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1.  The role of factor Xa inhibitors in venous thromboembolism treatment 
Three factor Xa inhibitors have been studied in the treatment of venous thromboembolism, both for acute therapy and as extended therapy to prevent recurrent events. Rivaroxaban, apixaban, and edoxaban have all proven to be effective in Phase III clinical trials for this indication when compared to current standard of therapy with similar or less bleeding. Nevertheless, the agents all offer different pharmacological profiles, which have an impact on patient selection and potential advantages in clinical practice.
PMCID: PMC4321604
anti-Xa inhibitors; apixaban; edoxaban; rivaroxaban; venous thromboembolism
2.  Long-term insulin glargine therapy in type 2 diabetes mellitus: a focus on cardiovascular outcomes 
Cardiovascular disease is the leading cause of mortality in type 2 diabetes mellitus. Hyperinsulinemia is associated with increased cardiovascular risk, but the effects of exogenous insulin on cardiovascular disease progression have been less well studied. Insulin has been shown to have both cardioprotective and atherosclerosis-promoting effects in laboratory animal studies. Long-term clinical trials using insulin to attain improved diabetes control in younger type 1 and type 2 diabetes patients have shown improved cardiovascular outcomes. Shorter trials of intensive diabetes control with high insulin use in higher risk patients with type 2 diabetes have shown either no cardiovascular benefit or increased all cause and cardiovascular mortality. Glargine insulin is a basal insulin analog widely used to treat patients with type 1 and type 2 diabetes. This review focuses on the effects of glargine on cardiovascular outcomes. Glargine lowers triglycerides, leads to a modest weight gain, causes less hypoglycemia when compared with intermediate-acting insulin, and has a neutral effect on blood pressure. The Outcome Reduction With Initial Glargine Intervention (ORIGIN trial), a 6.2 year dedicated cardiovascular outcomes trial of glargine demonstrated no increased cardiovascular risk.
PMCID: PMC4315664  PMID: 25657589
glargine; insulin; type 2 diabetes; cardiovascular disease; cardiovascular outcomes
3.  Prevention of stent thrombosis: challenges and solutions 
Stent thrombosis is an uncommon but serious complication which carries with it significant mortality and morbidity. This review analyzes the entity of stent thrombosis from a historical and clinical perspective, and chronicles the evolution of this condition through the various generations of stent development, from bare metal to first-generation, second-generation, and third-generation drug-eluting stents. It also delineates the specific risk factors associated with stent thrombosis and comprehensively examines the literature related to each of these risks. Finally, it highlights the preventative strategies that can be garnered from the existing data, and concludes that a multifactorial approach is necessary to combat the occurrence of stent thrombosis, with higher risk groups, such as patients with ST segment elevation myocardial infarction, meriting further research.
PMCID: PMC4315466  PMID: 25657588
stent thrombosis; preventative strategies; post-procedural myocardial infarction
4.  Real-world effectiveness of amlodipine/valsartan and amlodipine/valsartan/hydrochlorothiazide in high-risk patients and other subgroups 
The clinical EXCITE (EXperienCe of amlodIpine and valsarTan in hypErtension) study reported clinically relevant blood pressure (BP) reductions across all doses of amlodipine/valsartan (Aml/Val) and Aml/Val/hydrochlorothiazide (HCT) single-pill combinations. The study prospectively observed a multiethnic population of hypertensive patients for 26 weeks who were treated according to routine clinical practice. Here, we present the results in high-risk subgroups including the elderly, obese patients, and patients with diabetes or isolated systolic hypertension. In addition, we present a post hoc analysis as per prior antihypertensive monotherapy and dual therapy.
Patients prescribed Aml/Val or Aml/Val/HCT were assessed in this 26±8 week, noninterventional, multicenter study across 13 countries in the Middle East and Asia. Changes in mean sitting systolic BP, mean sitting diastolic BP, and overall safety were assessed.
Of a total of 9,794 patients analyzed, 8,603 and 1,191 patients were prescribed Aml/Val and Aml/Val/HCT, respectively. Among these, 15.5% were elderly, 32.5% were obese, 31.3% had diabetes, and 9.8% had isolated systolic hypertension. Both Aml/Val and Aml/Val/HCT single-pill combinations, respectively, were associated with clinically relevant and significant mean sitting systolic/diastolic BP reductions across all subgroups: elderly patients (−32.2/−14.3 mmHg and −38.5/−16.5 mmHg), obese patients (−32.2/−17.9 mmHg and −38.5/−18.4 mmHg), diabetic patients (−30.3/−16.1 mmHg and −34.4/−16.6 mmHg), and patients with isolated systolic hypertension (−25.5/−4.1 mmHg and −30.2/−5.9 mmHg). Incremental BP reductions with Aml/Val or Aml/Val/HCT single-pill combinations were also observed in patients receiving prior monotherapy or dual therapy for hypertension. Overall, both Aml/Val and Aml/Val/HCT were generally well tolerated.
