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1.  Neurogenic orthostatic hypotension in Parkinson’s disease: evaluation, management, and emerging role of droxidopa 
Neurogenic orthostatic hypotension (nOH) is due to failure of the autonomic nervous system to regulate blood pressure in response to postural changes due to an inadequate release of norepinephrine, leading to orthostatic hypotension and supine hypertension. nOH is common in Parkinson’s disease (PD). Prevalence varies throughout the course of PD, ranging from 40% to 60%, and resulting in symptomatic nOH in approximately half. Symptomatic nOH, including lightheadedness, can limit daily activities and lead to falls. Symptomatic nOH can also limit therapeutic options for treating PD motor symptoms. Clinical evaluation should routinely include symptom assessment and blood pressure measurement of supine, sitting, and 3-minute standing; 24-hour ambulatory blood pressure monitoring can also be helpful. Non-pharmacological management of symptomatic nOH involves education, physical maneuvers, and adequate hydration. Current pharmacological treatment of symptomatic nOH includes salt supplement, fludrocortisone, midodrine, pyridostigmine, and other empiric medications. Despite these options, treatment of symptomatic nOH remains suboptimal, often limited by severe increases in supine blood pressure. Droxidopa, an oral prodrug converted by decarboxylation to norepinephrine, is a promising therapeutic option for symptomatic nOH in PD, improving symptoms of nOH, daily activities, falls, and standing systolic blood pressure in several recent trials. These trials demonstrated short-term efficacy and tolerability, with comparable increases in standing and supine blood pressures. Longer-term studies are ongoing to confirm durability of treatment effect.
PMCID: PMC3979788
(pre)syncope; norepinephrine; autonomic; lightheadedness; treatment; falls
2.  Unmet needs in the management of acute myocardial infarction: role of novel protease-activated receptor-1 antagonist vorapaxar 
Platelet activation with subsequent aggregation is a complex process leading to thrombus formation, which remains a key component for atherothrombotic manifestations, in particular myocardial infarction. Therefore, antiplatelet therapies are pivotal for the treatment of these patients. Current oral antiplatelet therapies used for secondary prevention of ischemic recurrences include aspirin and adenosine diphosphate P2Y12 platelet-receptor antagonists. However, despite these therapies, patients who have experienced a myocardial infarction remain at risk for ischemic recurrences. Therefore, more aggressive secondary prevention measures have been an area of research, including identifying additional targets modulating platelet-activation and -aggregation processes. Among these, thrombin-mediated platelet activation via protease-activated receptors (PARs) has been subject to extensive clinical investigation. Several PAR-1 receptor antagonists have been developed. However, vorapaxar is the only one that has completed large-scale clinical investigation. The present manuscript will provide an overview on the role of thrombin-mediated signaling, the impact of PAR-1 blockade with vorapaxar on ischemic and bleeding outcomes, and the potential role for vorapaxar in clinical practice.
PMCID: PMC3979798
platelet aggregation; antiplatelet agent; protease-activated receptor 1; vorapaxar
3.  Benefit–risk assessment of rivaroxaban versus enoxaparin for the prevention of venous thromboembolism after total hip or knee arthroplasty 
Venous thromboembolism is a common complication after major orthopedic surgery. When prescribing anticoagulant prophylaxis, clinicians weigh the benefits of thromboprophylaxis against bleeding risk and other adverse events. Previous benefit–risk analyses of the REgulation of Coagulation in ORthopaedic surgery to prevent Deep vein thrombosis and pulmonary embolism (RECORD) randomized clinical studies of rivaroxaban versus enoxaparin after total hip (THA) or knee (TKA) arthroplasty generally used pooled THA and TKA results, counted fatal bleeding as both an efficacy and a safety event, and included the active and placebo-controlled portions of RECORD2, which might confound benefit–risk assessments. We conducted a post hoc analysis without these constraints to assess benefit–risk for rivaroxaban versus enoxaparin in the RECORD studies.
Patients and methods
Data from the safety population of the two THA and two TKA studies were pooled separately. The primary analysis compared the temporal course of event rates and rate differences between rivaroxaban and enoxaparin prophylaxis for symptomatic venous thromboembolism plus all-cause mortality (efficacy events) versus nonfatal major bleeding (safety events). Additionally, these rates were used to derive measures of net clinical benefit, number needed to treat (NNT), and number needed to harm (NNH) for these two end points.
