Additional Cardiovascular Risk Research Articles

A review of dipeptidyl peptidase-4 inhibitors. Hot topics from randomized controlled trials.

The first clinical study to investigate effects of dipeptidyl peptidase-4 (DPP-4) inhibition was published in 2002, and since then, numerous randomized controlled trials (RCTs) have shown that DPP-4 inhibitors are efficacious, safe and well-tolerated. This review will focus upon RCTs which have investigated DPP-4 inhibitors in patient groups which are often under-represented or excluded from typical phase 3 clinical trials. Large cardiovascular (CV) safety outcome trials in patients with established CV disease have confirmed that DPP-4 inhibitors are not associated with any additional CV risk in these already-at-high-risk individuals, while raising awareness of any uncommon adverse events, such as heart failure hospitalization seen in one of the trials. Studies in patients with kidney disease have shown DPP-4 inhibitors to be efficacious without increasing the risk of hypoglycaemia, irrespective of the degree of renal impairment, while data from the large CV trials as well as smaller RCTs have even pointed towards potential renoprotective effects such individuals. The use of DPP-4 inhibitors with insulin when therapy requires intensification may be beneficial without affecting the incidence or severity of hypoglycaemia, with these effects also being replicated in patients with chronic kidney disease, for whom other agents may not be suitable. Attention is now turning towards exploring the potential utility of DPP-4 inhibitors in other circumstances, including for in-hospital management of hyperglycaemia and in other metabolic disorders. Together, these RCTs raise the possibility that in the future, DPP-4 inhibitors may have a broader use which may extend beyond glycaemic control in the typical type 2 diabetes mellitus (T2DM) patient seen in general practice and may encompass conditions other than T2DM.

Lifestyle factors and subsequent ischemic heart disease risk after hematopoietic cell transplantation.

The objective of this study was to evaluate whether modifiable cardiovascular risk conditions and lifestyle factors were temporally associated with an increased risk for ischemic heart disease and overall mortality in a cohort of hematopoietic cell transplantation (HCT) survivors. HCT recipients who had survived for ≥1 year, were ≥20 years old, and had undergone transplantation between 1970 and 2010 at a transplant referral center were surveyed in 2010-2011 about cardiovascular health and lifestyle factors (n = 3833). Respondents (n = 2360 [61.6%]) were followed to 2016 for incident ischemic heart disease and overall mortality. Among the 2360 transplant survivors (median age at the baseline survey, 55.9 years; median time since transplantation, 10.8 years), 162 (6.9%) reported ischemic heart disease at the baseline survey. Among those without ischemic heart disease at the baseline survey (n = 2198), the 5-year cumulative incidence of subsequent ischemic heart disease was 4.3%. Obesity, dyslipidemia, diabetes, and physical inactivity at baseline were associated with an increased risk for subsequent ischemic heart disease (hazard ratio [HRs] ≥ 1.8). Greater physical activity and fruit/vegetable intake at baseline were associated with subsequent lower overall mortality (HRs ≤ 0.7). When jointly considered, each additional cardiovascular risk condition and each adverse lifestyle factor were independently associated with subsequent ischemic heart disease (HR for risk conditions, 1.4; 95% confidence interval [CI], 1.0-1.9; HR for lifestyle factors, 1.9; 95% CI, 1.2-2.9), and adverse lifestyle factors remained associated with overall mortality (HR, 1.8; 95% CI, 1.5-2.3). These results support strong efforts to promote healthy lifestyle behaviors and to treat cardiovascular risk factors aggressively in HCT survivors. This may reduce future ischemic heart disease and overall mortality in this high-risk population. Cancer 2018;124:1507-15. © 2018 American Cancer Society.

Cardiovascular Profile of Valbenazine: Analysis of Pooled Data from Three Randomized, Double-Blind, Placebo-Controlled Trials.