This large, multiethnic study supports the evidence that Aml/Val and Aml/Val/ HCT single-pill combinations are effective in diverse and clinically important subgroups of patients with hypertension.
PMCID: PMC4309775  PMID: 25653536
amlodipine; hydrochlorothiazide; single-pill combinations; real world; valsartan
5.  Scaffolds in vascular regeneration: current status 
An ideal vascular substitute, especially in <6 mm diameter applications, is a major clinical essentiality in blood vessel replacement surgery. Blood vessels are structurally complex and functionally dynamic tissue, with minimal regeneration potential. These have composite extracellular matrix (ECM) and arrangement. The interplay between ECM components and tissue specific cells gives blood vessels their specialized functional attributes. The core of vascular tissue engineering and regeneration relies on the challenges in creating vascular conduits that match native vessels and adequately regenerate in vivo. Out of numerous vascular regeneration concerns, the relevance of ECM emphasizes much attention toward appropriate choice of scaffold material and further scaffold development strategies. The review is intended to be focused on the various approaches of scaffold materials currently in use in vascular regeneration and current state of the art. Scaffold of choice in vascular tissue engineering ranges from natural to synthetic, decellularized, and even scaffold free approach. The applicability of tubular scaffold for in vivo vascular regeneration is under active investigation. A patent conduit with an ample endothelial luminal layer that can regenerate in vivo remains an unanswered query in the field of small diameter vascular tissue engineering. Besides, scaffolds developed for vascular regeneration, should aim at providing functional substitutes for use in a regenerative approach from the laboratory bench to patient bedside.
PMCID: PMC4304530  PMID: 25632236
scaffold; vascular regeneration; in vivo
6.  Adiponectin as a potential biomarker of vascular disease 
The increasing prevalence of diabetes and its complications heralds an alarming situation worldwide. Obesity-associated changes in circulating adiponectin concentrations have the capacity to predict insulin sensitivity and are a link between obesity and a number of vascular diseases. One obvious consequence of obesity is a decrease in circulating levels of adiponectin, which are associated with cardiovascular disorders and associated vascular comorbidities. Human and animal studies have demonstrated decreased adiponectin to be an independent risk factor for cardiovascular disease. However, in animal studies, increased circulating adiponectin alleviates obesity-induced endothelial dysfunction and hypertension, and also prevents atherosclerosis, myocardial infarction, and diabetic cardiac tissue disorders. Further, metabolism of a number of foods and medications are affected by induction of adiponectin. Adiponectin has beneficial effects on cardiovascular cells via its antidiabetic, anti-inflammatory, antioxidant, antiapoptotic, antiatherogenic, vasodilatory, and antithrombotic activity, and consequently has a favorable effect on cardiac and vascular health. Understanding the molecular mechanisms underlying the regulation of adiponectin secretion and signaling is critical for designing new therapeutic strategies. This review summarizes the recent evidence for the physiological role and clinical significance of adiponectin in vascular health, identification of the receptor and post-receptor signaling events related to the protective effects of the adiponectin system on vascular compartments, and its potential use as a target for therapeutic intervention in vascular disease.
PMCID: PMC4303398  PMID: 25653535
obesity; adiponectin; vascular disease
7.  Validation of two automatic devices for the self-measurement of blood pressure according to the ANSI/AAMI/ISO81060-2:2009 guidelines: the Omron BP765 (HEM-7311-ZSA) and the Omron BP760N (HEM-7320-Z) 
Allowing patients to measure their blood pressure (BP) at home will be the standard for evaluating the disease state as the process of clinical diagnosis, and it is recognized as having great clinical utility. To measure BP as accurately as possible, innovative techniques have been incorporated into home BP measurement devices.
The present study aimed to evaluate the performance of the Omron BP765 (HEM-7311-ZSA) and the Omron BP760N (HEM-7320-Z), which are equipped with functions to detect irregular pulses and arm movement that lead to inaccurate BP readings.
A team of three trained medical doctors validated the performance of these devices by comparing the data alternatively obtained from both devices with those from a standard mercury sphygmomanometer.
The magnitude of the difference in BP readings between the tested device and the standard mercury sphygmomanometer in the Omron BP765 and BP760N was within the range of ±3 mmHg (mean) allowed by the American National Standards Institute, Inc/Association for the Advancement of Medical Instrumentation/International Organization for Standardization (ANSI/AAMI/ISO) 81060-2:2009 guidelines.