After THA or TKA, and compared with enoxaparin, rivaroxaban therapy resulted in more efficacy events prevented than safety events caused, with benefits exceeding harms early and throughout treatment and follow-up. Relative to enoxaparin, rivaroxaban treatment prevented six efficacy events per harm event caused for THA, with NNT =262/NNH =1,711. For TKA, rivaroxaban treatment prevented four to five efficacy events per harm event caused, with NNT =102/NNH =442. Sensitivity analysis that included surgical-site bleeding resulted in NNH =345 for THA and NNH =208 for TKA.
In the RECORD studies, considering death, symptomatic venous thromboembolism, and major bleeding, rivaroxaban resulted in greater benefits than harms compared with enoxaparin. When incorporating surgical-site bleeding, rivaroxaban also results in greater benefit than harm for TKA and is balanced with enoxaparin for THA.
PMCID: PMC3971939
VTE; DVT; PE; thromboprophylaxis; total hip arthroplasty; total knee arthroplasty
4.  Reduction in cardiovascular risk using a proactive multifactorial intervention is consistent among patients residing in Pacific Asian and non-Pacific Asian regions: a CRUCIAL trial subanalysis 
Few trials have compared different approaches to cardiovascular disease prevention among Pacific Asian (PA) populations. The Cluster Randomized Usual Care versus Caduet Investigation Assessing Long-term-risk (CRUCIAL) trial demonstrated that a proactive multifactorial intervention (PMI) approach (based on single-pill amlodipine/atorvastatin) resulted in a greater reduction in calculated Framingham 10-year coronary heart disease (CHD) risk compared with usual care (UC) among hypertensive patients with additional risk factors. One-third of CRUCIAL patients resided in the PA region. The aim of this subanalysis was to compare two approaches to cardiovascular risk factor management (PMI versus UC) among patients residing in PA and non-PA regions.
This subanalysis of the CRUCIAL trial compared treatment-related changes in calculated CHD risk among patients residing in PA and non-PA regions. Sensitivity analyses were conducted among men and women and those with and without diabetes.
Overall, 448 patients (31.6%) resided in the PA region and 969 patients (68.4%) resided in non-PA regions. The PMI approach was more effective in reducing calculated CHD risk versus UC in both PA (−37.1% versus −3.5%; P<0.001) and non-PA regions (−31.1% versus −4.2%; P<0.001); region interaction P=0.131. PA patients had slightly greater reductions in total cholesterol compared with non-PA patients. PA patients without diabetes had slightly greater reductions in CHD risk compared with non-PA patients. Treatment effects were similar in men and women and those with diabetes.
The PMI approach was more effective in reducing calculated Framingham 10-year CHD risk compared with UC among men and women with and without diabetes residing in the PA and non-PA region.
PMCID: PMC3971943
cardiovascular disease; risk factors; hypertension; clinical trial; antihypertensive agents; anticholesteremic agents
5.  The “Pulse Time Index of Norm” highly correlates with the left ventricular mass index in patients with arterial hypertension 
Arterial stiffness, as measured by the pulse wave velocity (PWV), is recommended for routine use in clinical practice as an important parameter for the evaluation of cardiovascular risk.1 New 24-hour monitors (eg, with Vasotens® technology; Petr Telegin Company, Nizhny Novgorod, Russian Federation) provide single PWV measurements as well as several PWV measurements over a period of 24 hours.2 Such 24-hour pulse wave analysis led to the development of the novel Pulse Time Index of Norm (PTIN), which is defined as the percentage of a 24-hour period during which the PWV does not exceed the 10 m/second PWV threshold. The aim of this study is to test the new PTIN for correlation with the left ventricular mass index (LVMI).
Oscillometrically generated waveform files (n=137) used for clinical research studies were reanalyzed using the new 2013 version of the Vasotens technology program, which enables PTIN calculations.
A good correlation (r=−0.72) between the PTIN and the LVMI was shown, which was significantly above the blood pressure load (r=0.41).
The PTIN generated by the Vasotens technology can be recommended as an indicator of end organ damage via hypertension.
PMCID: PMC3964171  PMID: 24672245
pulse wave velocity; ambulatory; 24-hour; monitoring; PTIN; arterial stiffness; LVMI
6.  Association of hypertension and obesity with HIV and antiretroviral therapy in a rural tertiary health center in Nigeria: a cross-sectional cohort study 
There are few studies from Nigeria and Africa regarding the contribution of obesity and hypertension to cardiovascular risk in HIV-infected patients. This study investigates the prevalence of hypertension and obesity and their association with HIV infection and antiretroviral treatment (ART).