IntroductionValbenazine is a novel vesicular monoamine transporter 2 inhibitor approved for the treatment of tardive dyskinesia in adults.ObjectiveUsing data from double-blind, placebo-controlled trials, analyses were conducted to evaluate the cardiovascular effects of once-daily valbenazine in patients with a psychiatric disorder who developed tardive dyskinesia after exposure to a dopamine-blocking medication.MethodsData were pooled from three 6-week, double-blind, placebo-controlled trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), and KINECT 3 (NCT02274558). Data from the 42-week valbenazine extension period of KINECT 3 were also analyzed. Outcomes of interest included cardiovascular-related treatment-emergent adverse events, vital sign measurements, and electrocardiogram parameters.ResultsThe pooled safety population included 400 participants (placebo, n = 178; valbenazine 40 mg/day, n = 110; valbenazine 80 mg/day, n = 112). A history of cardiac disorders was present in 11.8% of participants, and 74.3% were taking a concomitant medication with known potential for QT prolongation. Mean changes from baseline to week 6 in supine vital signs and QTcF (Fridericia correction) were as follows for placebo, valbenazine 40 mg/day, and valbenazine 80 mg/day, respectively: systolic blood pressure (0.2, − 2.1, − 1.8 mmHg), diastolic blood pressure (− 0.1, − 1.6, − 1.2 mmHg), heart rate (− 1.7, − 2.2, − 1.7 bpm), QTcF interval (1.2, 1.1, 2.1 ms); all p > 0.05 for valbenazine vs. placebo. No statistically significant differences were observed between placebo and valbenazine in cardiovascular-related, treatment-emergent adverse events. No notable additional effects on cardiovascular outcomes were found with up to 48 weeks of valbenazine treatment.ConclusionsResults from double-blind, placebo-controlled trials showed no apparent difference between valbenazine and placebo on cardiovascular outcomes. No additional cardiovascular risk was detected during a longer extension study with valbenazine.

Managing diabetic kidney disease.

Diabetes mellitus (DM) is the leading cause of chronic kidney disease (CKD). This review covers the pillars of care essential for the management of diabetic kidney disease (DKD) including (1) early diagnosis, (2) improved glycaemic control, (3) treatment of hypertension, (4) identification and treatment of associated metabolic bone disease and (5) identification and effective management of dyslipidaemia and additional cardiovascular risk factors. We searched PubMed for articles using search terms: diabetic nephropathy, diabetic kidney disease, diabetes and chronic kidney disease. We used clinical guidelines from NICE, the Association of British Clinical Diabetologists (ABCD), the Joint British Societies (JBS) and the Kidney Disease: Improving Global Outcomes (KDIGO) working group. Multiple risk factor reduction targeting glycaemic control, blood pressure control, dyslipidaemia, smoking and management of obesity is important in preventing and in managing DKD. Guidelines disagree on the individualized glycaemic targets for patients with diabetic kidney disease. The growing number of patients with DKD is causing increased pressure on limited primary care and specialized services. New ways of managing patients using novel technology solutions are required. The use of novel anti-hyperglycaemic agents, particularly sodium glucose co-transporter 2 inhibitors and GLP-1 receptor agonists, has been associated with a reduction in cardiovascular disease and DKD.

Comparison of lipid levels in the diabetic and non diabetic patients: a study in a tertiary care hospital

Background: The incidence of coronary artery diseases is 3 to 5 times higher in both male and female diabetic patients compared to general population. Individuals with diabetes may have several forms of dyslipidemia leading to additive cardiovascular risk of hyperglycemia. This study was therefore conducted to identify the levels of lipidemia in the diabetic patients in our area.Methods: This study was conducted on 100 diabetic and 100 healthy patients, with 50 patients were males and 50 were females in both groups. Blood was collected in sodium fluoride tubes for all the patients for the estimation of glucose (both fasting and post prandial) and in serum tubes for lipids such as Triglycerides, Total cholesterol, High density cholesterol, Low density cholesterol and Very low density cholesterol.Results: The total cholesterol among the males who were diabetic was in the normal range in 46% and high in 20% of the patients. Among the control, i.e. non diabetic patients, 76% of them had total cholesterol in the normal range and high cholesterol levels were observed in only 8% of them. The levels of triglycerides, total cholesterol and LDL were significantly higher in the patients with diabetes, compared to the non diabetic patients. HDL in these patients was significantly low.Conclusions: The incidence of raised lipid levels in the diabetic patients is very high and since the elevated levels of lipids especially in these patients can lead to CHD and its complications, it is important for the monitoring of these levels throughout the course of the disease.

Effects of aliskiren on mortality, cardiovascular outcomes and adverse events in patients with diabetes and cardiovascular disease or risk: A systematic review and meta-analysis of 13,395 patients.

