Cardiology

Schiattarella, G. G., A. Sannino, G. Esposito and C. Perrino (2018). “Diagnostics and therapeutic implications of gut microbiota alterations in cardiometabolic diseases.” Trends Cardiovasc Med Aug 7. [Epub ahead of print].

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Alterations in gut microbiota composition and its metabolic activity are emerging as one of the most powerful determinants of cardiovascular disease. Although our knowledge of the precise molecular mechanisms by which gut microbiota influences cardiometabolic homeostasis is still limited, a growing body of knowledge has recently been uncovered about the potential modulation of microbiome for cardiovascular diagnostic and therapeutic aspects. The multitude of interactions between the microorganisms inhabiting the digestive tract and the host has been recognized crucial in the development and progression of atherosclerosis, obesity, diabetes and hypertension. Here, we summarize the role of gut microbiota in host physiology as well as in the pathophysiology of the most common cardio-metabolic disorders, discussing the potential therapeutic opportunities offered by interventions aimed at modifying microbiome composition and activity.

Packer, M. (2018). “Risk of heart failure in diabetic patients receiving sulfonylureas: reply.” Eur J Heart Fail 20(9): 1372.

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I sincerely appreciate the comments of Vaccaro et al. regarding their experience in the TOSCA.IT trial. It seems clear that theTOSCA.IT investigators took specifc steps to enroll a population of patients with type 2diabetes, who were at low risk of developingheart failure during follow-up. As a result, very few heart failure events were recorded in the trial, and consequently, the trial did not have adequate statistical power to determine if the risks of heart failure were truly similar inpatients taking sulfonylureas and pioglitazone. In order to validly conclude that the two classes of drugs were associated with similar risks of heart failure, the TOSCA.IT trial would have had to record 10timesasmanyheart failure events. Given the low risk of the population that was studied, achievement of this target number of events would have required the enrolment of substantially more patients and a far longer period of follow-up. Since this w as not practical, the results ofTOSCA.IT cannot provide reliable information concerning comparative risks of heart failure related to the use of sulfonylureas and pioglitazone. Even if additional data were to show that the increased risks of heart failure with sulfonylureas and pioglitazone were similar, it is important to worry about whether any increase in risk is acceptable, especially since certain antidiabetic medications (i.e. met-formin and sodium–glucose co-transporter 2inhibitors) appear to reduce the risk of heartfailure. Preventing heart failure and other macrovascular complications of diabetes is acritical goal of treatment. For most middle-aged to elderly patients with type 2 diabetes, the heightened risk of macrovascular events is much greater and occurs much earlier than the risk of microvascular events. Further-more, since risk reduction of macrovascular events is not clearly related to glycaemic control, the appropriate choice of an antidiabetic medication must be determined not only by its effects to lower glycated haemoglobin but by its independent actions to reduce the risk of cardiovascular death, myocardial infarction and heart failure. (Reply to Vaccaro’s comment on Packer, Are physicians neglecting the risk of heart failure in diabetic patients who are receiving sulfony-lureas? Lessons from the TOSCA.IT trial. Eur J Heart Fail 2018;20: 49–51.)

Packer, M. (2018). “Questioning the obvious: does dyspnoea really matter in heart failure?” Eur Heart J 39(30): 2822-2824

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Many patients with heart failure continue to exercise despite the experience of dyspnoea, until they feel that their legs can no longer carry them. So do patients with chronic heart failure stop exercising with dyspnoea or because of dyspnoea? If we were able to suppress the sensation of dyspnoea, would patients with heart failure be able to exercise longer? Many investigators who have closely evaluated patients with chronic heart failure believe this is unlikely. Our inability to answer these simple questions highlights how little we know about the factors that influence the capacity of patients with heart failure to perform and enjoy activities of daily living. We have spent several decades prolonging the lives of patients with heart failure, but we have spent little time studying the symptoms that bring them to medical attention in the first place. Since heart failure has become not only the major cause of cardiac death but also the major cause of cardiac disability, this is a conundrum that we can no longer ignore. (Excerpt from text, p. 2224; no abstract available.)

Packer, M. (2018). “The CABANA Trial: an honourable view.” Eur Heart J 39(30): 2770.