We conducted a cross-sectional cohort study in a rural tertiary health center in Nigeria. The data collected included demographic variables, blood pressure, body mass index (BMI), monthly income, educational attainment, HIV status and ART treatment, duration of treatment, and CD4 T-lymphocyte count.
A total of 403 participants met the inclusion criteria. There were 153 (38.0%) HIV-negative subjects (42.5% male, 57.5% female; mean age: 35.5±7.6 years), 120 (29.8%) HIV-positive drug-naïve subjects (42.5% male, 57.5% female; mean age: 36.5±9.1 years), and 130 (32.2%) HIV-positive subjects taking antiretroviral drugs (33.1% male, 66.9% female; mean age: 38.6±8.0 years). The prevalence of hypertension was 13.7% in HIV-negative subjects, 19.0% in HIV-positive drug-naïve subjects, and 12.3% in HIV-positive ART subjects. The prevalence of obesity was 15.9% in the HIV-negative group, 3% in the HIV-positive drug-naïve group, and 8% in the HIV-positive ART group. Multivariate regression analysis showed no relationship between hypertension and HIV status (P=0.293) or ART status (P=0.587). In contrast, BMI showed a strong relationship with HIV status (odds ratio: 0.281; 95% confidence interval: 0.089–0.884; P=0.030) but not with ART status (P=0.593). BMI was a significant predictor of hypertension.
HIV or ART status was not associated with hypertension. HIV infection was associated with a lower BMI, and a lower prevalence of obesity compared with HIV-negative subjects.
PMCID: PMC3964169  PMID: 24672244
cardiovascular risk; HIV infection; prevalence
7.  Practical guidance for using rivaroxaban in patients with atrial fibrillation: balancing benefit and risk 
Rivaroxaban is a direct factor Xa inhibitor that is widely available to reduce the risk of stroke or systemic embolism in patients with nonvalvular atrial fibrillation and one or more risk factors for stroke. Rivaroxaban provides practical advantages compared with warfarin and other vitamin K antagonists, including a rapid onset of action, few drug interactions, no dietary interactions, a predictable anticoagulant effect, and no requirement for routine coagulation monitoring. However, questions have emerged relating to the responsible use of rivaroxaban in day-to-day clinical practice, including patient selection, dosing, treatment of patients with renal impairment, conversion from use of vitamin K antagonists to rivaroxaban and vice versa, coagulation tests, and management of patients requiring invasive procedures or experiencing bleeding or an ischemic event. This article provides practical recommendations relating to the use of rivaroxaban in patients with nonvalvular atrial fibrillation, based on clinical trial evidence, relevant guidelines, prescribing information, and the authors’ clinical experience.
PMCID: PMC3956810  PMID: 24648742
novel oral anticoagulants; direct factor Xa inhibitor; peri-interventional management; practical guidance; rivaroxaban; stroke prevention
8.  Challenges associated with peripheral arterial disease in women 
Peripheral arterial disease (PAD) is an increasingly recognized disorder that is associated with functional impairment, quality-of-life deterioration, increased risk of cardiovascular ischemic events, and increased risk of total and cardiovascular mortality. Although earlier studies suggested that PAD was more common in men, recent reports based on more sensitive tests have shown that the prevalence of PAD in women is at least the same as in men, if not higher. PAD tends to present itself asymptomatically or with atypical symptoms more frequently in women than in men, and is associated with comorbidities or situations particularly or exclusively found in the female sex, such as osteoporosis, hypothyroidism, the use of oral contraceptives, and a history of complications during pregnancy. Fat-distribution patterns and differential vascular characteristics in women may influence the interpretation of diagnostic methods, whereas sex-related vulnerability to drugs typically used in subjects with PAD, differences in risk-factor distribution among sexes, and distinct responses to revascularization procedures in men and women must be taken into account for proper disease management. All these issues pose important challenges associated with PAD in women. Of note, this group has classically been underrepresented in research studies. As a consequence, several sex-related challenges regarding diagnosis and management issues should be acknowledged, and research gaps should be addressed in order to successfully deal with this major health issue.