Background:Aliskiren was shown to increase adverse events in patients with diabetes and concomitant renin–angiotensin blockade. We aim to investigate the efficacy and safety of aliskiren in patients with diabetes and increased cardiovascular risk or established cardiovascular disease.Methods:MEDLINE and Embase were searched for prospective studies comparing addition of aliskiren to standard medical therapy in patients with diabetes and cardiovascular disease, or ⩾1 additional cardiovascular risk factor (hypertension, abnormal lipid profile, microalbuminuria/proteinuria, chronic kidney disease). Relative risk for efficacy (all-cause mortality, combined cardiovascular mortality and hospitalisation) and safety (hyperkalaemia, hypotension, renal impairment) outcomes was calculated.Results:Of 2151 studies identified in the search, seven studies enrolling 13,395 patients were included. Aliskiren had no effect on all-cause mortality (relative risk: 1.05, 95% confidence interval: 0.90 to 1.24, p = 0.53), or combined cardiovascular mortality or heart failure hospitalisation (relative risk: 1.07, 95% confidence interval: 0.81 to 1.40, p = 0.64). Patients receiving aliskiren had a greater risk of developing hyperkalaemia (relative risk: 1.32, 95% confidence interval: 1.14 to 1.53, p = 0.0003) and renal impairment (relative risk: 1.15, 95% confidence interval: 1.02 to 1.30, p = 0.03), but not hypotension.Conclusion:Patients with diabetes and cardiovascular disease or cardiovascular risk do not benefit from the addition of aliskiren to standard medical therapy. Detrimental safety profile in pooled analysis supports current warnings.

Rheumatologists Modestly More Likely to Counsel Smokers in Visits Without Rheumatoid Arthritis Control: An Observational Study.

Among patients with rheumatoid arthritis (RA), smoking increases risk of severe RA and pulmonary and cardiovascular disease. Despite this, little is known about smoking cessation counseling by rheumatologists. We examined predictors of tobacco counseling in RA patients who smoke including the effect of perceived RA control. We hypothesized that patients with controlled RA would receive more counseling according to the competing demands model, which explains that preventive care gaps occur as a result of competing provider, patient, and clinic factors. This secondary data analysis involved RA patients with an additional cardiovascular disease risk factor identified in an academic medical center 2004-2011. Trained abstractors assessed documented smoking counseling and rheumatologists' impression of RA control in clinic notes. We used multivariable logistic regression to predict having received smoking cessation counseling, including sociodemographics and comorbidity in models. We abstracted 3396 RA visits, including 360 visits (10%) with active smokers. Perceived controlled RA was present in 31% of visits involving smokers (39% in nonsmokers). Beyond nurse documentation, providers documented smoking status in 39% of visit notes with smokers and smoking cessation counseling in 10%. Visits with controlled versus active RA were less likely to include counseling (odds ratio, 0.3; confidence interval, 0.1-0.97). Counseling was more likely in visits with prevalent cardiovascular, pulmonary, and psychiatric disease, but decreased with obesity. Smoking cessation counseling was documented in 10% of visits and was less likely when RA was controlled. Given smoking's impact on RA and long-term outcomes, systematic cessation counseling efforts are needed.

Offspring sex and parental health and mortality

Increased mortality has been observed in mothers and fathers with male offspring but little is known regarding specific diseases. In a register linkage we linked women born 1925–1954 having survived to age 50 (n = 661,031) to offspring and fathers (n = 691,124). Three approaches were used: 1) number of total boy and girl offspring, 2) sex of the first and second offspring and 3) proportion of boys to total number of offspring. A sub-cohort (n = 50,736 mothers, n = 44,794 fathers) from survey data was analysed for risk factors. Mothers had increased risk of total and cardiovascular mortality that was consistent across approaches: cardiovascular mortality of 1.07 (95% CI: 1.03–1.11) per boy (approach 2), 1.04 (1.01–1.07) if the first offspring was a boy, and 1.06 (1.01–1.10) if the first two offspring were boys (approach 3). We found that sex of offspring was not associated with total or cardiovascular mortality in fathers. For other diseases or risk factors no robust associations were seen in mothers or fathers. Increased cardiovascular risk in mothers having male offspring suggests a maternal disease specific mechanism. The lack of consistent associations on measured risk factors could suggest other biological pathways than those studied play a role in generating this additional cardiovascular risk.

Ambulatory blood pressure monitoring-derived short-term blood pressure variability in primary hyperparathyroidism.