The Omron BP765 and BP760N were found useful for the self-measurement of BP at home, and their performance fulfilled the requirement of the ANSI/AAMI/ISO 81060-2:2009 guidelines.
PMCID: PMC4295899  PMID: 25657587
blood pressure; self-measurement; device; validation; ANSI/AAMI/ISO 81060-2:2009
8.  Indirect and direct costs of acute coronary syndromes with comorbid atrial fibrillation, heart failure, or both 
The objective of this study was to determine the direct and indirect costs of acute coronary syndromes (ACS) alone and with common cardiovascular comorbidities.
A retrospective analysis was conducted using the Medical Expenditure Panel Survey from 1998 to 2009. Four mutually exclusive cohorts were evaluated: ACS only, ACS with atrial fibrillation (AF), ACS with heart failure (HF), and ACS with both conditions. Direct costs were calculated for all-cause and cardiovascular-related health care resource utilization. Indirect costs were determined from productivity losses from missed days of work. Regression analysis was developed for each outcome controlling for age, US census region, insurance coverage, sex, race, ethnicity, education attainment, family income, and comorbidity burden. A negative binomial regression model was used for health care utilization variables. A Tobit model was utilized for health care costs and productivity loss variables.
Total health care costs were greatest for those with ACS and both AF and HF ($38,484±5,191) followed by ACS with HF ($32,871±2,853), ACS with AF ($25,192±2,253), and ACS only ($17,954±563). Compared with the ACS only cohort, the mean all-cause adjusted health care costs associated with ACS with AF, ACS with HF, and ACS with AF and HF were $5,073 (95% confidence interval [CI] 719–9,427), $11,297 (95% CI 5,610–16,985), and $15,761 (95% CI 4,784–26,738) higher, respectively. Average wage losses associated with ACS with and without AF and/or HF amounted to $5,266 (95% CI −7,765, −2,767), when compared with patients without these conditions.
ACS imposes a significant economic burden at both the individual and society level, particularly when with comorbid AF and HF.
PMCID: PMC4284047  PMID: 25565859
acute coronary syndromes; comorbid atrial fibrillation; heart failure; costs
9.  Overview of saxagliptin efficacy and safety in patients with type 2 diabetes and cardiovascular disease or risk factors for cardiovascular disease 
Most individuals with type 2 diabetes mellitus have or will develop multiple independent risk factors for cardiovascular disease, particularly coronary artery disease (CAD). CAD is the leading cause of morbidity and mortality among individuals with type 2 diabetes mellitus, and treating these patients is challenging. The risk of hypoglycemia, weight gain, or fluid retention with some diabetes medications should be considered when developing a treatment plan for individuals with a history of CAD or at risk for CAD. Dipeptidyl peptidase-4 inhibitors are oral antihyperglycemic agents that inhibit the breakdown of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, resulting in increased glucose-dependent insulin secretion and suppression of glucagon secretion. Saxagliptin is a potent and selective dipeptidyl peptidase-4 inhibitor that improves glycemic control and is generally well tolerated when used as monotherapy and as add-on therapy to other antihyperglycemic medications. This review summarizes findings from recently published post hoc analyses of saxagliptin clinical trials that have been conducted in patients with and without a history of cardiovascular disease and in patients with and without various risk factors for cardiovascular disease. The results show that saxagliptin was generally well tolerated and consistently improved glycemic control, as assessed by reductions from baseline in glycated hemoglobin, fasting plasma glucose concentration, and postprandial glucose concentration, regardless of the presence or absence of baseline cardiovascular disease, hypertension, statin use, number of cardiovascular risk factors, or high Framingham 10-year cardiovascular risk score.
PMCID: PMC4278729  PMID: 25565858
cardiovascular disease; dipeptidyl peptidase-4 inhibitors; incretin; saxagliptin; type 2 diabetes mellitus
10.  Safety and effectiveness of a fixed-dose combination of olmesartan, amlodipine, and hydrochlorothiazide in clinical practice 
Clinical trials indicate that the use of fixed-dose combinations (FDCs) is associated with a higher level of treatment adherence and prolonged blood pressure (BP) control. The aim of this study was to document the safety and effectiveness of the FDC olmesartan/amlodipine/hydrochlorothiazide in patients with essential hypertension in clinical practice.
This multicenter, prospective, 24-week, noninterventional study enrolled 5,831 patients from primary care offices in Germany and Austria. Inclusion criteria were a diagnosis of essential hypertension and newly initiated treatment with the FDC.
