2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials.

This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the US Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibition in Kidney Transplant Recipients with Diabetes Mellitus.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibition has been shown to reduce cardiovascular mortality and preserve kidney function in patients with type 2 diabetes. Kidney transplant recipients with diabetes demonstrate increased risk and accelerated progression of micro- and macrovascular complications and may specifically benefit from SGLT2 inhibition. However, potential concerns of SGLT2 inhibition include volume depletion and urinary tract infections. OBJECTIVES: We report data on the use of SGLT2 inhibitors in a case series of ten patients with diabetes after kidney transplantation in order to analyze efficacy, safety, and the effect on renal function. METHODS: Patients with a stable allograft function and no history of recurrent urinary tract infections were eligible. The SGLT2 inhibitor empagliflozin was given as add-on to preexisting antidiabetic treatment with initial dose reduction of the latter. RESULTS: Median estimated glomerular filtration rate at baseline was 57 mL/min/1.73 m2 and remained stable throughout the follow-up of 12.0 (5.3-12.0) months. Median HbA1c decreased from 7.3 to 7.1%. The rate of urinary tract infections and other side effects was low. CONCLUSIONS: SGLT2 inhibition is feasible and well tolerated in selected kidney transplant recipients with diabetes. Whether SGLT2 inhibition is able to reduce cardiovascular mortality and improve allograft survival in these patients has to be addressed in further studies.

Niacin as antidyslipidemic drug.

Niacin is an important vitamin (B3) that can be used in gram doses to positively modify pathogenetically relevant lipid disorders: elevated LDL cholesterol, elevated non-HDL cholesterol, elevated triglycerides, elevated lipoprotein(a), and reduced HDL cholesterol. This review reports the latest published findings with respect to niacin's mechanisms of action on these lipids and its anti-inflammatory and anti-atherosclerotic effects. In the pre-statin era, niacin was shown to have beneficial effects on cardiovascular end-points; but in recent years, two major studies performed in patients whose LDL cholesterol levels had been optimized by a statin therapy did not demonstrate an additional significant effect on these end-points in the groups where niacin was administered. Both studies have several drawbacks that suggest that they are not representative for other patients. Thus, niacin still plays a role either as an additive to a statin or as a substitute for a statin in statin-intolerant patients. Moreover, patients with elevated triglyceride and low HDL cholesterol levels and patients with elevated lipoprotein(a) concentrations will possibly benefit from niacin, although currently the study evidence for these indications is rather poor. Niacin may be useful for compliant patients, however possible side effects (flushing, liver damage) and contraindications should be taken into consideration.

Effect of Levothyroxine Supplementation on the Cardiac Morphology and Function in Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-analysis.

CONTEXT: The impact of abnormal thyroid hormone levels on the cardiovascular system has been explored for decades. Recent emerging evidence suggests that subclinical thyroid dysfunction, especially subclinical hypothyroidism (SCH), significantly affects cardiac indices. OBJECTIVE: We aimed to determine whether levothyroxine (LT4), commonly used to treat hypothyroidism, affects cardiovascular indices in SCH patients. METHODS: This is a systematic review and meta-analysis. We searched online databases for studies analyzing cardiac morphology and functional changes in SCH patients before and after LT4 supplementation. A total of 294 SCH patients participated and finished the follow-up. The standard mean difference and 95% CI were calculated in fixed or random-effects models. The clinical outcomes analyzed in this study included 18 indicators, mainly covering cardiac morphology, myocardial performance (including various indicators of systolic and diastolic function), mitral wave flow, and systemic vascular resistance. RESULTS: A total of 11 studies met our search criteria. All studies explicitly mentioned that serum thyrotropin levels decreased to normal at follow-up. Our results suggest that the cardiac output (CO), left ventricular ejection fraction (LVEF), and the ratio of peak E velocity/peak A velocity were all significantly increased after LT4 supplementation compared with the baseline level. However, we found no clear evidence of significant morphological changes in the heart. CONCLUSION: Judging from the obvious changes in the CO, LVEF, and E/A ratio, LT4 supplementation can effectively improve the cardiac systolic and diastolic dysfunction prevalent in SCH patients. This study provides evidence of the recommendation for LT4 supplementation in adult SCH patients.