Primary hyperparathyroidism is associated with a cluster of cardiovascular manifestations, including hypertension, leading to increased cardiovascular risk. The aim of our study was to investigate the ambulatory blood pressure monitoring-derived short-term blood pressure variability in patients with primary hyperparathyroidism, in comparison with patients with essential hypertension and normotensive controls. Twenty-five patients with primary hyperparathyroidism (7 normotensive,18 hypertensive) underwent ambulatory blood pressure monitoring at diagnosis, and fifteen out of them were re-evaluated after parathyroidectomy. Short-term-blood pressure variability was derived from ambulatory blood pressure monitoring and calculated as the following: 1) Standard Deviation of 24-h, day-time and night-time-BP; 2) the average of day-time and night-time-Standard Deviation, weighted for the duration of the day and night periods (24-h "weighted" Standard Deviation of BP); 3) average real variability, i.e., the average of the absolute differences between all consecutive BP measurements. Baseline data of normotensive and essential hypertension patients were matched for age, sex, BMI and 24-h ambulatory blood pressure monitoring values with normotensive and hypertensive-primary hyperparathyroidism patients, respectively. Normotensive-primary hyperparathyroidism patients showed a 24-h weighted Standard Deviation (P < 0.01) and average real variability (P < 0.05) of systolic blood pressure higher than that of 12 normotensive controls. 24-h average real variability of systolic BP, as well as serum calcium and parathyroid hormone levels, were reduced in operated patients (P < 0.001). A positive correlation of serum calcium and parathyroid hormone with 24-h-average real variability of systolic BP was observed in the entire primary hyperparathyroidism patients group (P = 0.04, P = 0.02; respectively). Systolic blood pressure variability is increased in normotensive patients with primary hyperparathyroidism and is reduced by parathyroidectomy, and may potentially represent an additional cardiovascular risk factor in this disease.

Evolution of silent myocardial ischaemia prevalence and cardiovascular disease risk factor management in Type 2 diabetes over a 10‐year period: an observational study

To assess the evolution of silent myocardial ischaemia prevalence and of cardiovascular disease risk factor management over 10 years in people with Type 2 diabetes. This repeated cross-sectional study prospectively included 770 people with Type 2 diabetes who presented at our centre in the period 1999-2009. All had at least one additional cardiovascular disease risk factor, no history of coronary disease and were screened for silent myocardial ischaemia using myocardial perfusion imaging. The prevalence of silent myocardial ischaemia, clinical and biological variables and treatments were collected and compared among participants screened in three periods: 1999 to 2002; 2003 to 2005; and 2006 to 2009. We also identified predictive factors for silent myocardial ischaemia. Participants had a mean ± sd age of 62.3 ± 9.3 years, 57.4% were men and the mean time from diagnosis of diabetes was 13.4 ± 9.3 years. Overall, silent myocardial ischaemia screening was positive in 13.9% of participants. This prevalence decreased sharply over the 10-year study period (22.6% in 1999-2002, 13.7% in 2003-2005 and 5.9% in 2006-2009; P<0.0001). In parallel, diastolic and systolic blood pressure, HbA1c and LDL cholesterol significantly decreased and glitazone and statin use increased (all P<0.001). Male gender, peripheral artery disease, diastolic blood pressure >80 mmHg and LDL cholesterol >2.6 mmol/l were independently associated with silent myocardial ischaemia. Further adjustment showed the screening period had a significant effect, which erased the effects of diastolic blood pressure and LDL cholesterol. The prevalence of silent myocardial ischaemia decreased sharply over time, and control of the main cardiovascular disease risk factors improved. Although the causality link cannot be established, the present study supports current recommendations advocating glycaemic control and intensive management of cardiovascular factors instead of systematic screening.

Long-term follow-up of a hospital-based, multi-intervention programme in type 2 diabetes mellitus: impact on cardiovascular events and death.

ObjectiveTo report the long-term impact on cardiovascular (CV) outcomes and mortality of a 2-year hospital-based multi-interventional care programme as compared with general practitioner (GP)-provided standard care.MethodsPatients with type 2 diabetes with ≥ 1 additional CV risk factor were randomized to 2 years of specialist-based, multi-intervention comprising lifestyle modification and specific pharmacological treatment, or GP-based standard care. After the 2-year intervention period, all participants returned to pre-study care, but were followed up for CV outcomes and mortality. The primary outcome was time to any first severe CV event or death.ResultsA total of 120 patients (31 women) were enrolled in the study. During the mean ± SD observational period of 8.7 ± 2.0 years, 27 patients (16 and 11 in the multi-intervention and standard care groups, respectively) experienced at least one primary outcome event, with a hazard ratio (HR) if allocated to the multi-intervention group of 1.73 (95% confidence interval (CI) 0.80, 3.75). The HR for total mortality was 1.82 (95% CI 0.66, 5.01).ConclusionsHospital-based multi-intervention in patients with type 2 diabetes mellitus improved long-term glycaemic control, but failed to reduce CV outcomes and deaths.Clinical trials.gov id: NCT00133718.