The mean age of patients was 63.5 years, almost 50% of patients had a time since diagnosis of essential hypertension of over 5 years, and approximately 70% of patients had at least one cardiovascular risk factor, including 29.4% of patients with diabetes mellitus. Following approximately 24 weeks of treatment, the mean reduction in systolic/diastolic BP was 29.0/14.0 mmHg, a BP response was observed by 94.2% of patients, and a target BP of <140/90 mmHg was attained in 67.5% of patients. At least one adverse drug reaction (ADR) was experienced by 1.2% of patients, with the most common being peripheral edema. Subanalyses demonstrated that the following factors did not have a significant influence on the ADR rate: age (<65 years versus ≥65 years), diabetes mellitus (no/yes), cardiovascular risk (low/high), and concomitant medication (no/yes).
This study demonstrates that in clinical practice, treatment with the three-drug combination as an FDC tablet resulted in a very high proportion of patients with a BP response and control, accompanied by a very low rate of ADRs.
PMCID: PMC4275113  PMID: 25565857
hypertension; clinical practice; fixed-dose combination; blood pressure; adverse drug reactions
11.  Effects of exercise timing on sleep architecture and nocturnal blood pressure in prehypertensives 
During nocturnal sleep, blood pressure (BP) “dips” compared to diurnal BP, reducing stress on the cardiovascular system. Both the hypotensive response elicited by acute aerobic exercise and sleep quality can impact this dipping response.
The purpose of this study was to investigate the effects of aerobic exercise timing on circadian BP changes and sleep architecture.
Materials and methods
Twenty prehypertensive subjects completed the study. During four test sessions, participants first completed a graded exercise test to exhaustion and then performed 30 minutes of treadmill exercise at 7 am (7A), 1 pm (1P), and 7 pm (7P) in a random, counterbalanced order at 65% of the heart rate obtained at peak oxygen uptake. An ambulatory cuff was used to monitor BP responses during 24 hours following exercise, and an ambulatory sleep-monitoring headband was worn during sleep following each session.
Aerobic exercise at 7A invoked a greater dip in nocturnal systolic BP than exercise at 1P or 7P, although the greatest dip in nocturnal diastolic BP occurred following 7P. Compared to 1P, 7A also invoked greater time spent in deep sleep.
These data indicate that early morning may be the most beneficial time to engage in aerobic exercise to enhance nocturnal BP changes and quality of sleep.
PMCID: PMC4270305  PMID: 25540588
nocturnal dipping; prehypertension; aerobic exercise
12.  Prevalence of risk factors at presentation and early mortality in patients aged 80 years or older with ST-segment elevation myocardial infarction 
Elderly patients with ST-segment elevation myocardial infarction (STEMI) are at high risk for complications and early mortality; still, they are underrepresented in clinical trials and observational studies. We studied the risk profiles at presentation and early mortality in elderly (≥80 years) versus younger (<80 years) STEMI patients.
This was a prospective cohort study.
The study population comprised 4,092 consecutive STEMI patients admitted to Oslo University Hospital, Ulleval from 2006 to 2010. Baseline characteristics at admission were recorded, as well as in-hospital mortality. Etiologic strategy was used in the analyses.
Patients ≥80 years of age (n=536) were more likely to be women and have prior myocardial infarction, angina, and stroke, but were less likely to be current smokers. The crude in-hospital mortality was 16.2% in patients aged 80 years and older versus 3.5% in those younger than 80 years. The adjusted odds ratio for mortality in patients aged 80 years and older versus those younger than 80 years increased with increasing levels of serum creatinine and total cholesterol. In patients with low levels of serum creatinine and total cholesterol, the odds ratio was 3.01 (95% confidence interval, 1.86–4.93; P=0.0001); increasing to 11.72 (95% confidence interval, 5.26–26.3; P=0.001) in patients with high levels.
High levels of serum cholesterol and creatinine were important risk factors for early mortality in elderly patients. Depending on the levels of cholesterol and creatinine, in-hospital mortality in patients aged 80 years and older varied from a threefold to an almost twelvefold risk compared with younger patients.
PMCID: PMC4266339  PMID: 25525366
ST-segment elevation myocardial infarction; mortality; elderly patients; octogenarian; creatinine; total cholesterol
13.  Complications of the endovascular management of acute ischemic stroke 
Acute ischemic stroke is a significant source of morbidity and mortality across the globe. Currently, the only US Food and Drug Administration approved medical treatment of acute ischemic stroke is intravascular (IV) alteplase. While IV thrombolysis has been shown to decrease morbidity and mortality from acute ischemic stroke, it is limited in both its efficacy in certain types of stroke, as well as in its generalizability. It has been shown that time to revascularization is one of the most important predictors of outcomes in acute ischemic stroke, and thus clinicians have turned to endovascular options in efforts to improve outcomes from stroke. Direct intra-arterial thrombolysis was one of the first of such efforts to improve efficacy rates and increase the timeline for thrombolytic therapy. More recently, investigators and clinicians have turned to newer endovascular options in attempts to further improve recanalization rates. Many different endovascular techniques have been employed and are growing exponentially in use. Examples include stenting, as well as mechanical thrombectomy with both older-generation devices and newer stent retrieval technology. While the majority of the literature focuses on the effectiveness of different techniques, such as recanalization rates and major overall outcomes such as death and disability, there is very little literature on the complications of the different techniques. The purpose of this article is to review the different forms of endovascular treatment of acute ischemic stroke and their associated complications.