Body Mass Index Influence on the Clinical Outcomes for Nonvalvular Atrial Fibrillation Patients Admitted to a Hospital Treated with Direct Oral Anticoagulants: A Retrospective Cohort Study.

BACKGROUND: Considering that the current fixed dose of direct oral anticoagulants (DOACs) might have insufficient anticoagulation effect for overweight patients, the aim of this study was to compare the effectiveness and safety of anticoagulation between dabigatran and rivaroxaban in different body mass index (BMI) population. METHODS: We conducted a retrospective cohort study of 2402 DOAC anticoagulated patients with atrial fibrillation who underwent catheter ablation (1290 dabigatran, 53.7% and 1112 rivaroxaban, 46.3%) between January 2017 and December 2018. Patients were distributed based on the BMI into nonobese (1362, BMI <25 kg/m2), preobese (521, BMI 25.0-29.9 kg/m2), class I obese (344, BMI 30.0-34.9 kg/m2) and class II+ obese (175, BMI ≥35.0 kg/m2). We collected information regarding clinical features, laboratory data, bleeding complications and systemic embolic events from the electrical medical records system during 12 months. RESULTS: The incidence of systemic embolism and stroke complications was higher in the class II+ obese group (P=0.001 and P=0.003). The incidence of bleeding complications and the levels of anticoagulation parameters under the bleeding threshold were similar among the four groups (P>0.05). Cumulative Kaplan-Meier analysis illustrated that rivaroxaban-treated patients who belonged to higher BMI subgroups were more likely to experience shorter time to thrombosis (TTT) (12-month TTT rates of 0.5% for nonobese vs 1.7% for class I obese patients, HR=3.716, P=0.005; 12-month TTT rates of 0.5%, for nonobese vs 4.0% for class II+ obese patients, HR=6.843, P=0.001). However, no statistical significant difference in terms of the time to bleeding complications and the time to cumulative events among the four groups was observed. By multivariate analysis, a higher BMI value (BMI ≥25 kg/m2) (P=0.019; OR=2.094, 95%CI: 1.129-3.883) was an independent predictor for thrombosis in patients treated with dabigatran or rivaroxaban. Positive linear relationship was observed between BMI levels and occurrence rate of thrombosis and bleeding in under anticoagulation patients with NVAF (R2=0.451 and R2=0.383, respectively). CONCLUSION: The fixed dose of 15 mg rivaroxaban might carry a risk of under exposure, which would lead to an increase of thromboembolic complications in patients with high BMI. Therefore, rivaroxaban dose increase was suggested for obese patients. Use of DOACs appears to have considerable safety in obese patients.

Postponement of cardiovascular outcomes by statin use: A systematic review and meta-analysis of randomized clinical trials.

OBJECTIVE: To estimate the average outcome postponement (gain in days to an event) for cardiovascular outcomes in a meta-analysis of randomized, controlled statin trials, including any myocardial infarction, any stroke and cardiovascular death. DESIGN: Systematic review of large randomized, placebo-controlled trials of statin use, including a random-effects meta-analysis of all included trials. DATA SOURCES: We searched MEDLINE (15 July 2019) and ClinicalTrials.gov (16 October 2019). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomized, placebo-controlled trials of statin use that included at least 1000 participants. We identified 15 cardiovascular outcomes that were reported in more than 2 trials. RESULTS: We included 19 trials. The summary outcome postponements for the 15 cardiovascular outcomes varied between -1 and 38 days. For four major outcomes, the summary outcome postponement in days was as follows: cardiovascular mortality, 9.27 days (95% CI: 3.6 to 14.91; I2  = 72%; 9 trials) non-vascular and non-cardiovascular mortality, 1.5 days (95% CI: -2.2 to 5.3; I2  = 0%; 6 trials) any myocardial infarction 18.0 days (95% CI; 12.1 to 24.1; I2  = 92%; 15 trials); and any stroke, 6.1 days (95% CI; 2.86 to 9.39; I2  = 66%; 14 trials). CONCLUSION: Statin treatment provided a small, average postponement of cardiovascular outcomes during trial duration.

2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials.