Associations between interarm differences in blood pressure and cardiovascular disease outcomes: protocol for an individual patient data meta-analysis and development of a prognostic algorithm

IntroductionIndividual cohort studies in various populations and study-level meta-analyses have shown interarm differences (IAD) in blood pressure to be associated with increased cardiovascular and all-cause mortality. However, key questions remain,...

Arterial stiffness is increased in nondiabetic, nonhypertensive postmenopausal women with nonalcoholic fatty liver disease.

The purpose of this study was to assess the relationship between nonalcoholic fatty liver disease (NAFLD) and arterial stiffness in nondiabetic, nonhypertensive postmenopausal women with and without metabolic syndrome. We divided 1007 postmenopausal women into two groups (NAFLD and controls) and then three groups (NAFLD with metabolic syndrome, NAFLD without metabolic syndrome, and controls), respectively. To exclude the influence of confounding factors, we studied a specifically selected group with no additional cardiovascular risk. Carotid intima-media thickness (CIMT), carotid-femoral pulse wave velocity (cf-PWV), and flow-mediated dilatation (FMD) were measured in all study patients and controls. Patients with NAFLD had significantly greater CIMT than did controls (P < 0.001). cf-PWV was also significantly higher in patients with NAFLD than in controls (P < 0.001). We found significantly decreased FMD in patients with NAFLD than in control patients (P < 0.001). Although patients with NAFLD and metabolic syndrome had greater CIMT and cf-PWV and less FMD than healthy patients did (P < 0.05), there were no significant differences in CIMT, cf-PWV, and FMD (P > 0.05) between patients with NAFLD with and without metabolic syndrome. The presence of NAFLD is associated with an increased risk of arterial stiffness in postmenopausal women, independent of the presence of metabolic syndrome.

58 Optimal risk stratification pathways for patients with suspected acute coronary syndrome

BackgroundNovel pathways utilise low concentrations of cardiac troponin and a normal ECG to risk stratify patients with suspected acute coronary syndrome. However, clinical risk scores incorporating additional cardiovascular risk factors...

Association between antibodies to carbamylated proteins and subclinical atherosclerosis in rheumatoid arthritis patients

BackgroundRheumatoid arthritis (RA) patients carry a high risk of cardiovascular morbidity and mortality. The excess of cardiovascular disease cannot be entirely explained by traditional risk factors and the immune system contributes to the development of atherosclerosis. Moreover, post-translational modifications such as citrullination and carbamylation have been linked to inflammation and atherosclerosis. Anti-carbamylated proteins antibodies (anti-CarP) are a new subset of autoantibodies identified in RA patients. This study aimed to investigate a possible association between anti-CarP and subclinical atherosclerosis in RA patients.MethodsWe enrolled RA patients and normal healthy controls (NHS) without known cardiovascular risk factors or heart disease. Cardiovascular risk was assessed using the Modified Systemic Coronary Risk Evaluation (mSCORE). Anti-CarP were investigated by a solid phase “home-made” ELISA. Anti-citrullinated protein antibodies (ACPA) and Rheumatoid Factor (RF) were investigated by ELISA assays. Subclinical atherosclerosis was evaluated by brachial artery Flow-Mediated Dilatation (FMD) and Carotid Intima-Media Thickness (c-IMT) while arterial stiffness by Ankle-Brachial Index (ABI) and Cardio-Ankle Vascular Index (CAVI).ResultsWe enrolled 50 RA patients (34 F and 16 M, mean age 58.4 ± 13.1 years, mean disease duration 127 ± 96.7 months) and 30 age and sex matched NHS. According to the mSCORE, 58% of patients had a low risk, 32% a moderate and 8% a high risk for cardiovascular disease. FMD was significantly lower in RA patients than in NHS (5.6 ± 3.2 vs 10.7 ± 8.1%; p < 0.004) and CAVIs significantly higher in a RA patients compared to NHS (left CAVI 8.9 ± 1.7 vs 8.1 ± 1.5; p < 0.04 for and right CAVI 8.8 ± 1.6 vs 8.0 ± 1.4; p < 0.04 for the). ABI and c-IMT did not differ between the two populations. The multivariate regression analysis showed a significant association of anti-CarP antibodies with FMD, left and right CAVI and both c-IMT (r = 1.6 and p = 0.05; r = 1.7 and p = 0.04; r = 2.9 and p = 0.05; r = 1.5 and p = 0.03; r = 1.1 and p = 0.03 respectively).ConclusionsThis study confirms that RA patients, without evidence of cardiovascular disease or traditional risk factors, have an impaired endothelial function. Moreover, we found an association with anti-CarP antibodies suggesting a possible contribution of these autoantibodies to endothelial dysfunction, the earliest stage of atherosclerosis. Besides ultrasound assessment, anti-CarP should be assessed in RA patients and considered an additional cardiovascular risk factor.