PMCID: PMC4259256  PMID: 25506222
alteplase; endovascular techniques; revascularization
14.  Macitentan for the treatment of pulmonary arterial hypertension 
Macitentan is the most recently approved dual endothelin-receptor antagonist (ERA) for the treatment of symptomatic pulmonary arterial hypertension. Compared to other available ERAs, it demonstrates superior receptor-binding properties, with consequently improved tissue penetration, and a longer duration of action allowing for once-daily dosing. It has a favorable adverse-effect profile, with notably no demonstrable increase in the risk of hepatotoxicity or peripheral edema, but like other ERAs, it is potentially limited by significant anemia. Phase I data have demonstrated a favorable drug–drug interaction profile and no need for dose adjustment with hepatic and renal impairment. In the pivotal SERAPHIN study, treatment of symptomatic pulmonary arterial hypertension patients with macitentan led to statistically significant improvements in functional class, exercise tolerance, and hemodynamic parameters, in addition to a reduction in morbidity in an event-driven long-term trial.
PMCID: PMC4251661  PMID: 25473292
endothelin; endothelin receptor antagonists; macitentan; pulmonary arterial hypertension
15.  Changes in body weight after 24 weeks of vildagliptin therapy as a function of fasting glucose levels in patients with type 2 diabetes 
In order to test the hypothesis that the degree of weight change with the dipeptidyl peptidase-4 inhibitor vildagliptin is dependent on the level of glycemic control at baseline, the weight changes from pooled monotherapy studies after 24 weeks of therapy with vildagliptin were assessed versus the fasting plasma glucose (FPG) levels at baseline.
Data were pooled from eight clinical monotherapy trials including 2,340 previously drug-naïve patients with type 2 diabetes mellitus who received vildagliptin monotherapy (50 mg once daily [n=359] or 50 mg twice daily [n=1,981]). The trials were all randomized, double-blind, controlled clinical trials with a prespecified week 24 study visit.
Linear regression analysis of weight change after 24 weeks relative to baseline FPG showed an intercept of −2.259 kg (95% confidence interval −2.86, −1.66; P<0.0001) and a positive slope of 0.1552 kg (95% confidence interval 0.10–0.21; P<0.0001). Neutral caloric balance (no weight change) was observed at a FPG of 14.6 mmol/L (263 mg/dL). Baseline FPG values below and above this threshold were associated with weight loss and weight gain, respectively. For instance, from this analysis, a baseline FPG of 8 mmol/L (144 mg/dL) predicts a weight loss of 1 kg.
The present analysis showed that treatment with vildagliptin results in a negative caloric balance when glucose levels are below the renal threshold at baseline.
PMCID: PMC4242898  PMID: 25429228
dipeptidyl peptidase-4 inhibitor; glucagon-like peptide-1; renal threshold; sodium-glucose cotransporter-2 inhibitor; hyperglycemia
16.  Uptitrating amlodipine significantly reduces blood pressure in diabetic patients with hypertension: a retrospective, pooled analysis 
Diabetic patients with hypertension are approximately twice as likely to develop cardiovascular disease as non-diabetic patients with hypertension. Given that hypertension affects ∼60% of patients with diabetes, effective blood pressure (BP) management is important in this high-risk population. This post-hoc analysis pooled data from six clinical studies to quantify additional BP efficacy achieved when titrating hypertensive diabetic patients from amlodipine 5 mg to 10 mg. Approximately half of the diabetic patients were male (44/98; 44.9%) with a mean (standard deviation [SD]) age of 60.6 (9.6) years and a baseline mean (standard error [SE]) systolic blood pressure/diastolic blood pressure (SBP/DBP) of 150.8 (1.30)/87.5 (0.94) mmHg while on amlodipine 5 mg (159.1 [1.40]/92.6 [0.94] mmHg prior to treatment). In comparison, 350/610 (57.4%) non-diabetic patients were male with a mean (SD) age of 58.7 (11.1) years and baseline mean (SE) SBP/DBP of 150.3 (0.62)/90.9 (0.41) mmHg while on amlodipine 5 mg (160.0 [0.67]/96.2 [0.45] mmHg prior to treatment). Increasing amlodipine from 5 mg to 10 mg lowered sitting SBP by −12.5 mmHg (95% confidence interval (CI): −15.5, −9.5; P<0.0001) and DBP by −6.0 mmHg (−7.4, −4.6; P<0.0001) in diabetic patients; and SBP by −12.4 mmHg (−13.5, −11.3; P<0.0001) and DBP by −7.3 mmHg (−8.0, −6.7; P<0.0001) in non-diabetic patients. In total, 12.0% (95% CI: 6.4, 20.0) of diabetic patients achieved their BP goal versus 46.4% (42.4, 50.4) of non-diabetic patients after titration to amlodipine 10 mg. Overall, 22.0% of diabetic patients experienced 31 adverse events (AEs) and 28.9% of non-diabetic patients experienced 282 AEs. Serious AEs were reported by one (1.0%) diabetic and five (0.8%) non-diabetic patients. In this analysis, increasing amlodipine from 5 mg to 10 mg produced a clinically significant reduction in the BP of diabetic hypertensive patients, similar to non-diabetic patients, highlighting the importance of optimizing amlodipine titration in this high-risk population.