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The CABANA trial randomized 2204 patients with atrial fibrillation to catheter ablation (n = 1108) or drug therapy to achieve rate or rhythm control (n = 1096). Both groups were anticoagulated, and most patients in the non-ablation group received membrane-active antiarrhythmic drugs. Only 10% had atrial fibrillation for >1 year; 15% had a history of heart failure. The original primary endpoint was all-cause mortality, which was amended to a combined endpoint of death, disabling stroke, serious bleeding, or cardiac arrest. The original trial design anticipated that 25–30% of the patients assigned to drug therapy would receive ablation later in the trial. The investigators pre-specified that success of the trial would be determined by intention-to-treat analysis on the amended primary endpoint. This was an open-label trial; event adjudication was not blinded to the patients’ rhythm. Patients were followed for ≈5 years. According to the reported results, the ablation and non-ablation groups did not differ with respect to the risk of the original primary endpoint (P = 0.377) or the amended primary endpoint (P = 0.303). Ablation did not reduce the risk of any component of the primary endpoint. There was a nominally significant reduction in the combined risk of death or cardiovascular hospitalization, which was likely related to a decrease in admissions for atrial fibrillation in the ablation group. No particular benefit was seen in patients with heart failure. Unfortunately, the investigators showed ‘per-protocol’ and ‘as-treated’ analyses, which converted the randomized trial into an observational study . . . The CABANA trial is an important study that yielded a clear result, i.e. ablation does not prevent the serious consequences of atrial fibrillation. There is little justification to perform confounded observational analyses or rely on derivative subgroup effects. If this were a trial of a new pharmaceutical agent, these questionable analyses would be uniformly rejected as ‘wishful thinking’ and would not influence guidelines. Since ablation procedures are expensive, carry risks and are available to very few, evaluation of their efficacy should not be held to a lower standard of evidence. These thoughts on the CABANA trial are preliminary. We await publication of the full manuscript and a description of the analytical methods to fully understand how the investigators viewed their data. (Excerpt from text, p. 2770; no abstract available.)

Carpenter, J. P., J. S. Lane, 3rd, J. Trani, S. Hussain, C. Healey, C. J. Buckley, H. Hashemi and R. Cuff (2018). “Refinement of anatomic indications for the Nellix System for endovascular aneurysm sealing based on 2-year outcomes from the EVAS FORWARD IDE trial.” J Vasc Surg 68(3): 720-730.e721.

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BACKGROUND: The Nellix System (Endologix, Inc, Irvine, Calif) for endovascular aneurysm sealing (EVAS) is a novel approach to abdominal aortic aneurysm treatment and conceptually different from endovascular aneurysm repair, whereby polymer is employed to fill and actively manage the abdominal aortic aneurysm sac. One-year safety and effectiveness results of the Nellix pivotal trial demonstrated encouraging outcomes with very low morbidity and mortality and high procedural and treatment success. Two-year imaging revealed a signal of migration, leading to a field safety notification issued by the manufacturer on October 21, 2016, and a dedicated root cause analysis, resulting in refinements to the instructions for use (IFU). We report the 2-year results of the investigational device exemption pivotal trial stratified according to the new and original criteria for selection of patients. METHODS: Comprehensive engineering evaluations, statistical analyses, and clinical assessments were conducted looking at patients enrolled in the pivotal trial (N = 150), roll-in cohort (N = 29), and continued access program (N = 154). All patients in all cohorts were treated on-IFU at the time of enrollment. Logistic regression models supported the mechanism that migration with Nellix is associated with a small aortic flow lumen relative to a large aneurysm thrombus burden and large aortic neck diameters. Based on these findings, refinements to the IFU criteria were applied, excluding patients with a thrombus index (maximum aneurysm sac/maximum flow lumen diameter) >1.4, aortic neck diameter >28 mm, and aortic neck conicity (>10% diameter change along the infrarenal neck) and requiring a 10-mm distal seal zone in the iliac artery. RESULTS: Freedom from all-cause mortality at 2 years was 94%. Patient outcomes were then stratified on the refined morphologic criteria and analyzed retrospectively. Two-year freedom from composite endoleak was high among both cohorts (95% on-IFU vs 92% off-IFU). Freedom from migration was 97.7% on-IFU vs 93.2% off-IFU (P = .0125). Freedom from aneurysm enlargement was 98.1% on-IFU vs 93.5% off-IFU (P value is not available because of failure of log-rank test assumptions). Composite freedom from migration, type IA endoleak, or aneurysm expansion was 95.9% among the on-IFU cohort vs 85.1% in the off-IFU cohort (P = .0017). CONCLUSIONS: Consistent with the introduction of a novel therapy, the presentation of failure modes of EVAS over time was inevitable. Using detailed imaging as well as engineering and statistical analysis, we were able to understand risk factors for adverse events specific to EVAS and defined those patients best suited for Nellix. With this EVAS-specific approach to defining IFU, on-IFU patients were identified as those with large aneurysms with little thrombus that would be prone to type II endoleaks and sac expansion with traditional devices. When treated with Nellix, these patients were predicted to experience exceptional results, especially with regard to a low composite endoleak rate and low all-cause mortality.