Design and rationale of the ODYSSEY DM-DYSLIPIDEMIA trial: lipid-lowering efficacy and safety of alirocumab in individuals with type 2 diabetes and mixed dyslipidaemia at high cardiovascular risk

BackgroundType 2 diabetes mellitus (T2DM) is often associated with mixed dyslipidaemia, where non-high-density lipoprotein cholesterol (non-HDL-C) levels may more closely align with cardiovascular risk than low-density lipoprotein cholesterol (LDL-C). We describe the design and rationale of the ODYSSEY DM-DYSLIPIDEMIA study that assesses the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, versus lipid-lowering usual care in individuals with T2DM and mixed dyslipidaemia at high cardiovascular risk with non-HDL-C inadequately controlled despite maximally tolerated statin therapy. For the first time, atherogenic cholesterol-lowering with a PCSK9 inhibitor will be assessed with non-HDL-C as the primary endpoint with usual care as the comparator.MethodsDM-DYSLIPIDEMIA is a Phase 3b/4, randomised, open-label, parallel group, multinational study that planned to enrol 420 individuals. Main inclusion criteria were T2DM and mixed dyslipidaemia (non-HDL-C ≥100 mg/dl [≥2.59 mmol/l], and triglycerides ≥150 and <500 mg/dl [≥1.70 and <5.65 mmol/l]) with documented atherosclerotic cardiovascular disease or ≥1 additional cardiovascular risk factor. Participants were randomised (2:1) to alirocumab 75 mg every 2 weeks (Q2W) or lipid-lowering usual care on top of maximally tolerated statin (or no statin if intolerant). If randomised to usual care, investigators were able to add their pre-specified choice of one of the following to the patient’s current statin regimen: ezetimibe, fenofibrate, omega-3 fatty acids or nicotinic acid, in accordance with local standard-of-care. Alirocumab-treated individuals with non-HDL-C ≥100 mg/dl at week 8 will undergo a blinded dose increase to 150 mg Q2W at week 12. The primary efficacy endpoint is non-HDL-C change from baseline to week 24 with alirocumab versus usual care; other lipid levels (including LDL-C), glycaemia-related measures, safety and tolerability will also be assessed. Alirocumab will be compared to fenofibrate in a secondary analysis.ResultsRecruitment completed with 413 individuals randomised in 14 countries worldwide. Results of this trial are expected in the second quarter of 2017.ConclusionsODYSSEY DM-DYSLIPIDEMIA will provide information on the efficacy and safety of alirocumab versus lipid-lowering usual care in individuals with T2DM and mixed dyslipidaemia at high cardiovascular risk using non-HDL-C as the primary efficacy endpoint.Trial registration NCT02642159 (registered December 24, 2015)

Outcomes of open and endovascular lower extremity revascularization in active smokers with advanced peripheral arterial disease