PMCID: PMC4240189  PMID: 25484592
hypertension; diabetes; calcium channel blockers; cardiovascular disease prevention; efficacy
18.  Direct oral anticoagulants in the treatment of venous thromboembolism, with a focus on patients with pulmonary embolism: an evidence-based review 
Pulmonary embolism (PE) is a relatively common cardiovascular emergency. PE and deep vein thrombosis (DVT) are considered expressions of the same disease, termed as venous thromboembolism (VTE). In the present review, we describe and meta-analyze the efficacy and safety data available with the direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) in clinical trials testing these new compounds in the acute/long-term and extended therapy of VTE, providing subgroup analyses in patients with index PE. We analyzed ten studies in 35,019 randomized patients. A total of 14,364 patients (41%) had index PE. In the acute/long-term treatment of VTE, the DOAC showed comparable efficacy in preventing recurrent VTE to standard treatment in patients with index PE (risk ratio [RR]: 0.88; 95% confidence interval [CI]: 0.70–1.11) and index DVT (RR: 0.93; 95% CI: 0.75–1.16) (P for subgroup differences =0.76). VTE recurrence depending on PE anatomical extension and presence/absence of right ventricular dysfunction was only reported in two trials, with results being consistent with those obtained in the overall study populations. In the single trial comparing extended therapy of VTE with DOAC versus warfarin, the point estimate for recurrent VTE tended to disfavor the DOAC in patients with index PE (RR: 2.05; 95% CI: 0.83–5.03) and in patients with index DVT (RR: 1.11; 95% CI: 0.49–2.50) (P for subgroup differences =0.32). In trials that compared DOAC versus placebo for extended therapy, the reduction in recurrent VTE was consistent in patients with PE (RR: 0.15; 95% CI: 0.01–1.82) and in patients with DVT (RR: 0.25; 95% CI: 0.10–0.61) (P for subgroup differences =0.71). The DOAC were associated with a consistently lower risk of clinically relevant bleeding (CRB) than standard treatment of acute VTE and higher risk of CRB than placebo for extended therapy of VTE regardless of index event. In summary, the DOAC were as effective as, and safer than, standard treatment of (hemodynamically stable) PE. Their efficacy in preventing recurrent VTE seemed consistent regardless of anatomical extension of PE (extensive, intermediate, or limit) or presence/absence of right ventricular dysfunction although the data are limited. For extended therapy, the DOAC were more effective than placebo in preventing recurrent VTE but were associated with an increase in CRB regardless of index event.
PMCID: PMC4230169  PMID: 25404858
anticoagulant; pulmonary embolism; dabigatran; apixaban; rivaroxaban; edoxaban
19.  A new coronary artery disease grading system correlates with numerous routine parameters that were associated with atherosclerosis: a grading system for coronary artery disease severity 
Several scoring systems have tried to determine the severity of coronary artery disease (CAD) to investigate the connection between CAD severity and laboratory parameters.
In total, 189 male (mean age: 61.86±10.77 years) and 75 female CAD patients (mean age: 67.84±7.70 years) were recruited and underwent angiography, which determined stenosis grade, of 17 coronary segments: no points for each nonstenosed segment or only calcified segments, one point for each stenosis from <30% to <50%, two points for each stenosis from 50% to <70%, and three points for each stenosis >70%. The points were added and should represent the severity of patients’ CAD.
The coronary score correlated positively with systolic blood pressure, creatinine, blood urea nitrogen, lipase, glucose, glycated hemoglobin, triglycerides, C-reactive protein, fibrinogen Clauss, and leukocytes, and correlated negatively with Cl−, iron, and high-density lipoprotein cholesterol. Stepwise multiple regression analysis with backward elimination revealed diabetes status, sex, and fibrinogen Clauss as significant predictors of coronary score.
