We evaluated the efficacy and safety of alirocumab in patients with ASCVD and/or HeFH on a maximally tolerated dose of statin (rosuvastatin 20 or 40 mg, atorvastatin 40 or 80 mg, or simvastatin 80 mg, or lower doses with an investigator-approved reason) +/- other lipid-lowering therapies from 5 placebo-controlled phase 3 trials (52 to 78 weeks). Patients with (n = 2,449) and without (n = 1,050) ASCVD were pooled from the FH I, FH II, HIGH FH, LONG TERM, and COMBO I trials. Patients with HeFH with (n = 575) and without ASCVD (n = 682) were pooled from all trials except COMBO I. High-intensity statins were utilized in 55.7% to 59.0% and in 72.4% to 87.6% of the ASCVD and the HeFH groups, respectively. Efficacy end points included LDL-C percent change from baseline to week 24 stratified by alirocumab dose. Mean baseline demographics and lipid levels were comparable in alirocumab- and placebo-treated patients. LDL-C reductions from baseline at week 24 ranged from 46.6% to 51.3% for alirocumab 75/150 mg and from 54.1% to 61.9% for alirocumab 150 mg in ASCVD and HeFH groups and were sustained for up to 78 weeks. LDL-C reductions with alirocumab were independent of ASCVD and/or HeFH status (interaction p value >0.05). Concordant results were observed for other lipids analyzed. The overall safety in the subgroups analyzed was similar in both treatment arms. Injection-site reactions were observed more frequently with alirocumab versus placebo.

Majtan, T., E. M. Bublil, I. Park, E. Arning, T. Bottiglieri, F. Glavin and J. P. Kraus (2018). “Pharmacokinetics and pharmacodynamics of PEGylated truncated human cystathionine beta-synthase for treatment of homocystinuria.” Life Sci 200: 15-25. May 1.

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AIMS: PEGylated human truncated cystathionine beta-synthase, lacking the C-terminal regulatory domain (PEG-CBS), is a promising preclinical candidate for enzyme replacement therapy in homocystinuria (HCU). It was designed to function as a metabolic sink to decrease the severely elevated plasma and tissue homocysteine concentrations. In this communication, we evaluated pharmacokinetics (PK), pharmacodynamics (PD) and sub-chronic toxicity of PEG-CBS in homocystinuric mice, wild type rats and monkeys to estimate the minimum human efficacious dose for clinical trials. MAIN METHODS: Animal models received single or multiple doses of PEG-CBS. Activity of PEG-CBS and sulfur amino acid metabolites were determined in plasma and used to determine PK and PD. KEY FINDINGS: The plasma half-lives of PEG-CBS after a single subcutaneous (SC) injection were approximately 20, 44 and 73h in mouse, rat and monkey, respectively. The SC administration of PEG-CBS resulted in a significant improvement or full correction of metabolic imbalance in both blood and tissues of homocystinuric mice. The PD of PEG-CBS in mouse was dose-dependent, but less than dose-proportional, with the maximal efficacy achieved at 8mg/kg. PEG-CBS was well-tolerated in mice and monkeys, but resulted in dose-dependent minimal-to-moderate inflammation at the injection sites and vacuolated macrophages in rats. Allometric scaling of animal data was linear and the estimated human efficacious dose was determined as 0.66mg/kg administered once a week. SIGNIFICANCE: These results provide critical preclinical data for the design of first-in-human PEG-CBS clinical trial.

Mack, M. and M. Hamandi (2018). “Is it time for national systems of care for valvular heart disease?” EuroIntervention 13(18): e2109-e2111.

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There are new proposals posited in both Europe and the USA to create “systems of care” for diagnosing, managing and treating valve disease patients. The operating principle of both is to provide the right treatment, to the right patient, at the right time, while taking into account the patient’s wishes. Although this system of care concept is a relatively recent one for the management of patients with valvular heart disease, it is not a new concept in healthcare for the treatment of other diseases. Numerous examples exist in the USA that serve as precedent for a valve disease system of care. Starting in 1960, the National Cancer Institute in the USA created a highly successful nationwide three-tiered system for cancer care2. The American College of Surgeons in 1976 built a universally adopted four-tiered system of trauma centres. Likewise, national systems of care have been built for acute stroke management (Brain Attach Coalition), treatment of acute myocardial infarction (ACC/AHA door-to-balloon time programme) and bariatric surgery centres for patients with obesity. Building on the experience and lessons learned from the national programmes for management of these conditions, national systems of care for patients with valvular heart disease are being proposed in both Europe and the USA. A pilot programme for TAVI exists that gives some insight into how a system of care could work. In the Canadian province of British Columbia, a province-wide programmatic approach has been undertaken. There are four programmes performing TAVI in the province. They are linked together in a network in which three “primary valve centres” perform transfemoral TAVI while more complex patients with extensive comorbidities and/or needing alternative access approaches or valve-in-valve procedures are referred to a single advanced tertiary valve centre in Vancouver. Open lines of communication, readily available consultation and mentoring are maintained within the network. With TAVI, in which there is evidence for a “volume-outcome” relationship, they seem to have struck the right balance between maintaining optimal care while providing broad geographic patient access. So, can this concept of a valve network system of care be scaled to a national level? (Excerpt from text, p. e2110; no abstract available.)