ObjectiveConcern over perioperative and long-term durability of lower extremity revascularizations among active smokers is a frequent deterrent for vascular surgeons to perform elective lower extremity revascularization. In this study, we examined perioperative outcomes of lower extremity endovascular (LEE) revascularization and open lower extremity bypass (LEB) in active smokers with intermittent claudication (IC) and critical limb ischemia (CLI). MethodsActive smokers undergoing LEE or LEB from 2011 to 2014 were identified in the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) targeted vascular data set. Patient demographics, comorbidities, anatomic features, and perioperative outcomes were compared between LEE and LEB procedures. Subgroup analysis was performed for patients undergoing revascularization for IC and CLI independently. ResultsFrom 2011 to 2014, 4706 lower extremity revascularizations were performed in active smokers (37% of all revascularizations). In this group, 1497 were LEE (55.6% for CLI, 13.4% for below-knee pathology) and 3209 were LEB (68.9% CLI, 34.7% below-knee). Patients undergoing LEE had higher rates of female gender, hypertension, end-stage renal disease, and diabetes (all P ≤ .02). LEE patients also had a higher frequency of prior percutaneous interventions (22.7% vs 17.2%; P < .01) and preoperative antiplatelet therapy (82.3% vs 78.7%; P = .02). On risk-adjusted multivariate analysis, LEE patients had higher need for reintervention on the treated arterial segment than LEB (5.1% vs 5.2%; odds ratio [OR], 1.52; 95% confidence interval [CI], 1.08-2.13; P = .02) but had lower wound complications (3.1% vs 13.2%; OR, 0.32; 95% CI, 0.23-0.45; P < .01) and no statistically significant difference in 30-day mortality (0.6% vs 0.9%), myocardial infarction or stroke (1.1% vs 2.6%), or major amputation (3.2% vs 2.1%) in the overall cohort of active smokers. In the IC subgroup, myocardial infarction or stroke was significantly higher in the LEB group (1.9% vs 0.6%; OR, 1.83; 95% CI, 1.17-1.97; P = .03), although no difference was found in the CLI subgroup (2.8% vs 1.4%; OR, 0.75; 95% CI, 0.37-1.52; P = .42,). Also in IC group, there was a trend for lower major amputation rates ≤30 days in the LEE group, whereas in the CLI group, LEE had a trend toward higher risk of early amputation compared with LEB. ConclusionsIn active smokers, LEB for IC and CLI requires fewer reinterventions but is associated with a higher rate of postoperative wound complications compared with LEE revascularization. However, the risk for limb amputation is higher in actively smoking patients when treated by LEE compared with LEB for CLI. Importantly, cardiovascular complications are significantly higher in actively smoking patients with IC undergoing LEB compared with LEE. This additional cardiovascular risk should be carefully weighed when proposing LEB for actively smoking patients with nonlimb-threatening IC.

Heart‐rate Corrected QT Interval Prolongation in Impaired Fasting Glucose and Type 2 Diabetes: The Polish Norwegian Study (PONS)

IntroductionProlonged QT interval is associated with cardiac arrhythmias and sudden death. Type 2 diabetes mellitus (DM) is associated with increased risk of arrhythmias. Repolarization abnormalities may play a role in increasing the arrhythmic risk in patients with DM.PurposeTo estimate QT interval across the entire spectrum of glucose abnormalities.MethodsCross‐sectional data from an ongoing cohort study, following a standardized protocol. The QT intervals were obtained from digital standard 12‐lead resting ECG. Heart rate correction (QTc) was performed with Bazett's formula. Plasma total, LDL, HDL cholesterol, triglycerides and glucose were measured in a fasting state. We classified glucose metabolism in three categories: normal (no DM and fasting glucose &lt;100 mg/dL), impaired fasting glucose (IFG, no DM and fasting glucose between 100–125.9 mg/dL) and diabetes (history of diabetes or antidiabetic medication or fasting glucose &gt;= 126 mg/dL). We considered as normal, QTc values &lt; 430 ms for men and &lt; 450 ms for women. After excluding medication known to influence the QT interval (antiarrhythmics, digoxin, antipsychotics), the analytic sample size was 11068 participants, ages 45 to 64 years. Multivariable linear and logistic models were used for analyses.ResultsMean (SD) QTc was 413.60 ms (27.37) for men and 421.40 (23.97) ms for women. The overall prevalence of IFG was 23.74% and of DM was 8.43%. The mean (95%CI) QTc was 417.72 ms (417.14–418.30) in the normal glycemic group, 419.88 ms (418.90–420.86) in the IFG group and 424.70 ms (423.06–426.34) in the DM group. After adjustment for age, sex, prevalent cardiovascular disease, hypertension, left ventricular hypertrophy and BMI, these QTc means were 418.06 ms (417.47–418.64), 419.38 ms (418.39–420.37) and 423.45 ms (421.77–425.13) respectively. The likelihood of a higher than normal sex‐specific, age‐adjusted QT interval was 79% higher in those with IFG (OR 1.79, 95% CI 1.50–2.14), compared to those with normal glucose metabolism. After additional adjustment for prevalent cardiovascular disease, hypertension, left ventricular hypertrophy and BMI, these figures remained statistically significant (IGF: OR 1.19, 95% CI 1.04–1.40), DM: OR 1.57, 95%CI 1.30–1.88). History of DM or current antidiabetic drug use was associated with a 46% increase in the odds of a higher than normal sex‐specific QTc interval (OR, 95% CI 1.46, 1.20–1.79), after multivariable adjustment. Among normal glucose and IFG groups, each one additional cardiovascular risk factor increased the likelihood of a higher than normal QTc by 15% (OR, 95% CI 1.11–1.23). However, this effect was not present among those with diabetes. Diabetes duration and/or glucose control in diabetics, was not associated with QTc.ConclusionWe found a progressively increasing QTc interval from normal glucose to IFG and diabetes. Our results suggest that abnormalities in glucose metabolism impact ventricular repolarization, independent of the presence of other cardiovascular risk factors accompanying the diabetic state.Support or Funding InformationThe data collection was supported by a grant from the Polish‐Norwegian Research Fund (PNRF‐228‐AI‐1/07)