The coronary score delivers a quite simple but very precise tool for the quantification of CAD severity. These results show plainly the connection between CAD severity and the lipid, glucose, coagulation, and immunologic status of CAD patients, and substantiate the importance of sufficient treatment in this group of patients – in particular, CAD patients suffering from type 2 diabetes mellitus. The coronary score would offer a suitable tool for the investigation of the connection between CAD and new biomarkers. Further studies are needed to investigate the correlation of the coronary score with outcome parameters (eg, death).
PMCID: PMC4230172  PMID: 25404859
coronary artery disease; grading system; angiography; diabetes mellitus; atherosclerosis
20.  Improving medication adherence in hypercholesterolemia: challenges and solutions 
Medication nonadherence is a prevalent public health issue that contributes to significant medical costs and detrimental health outcomes. This is especially true in patients with hypercholesterolemia, a condition affecting millions of American adults and one that is associated with increased risk for coronary and cerebrovascular events. Considering the magnitude of outcomes related to this disease, the medical community has placed significant emphasis on addressing the treatment for high cholesterol, and progress has been made in recent years. However, poor adherence to therapy continues to plague health outcomes and more must be understood and done to address suboptimal medication taking. Here we provide an overview of the reasons for poor medication adherence in patients with hypercholesterolemia and describe recent efforts to curb nonadherence. Suggested approaches for improving medication taking in patients with high cholesterol are also provided to guide practitioners, patients, and payers.
Video abstract
PMCID: PMC4226449  PMID: 25395859
medication use; lipid management; cardiovascular disease
21.  Congenital anomaly of the inferior vena cava and factor V Leiden mutation predisposing to deep vein thrombosis 
A previously healthy 21-year-old man presented with back pain, bilateral extremity pain, and right lower extremity weakness, paresthesias, and swelling. Sonographic examination revealed diffuse deep vein thrombosis (DVT) in the femoral and popliteal venous system. CT imaging revealed hypoplasia of the hepatic inferior vena cava (IVC) segment with formation of multiple varices and collateral veins around the kidneys. Hematologic workup also discovered a factor V Leiden mutation, further predisposing the patient to DVT. The rare, often overlooked occurrence of attenuated IVC, especially in the setting of hypercoagulable state, can predispose patients to significant thrombosis.
Video abstract
PMCID: PMC4226457  PMID: 25395858
inferior vena cava (IVC); deep vein thrombosis (DVT); lower extremities; thrombophilic; venography
22.  Optimal management of infrainguinal arterial occlusive disease 
Peripheral arterial occlusive disease is becoming a major health problem in Western societies as the population continues to age. In addition to risk of limb loss, the complexity of the disease is magnified by its intimate association with medical comorbidity, especially cardiovascular and cerebrovascular disease. Risk factor modification and antiplatelet therapy are essential to improve long-term survival. Surgical intervention is indicated for intermittent claudication when a patient’s quality of life remains unacceptable after a trial of conservative therapy. Open reconstruction and endovascular revascularization are cornerstone for limb salvage in patients with critical limb ischemia. Recent advances in catheter-based technology have made endovascular intervention the preferred treatment approach for infrainguinal disease in many cases. Nevertheless, lower extremity bypass remains an important treatment strategy, especially for reasonable risk patients with a suitable bypass conduit. In this review, we present a summary of current knowledge about peripheral arterial disease followed by a review of current, evidence-based medical and surgical therapy for infrainguinal arterial occlusive disease.
PMCID: PMC4216027  PMID: 25368519
peripheral vascular disease; peripheral arterial disease; critical limb ischemia; claudication; infrainguinal bypass; endovascular infrainguinal intervention
23.  Consumption of water containing over 3.5 mg of dissolved hydrogen could improve vascular endothelial function 
The redox imbalance between nitric oxide and superoxide generated in the endothelium is thought to play a pivotal role in the development of endothelial dysfunction. A third reactive oxygen species (ROS), H2O2, is known to have both beneficial and detrimental effects on the vasculature. Nonetheless, the influence of the hydroxyl radical, a byproduct of H2O2 decay, is unclear, and there is no direct evidence that the hydroxyl radical impairs endothelial function in conduit arteries. Molecular hydrogen (H2) neutralizes detrimental ROS, especially the hydroxyl radical.
To assess the influence of the hydroxyl radical on the endothelium and to confirm that a gaseous antioxidant, H2, can be a useful modulator of blood vessel function.