This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the U.S. Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.

PCSK9 antibodies: A new class of lipid-lowering drugs.

The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein (LDL) receptor (LDLR) and directs it to the lysosome for degradation. This results in decreased numbers of LDLR available on the cell surface to bind LDL particles and remove them from the circulation and a subsequent increase in circulating LDL-cholesterol (LDL-C) concentrations. Since the role PCSK9 plays in LDL-C metabolism has been discovered in 2003, there have been major efforts in finding efficient and safe methods to inhibit it. Amongst those, the PCSK9 antibodies are the furthest in development, with multiple phase III and cardiovascular endpoint trials already underway. These fully human monoclonal antibodies have been extensively studied in a wide range of subjects such as in those with statin intolerance, as add-on to statin therapy, as monotherapy and in patients with familial hypercholesterolemia. PCSK9 antibodies have shown to be associated with a consistent robust additional decrease in LDL-C concentrations of around 50-70%. If the safety data from the ongoing phase III trials remain as reassuring as the data available till now, PCSK9 antibodies are going to offer a new, powerful therapeutic option to decrease LDL-C concentrations and hopefully cardiovascular risk.

Adverse effects and safety of SGLT-2 inhibitors.

In type 2 diabetes (T2DM), glycaemic control delays the development and slows the progression of complications. Although there are numerous glucose-lowering agents in clinical use, only approximately half of T2DM patients achieve glycaemic control, while undesirable side-effects, such as hypoglycaemia and body weight gain, often impede treatment in those taking these medications. Thus, there is a need for novel agents and treatment options. Sodium-glucose cotransporter-2 inhibitors (SGLT-2-i) have recently been developed for the treatment of T2DM. The available data suggest a good tolerability profile for the three available drugs - canagliflozin, dapagliflozin and empagliflozin - approved by the US Food and Drug Administration (FDA) for the American market as well as in other countries. The most frequently reported adverse events with SGLT-2-i are female genital mycotic infections, urinary tract infections and increased urination. The pharmacodynamic response to SGLT-2-i declines with increasing severity of renal impairment, requiring dosage adjustments or restrictions with moderate-to-severe renal dysfunction. Most patients treated with SGLT-2-i also have a modest reduction in blood pressure and modest effects on serum lipid profiles, some of which are beneficial (increased high-density lipoprotein cholesterol and decreased triglycerides) and others which are not (increased low-density lipoprotein cholesterol, LDL-C). A number of large-scale and longer-term cardiovascular trials are now ongoing. In patients treated with dapagliflozin, a non-significant excess number of breast and bladder cancers has been reported; considered as due to a bias, this is nevertheless being followed in the ongoing trials. No other significant safety issues have been reported so far. Although there is some benefit for several cardiovascular risk factors such as HbA1c, high blood pressure, obesity and increases in LDL-C, adequately powered trials are still required to determine the effects of SGLT-2-i on macrovascular outcomes.

The sleep apnea cardiovascular endpoints (SAVE) trial: Rationale and start-up phase.

THE SLEEP APNEA CARDIOVASCULAR ENDPOINTS (SAVE) STUDY (CLINICAL TRIALS REGISTRATION NUMBER: NCT00738170) is an academic initiated and conducted, multinational, open, blinded endpoint, randomised controlled trial designed to determine whether treatment of obstructive sleep apnea (OSA) with continuous positive airways pressure (CPAP) can reduce the incidence of serious cardiovascular events in patients with established cardiovascular disease. The answer to this question is of major importance to populations undergoing ageing and lifestyle changes all over the world. The SAVE study brings together respiratory, sleep and cardiovascular clinician-scientists in a unique interdisciplinary collaborative effort with industry sponsors to conduct the largest and most ambitious clinical trial yet conducted in the field of sleep apnea, with a global recruitment target of 5000 patients. Following its launch in Australia and China in late 2008, SAVE has now entered a phase of international expansion with new recruitment networks being established in New Zealand, India and Latin America. This article describes the rationale for the SAVE study, the considerations behind its design, and progress thus far in establishing the recruitment network. The report emphasises the important role that Chinese sleep and cardiovascular investigators have played in the start-up phase of this landmark international project.