Efficacy and safety of alirocumab in insulin-treated patients with type 1 or type 2 diabetes and high cardiovascular risk: Rationale and design of the ODYSSEY DM–INSULIN trial

AimsThe coadministration of alirocumab, a PCSK9 inhibitor for treatment of hypercholesterolaemia, and insulin in diabetes mellitus (DM) requires further study. Described here is the rationale behind a phase-IIIb study designed to characterize the efficacy and safety of alirocumab in insulin-treated patients with type 1 (T1) or type 2 (T2) DM with hypercholesterolaemia and high cardiovascular (CV) risk. MethodsODYSSEY DM–INSULIN (NCT02585778) is a randomized, double-blind, placebo-controlled, multicentre study that planned to enrol around 400 T2 and up to 100 T1 insulin-treated DM patients. Participants had low-density lipoprotein cholesterol (LDL-C) levels at screening≥70mg/dL (1.81mmol/L) with stable maximum tolerated statin therapy or were statin-intolerant, and taking (or not) other lipid-lowering therapy; they also had established CV disease or at least one additional CV risk factor. Eligible patients were randomized 2:1 to 24weeks of alirocumab 75mg every 2weeks (Q2W) or a placebo. Alirocumab-treated patients with LDL-C≥70mg/dL at week 8 underwent a blinded dose increase to 150mg Q2W at week 12. Primary endpoints were the difference between treatment arms in percentage change of calculated LDL-C from baseline to week 24, and alirocumab safety. ResultsThis is an ongoing clinical trial, with 76 T1 and 441 T2 DM patients enrolled; results are expected in mid-2017. ConclusionThe ODYSSEY DM–INSULIN study will provide information on the efficacy and safety of alirocumab in insulin-treated individuals with T1 or T2 DM who are at high CV risk and have hypercholesterolaemia not adequately controlled by the maximum tolerated statin therapy.

Effect of gender and adiposity on in vivo vascular function in young African Americans

The relationship between obesity and high blood pressure is not as strong among African Americans (AA) as compared to Caucasians. We designed the current study to determine the effect of adiposity on vascular endothelial function (a harbinger of hypertension) among young healthy AA without additional cardiovascular disease risk factors. A total of 108 AA subjects (46 women) between the ages of 18 and 45 years were recruited. All the subjects were normotensive, nonsmokers, and normoglycemic. Anthropometric and cardiovascular disease risk factor measurements (lipid, insulin resistance, and inflammatory markers) were obtained. Vascular endothelial function was measured by brachial artery flow-mediated dilation (FMD). Adiposity distribution was measured by using magnetic resonance imaging scan. There were no gender differences in age and levels of blood pressure, lipids, insulin resistance, and inflammatory markers. Women had higher total body fat percentage and higher peripheral adiposity compared to men. We observed that total and central adiposity did not correlate significantly with brachial artery FMD in women (r = −0.12 and r = 0.23, respectively; P = NS). However, in men, waist circumference was positively associated with FMD (r = 0.3, P ≤ .05). Hyperemic flow was negatively correlated significantly with total and central adiposity in men (r = −0.34 and r = −0.48, respectively; P < .05), but not in women (r = −0.26 and r = 0.03, respectively; P = NS). Our study suggests that increased adiposity may pose greater risk to AA men compared to AA women by adversely affecting resistance vessel function (as measured by hyperemic flow). Larger studies are necessary to validate these findings.