The efficacy of water containing a high concentration of H2 was tested by measuring flow-mediated dilation (FMD) of the brachial artery (BA). The subjects were randomly divided into two groups: the high-H2 group, who drank high-H2 water containing 7 ppm H2 (3.5 mg H2 in 500 mL water); and the placebo group. Endothelial function was evaluated by measuring the FMD of the BA. After measurement of diameter of the BA and FMD at baseline, volunteers drank the high-H2 water or placebo water immediately and with a 30-minute interval; FMD was compared to baseline.
FMD increased in the high-H2 group (eight males; eight females) from 6.80%±1.96% to 7.64%±1.68% (mean ± standard deviation) and decreased from 8.07%±2.41% to 6.87%±2.94% in the placebo group (ten males; eight females). The ratio to the baseline in the changes of FMD showed significant improvement (P<0.05) in the high-H2 group compared to the placebo group.
H2 may protect the vasculature from shear stress-derived detrimental ROS, such as the hydroxyl radical, by maintaining the nitric oxide-mediated vasomotor response.
PMCID: PMC4207582  PMID: 25378931
flow-mediated dilation; reactive oxygen species; molecular hydrogen; hydroxyl radical; 5–7 ppm; peroxynitrite
24.  N-terminal fragment of probrain natriuretic peptide is associated with diabetes microvascular complications in type 2 diabetes 
Circulating levels of N-terminal fragment of probrain natriuretic peptide (NT-proBNP) are established as a risk factor for cardiovascular disease and mortality in patients with diabetes, as well as in the general population. We sought to examine the possibility of NT-proBNP as a biomarker of microvascular complications in patients with type 2 diabetes.
Materials and methods
In total, 277 outpatients with type 2 diabetes were consecutively enrolled as a hospital cohort. Two hundred and seventeen of these patients (132 males; mean age, 63.4 years) were designated as cases with any of the diabetic complications (retinopathy, neuropathy, nephropathy, ischemic heart disease, strokes, peripheral artery disease), and 60 (42 males; mean age, 54.1 years) were set as controls without clinical evidence of diabetic complications. Diabetic complications were evaluated by medical record and routine laboratory examinations. NT-proBNP was measured and investigated with regard to the associations with diabetic complications.
Mean NT-proBNP levels were significantly higher in patients with any of the diabetic complications (59 versus 33 pg/mL; P<0.0001). In logistic regression analysis, NT-proBNP levels >79 pg/mL, which was the highest tertile, were independently associated with a 5.04 fold increased risk of all complications (P<0.0051) compared to the lowest tertile (NT-proBNP levels <31 pg/mL). Odd ratios of cardiovascular disease and nephropathy, neuropathy, and retinopathy were 9.33, 6.23, 6.6 and 13.78 respectively, in patients with NT-proBNP values in the highest tertile (>79 pg/mL), independently of age, sex, duration of diabetes or other risk factors, such as body mass index or hemoglobin A1c. In addition, NT-proBNP levels were associated with surrogate markers of atherosclerosis, such as brachial-ankle pulse wave velocity (r=0.449, P<0.0001) and left ventricular hypertrophy (r=0.212, P<0.001).
In this hospital-based cohort of type 2 diabetes, the NT-proBNP levels were associated with systemic atherosclerosis and comorbid diabetic microvascular as well as macrovascular complications. It is useful to stratify high-risk diabetic patients by measuring NT-proBNP and to start comprehensive care for preventing the progression of diabetic complications. It is necessary to elucidate the underlying mechanism for the progression of diabetic complications represented by an elevation of NT-proBNP and to demonstrate the ability of NT-proBNP as a predictive global biomarker for diabetic complications in Japanese type 2 diabetic patients.
PMCID: PMC4199566  PMID: 25328404
NT-proBNP; diabetic complication; biomarker
25.  Endothelial function testing and cardiovascular disease: focus on peripheral arterial tonometry 
During recent decades, a number of methods have been developed to assess endothelial function, contributing to a better understanding of the pathophysiology of cardiovascular disease. Recently, the advent of noninvasive, reproducible techniques for assessment of endothelial function has opened novel possibilities of application in the clinical setting. Peripheral arterial tonometry is a relatively novel, user-friendly technique measuring finger pulse volume amplitude changes induced by reactive hyperemia following 5 minutes of ischemia in the upper limb. Current evidence indicates that this technique has the potential to significantly impact the field of cardiovascular research and prevention of cardiovascular disease. However, a number of methodological, pathophysiological, and clinical aspects still need to be clarified before widespread application of this promising technique. This review focuses on the current knowledge and future perspectives of peripheral arterial tonometry, in comparison with the most widely used noninvasive technique, ie, flow-mediated dilation.
PMCID: PMC4196841  PMID: 25328403
endothelium; reactive hyperemia; microcirculation

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