Lu, C. Y., R. B. Penfold, S. Toh, J. L. Sturtevant, J. M. Madden, G. Simon, B. K. Ahmedani, G. Clarke, K. J. Coleman, L. A. Copeland, Y. G. Daida, R. L. Davis, E. M. Hunkeler, A. Owen-Smith, M. A. Raebel, R. Rossom, S. B. Soumerai and M. Kulldorff (2018). “Near Real-time Surveillance for Consequences of Health Policies Using Sequential Analysis.” Med Care 56(5): 365-372.

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BACKGROUND: New health policies may have intended and unintended consequences. Active surveillance of population-level data may provide initial signals of policy effects for further rigorous evaluation soon after policy implementation. OBJECTIVE: This study evaluated the utility of sequential analysis for prospectively assessing signals of health policy impacts. As a policy example, we studied the consequences of the widely publicized Food and Drug Administration’s warnings cautioning that antidepressant use could increase suicidal risk in youth. METHOD: This was a retrospective, longitudinal study, modeling prospective surveillance, using the maximized sequential probability ratio test. We used historical data (2000-2010) from 11 health systems in the US Mental Health Research Network. The study cohort included adolescents (ages 10-17 y) and young adults (ages 18-29 y), who were targeted by the warnings, and adults (ages 30-64 y) as a comparison group. Outcome measures were observed and expected events of 2 possible unintended policy outcomes: psychotropic drug poisonings (as a proxy for suicide attempts) and completed suicides. RESULTS: We detected statistically significant (P<0.05) signals of excess risk for suicidal behavior in adolescents and young adults within 5-7 quarters of the warnings. The excess risk in psychotropic drug poisonings was consistent with results from a previous, more rigorous interrupted time series analysis but use of the maximized sequential probability ratio test method allows timely detection. While we also detected signals of increased risk of completed suicide in these younger age groups, on its own it should not be taken as conclusive evidence that the policy caused the signal. A statistical signal indicates the need for further scrutiny using rigorous quasi-experimental studies to investigate the possibility of a cause-and-effect relationship. CONCLUSIONS: This was a proof-of-concept study. Prospective, periodic evaluation of administrative health care data using sequential analysis can provide timely population-based signals of effects of health policies. This method may be useful to use as new policies are introduced.

Lima, B., O. Dur, J. Chuang, T. Chamogeorgakis, D. J. Farrar, K. S. Sundareswaran, J. Felius, S. M. Joseph, S. A. Hall and G. V. Gonzalez-Stawinski (2018). “Novel Cardiac Coordinate Modeling System for Three-Dimensional Quantification of Inflow Cannula Malposition of HeartMate II LVADs.” Asaio j 64(2): 154-158.

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Optimal function of left ventricular assist devices (LVADs) depends on proper alignment of the inflow cannula (IC). Quantitative guidelines for IC angulation are lacking because of variation in cardiac geometry and difficulty in analyzing three-dimensional (3D) cannula orientation relative to the left ventricle (LV). Based on contrast-enhanced computed tomography images from five normal and five clinically malpositioned IC cases in patients with HeartMate II LVADs, we developed a method for 3D quantification of IC malpositioning. Using Mimics image software (Materialise, Leuven, Belgium), the native heart, major arteries, and LVAD were segmented to create patient-specific 3D models, allowing LV cavity volume and long-axis length to be measured directly. The deviation of the IC was quantified in a cylindrical coordinate system at the IC insertion point relative to the mitral valve and septum, and IC occlusion was assessed by the distance between cannula inlet and the proximal endocardium. Compared with normal cases, patients with malpositioned pumps had shorter LV length (p = 0.03) and reduced pump pocket depth (p = 0.009). Malpositioned pumps may experience greater obstruction by the nearby myocardium. This quantitative 3D modeling tool may help identify different modes of pump malalignment and migration and may facilitate preoperative planning and minimally invasive approaches via virtual LVAD implantation.E