Video abstract
PMCID: PMC3956880  PMID: 24648743
peripheral arterial disease; women; diagnosis; management
9.  Pantethine, a derivative of vitamin B5, favorably alters total, LDL and non-HDL cholesterol in low to moderate cardiovascular risk subjects eligible for statin therapy: a triple-blinded placebo and diet-controlled investigation 
High serum concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for coronary heart disease. The efficacy of pantethine treatment on cardiovascular risk markers was investigated in a randomized, triple-blinded, placebo-controlled study, in a low to moderate cardiovascular disease (CVD) risk North American population eligible for statin therapy, using the National Cholesterol Education Program (NCEP) guidelines. A total of 32 subjects were randomized to pantethine (600 mg/day from weeks 1 to 8 and 900 mg/day from weeks 9 to16) or placebo. Compared with placebo, the participants on pantethine showed a significant decrease in total cholesterol at 16 weeks (P=0.040) and LDL-C at 8 and 16 weeks (P=0.020 and P=0.006, respectively), and decreasing trends in non-high-density lipoprotein cholesterol at week 8 and week 12 (P=0.102 and P=0.145, respectively) that reached significance by week 16 (P=0.042). An 11% decrease in LDL-C from baseline was seen in participants on pantethine, at weeks 4, 8, 12, and 16, while participants on placebo showed a 3% increase at week 16. This decrease was significant between groups at weeks 8 (P=0.027) and 16 (P=0.010). The homocysteine levels for both groups did not change significantly from baseline to week 16. Coenzyme Q10 significantly increased from baseline to week 4 and remained elevated until week 16, in both the pantethine and placebo groups. After 16 weeks, the participants on placebo did not show significant improvement in any CVD risk end points. This study confirms that pantethine lowers cardiovascular risk markers in low to moderate CVD risk participants eligible for statins according to NCEP guidelines.
PMCID: PMC3942300  PMID: 24600231
nutritional and metabolic diseases; hypercholesterolemia; pantethine; cardiovascular diseases; dietary supplements; controlled clinical trial
10.  Current perspectives on the use of intravenous recombinant tissue plasminogen activator (tPA) for treatment of acute ischemic stroke 
In 1995, the NINDS (National Institute of Neurological Disorders and Stroke) tPA (tissue plasminogen activator) Stroke Study Group published the results of a large multicenter clinical trial demonstrating efficacy of intravenous tPA by revealing a 30% relative risk reduction (absolute risk reduction 11%–15%) compared with placebo at 90 days in the likelihood of having minimal or no disability. Since approval in 1996, tPA remains the only drug treatment for acute ischemic stroke approved by the US Food and Drug Administration. Over the years, an abundance of research and clinical data has supported the safe and efficacious use of intravenous tPA in all eligible patients. Despite such supporting data, it remains substantially underutilized. Challenges to the utilization of tPA include narrow eligibility and treatment windows, risk of symptomatic intracerebral hemorrhage, perceived lack of efficacy in certain high-risk subgroups, and a limited pool of neurological and stroke expertise in the community. With recent US census data suggesting annual stroke incidence will more than double by 2050, better education and consensus among both the medical and lay public are necessary to optimize the use of tPA for all eligible stroke patients. Ongoing and future research should continue to improve upon the efficacy of tPA through more rapid stroke diagnosis and treatment, refinement of advanced neuroimaging and stroke biomarkers, and successful demonstration of alternative means of reperfusion.
PMCID: PMC3938499  PMID: 24591838
IV tPA; rtPA; t-PA; rt-PA; cerebrovascular disease; cerebrovascular accident
11.  Effect of eprosartan-based antihypertensive therapy on coronary heart disease risk assessed by Framingham methodology in Canadian patients: results of the POWER survey 
The Canadian Hypertension Education Program (CHEP) has identified blood pressure (BP) control as a key target for an overall reduction in cardiovascular disease risk. The POWER survey (Physicians’ Observational Work on Patient Education According to their Vascular Risk) used Framingham methodology to investigate the impact of an angiotensin-receptor-blocker-based regimen on arterial BP and total coronary heart disease (CHD) risk in a subset of patients recruited in Canada.
309 Canadian practices screened for patients with either newly diagnosed or uncontrolled mild/moderate hypertension (sitting systolic blood pressure [SBP] >140 mmHg with diastolic blood pressure [DBP] <110 mmHg). Treatment comprised eprosartan 600 mg/day with add-on antihypertensive therapy after 1 month if required. The primary efficacy variable was change in SBP at 6 months; the secondary variable was the absolute change in the Framingham 10-year CHD risk score.
1,385 patients were identified, of whom 1,114 were included in the intention-to-treat (ITT) cohort. Thirty-eight point four percent of ITT patients were managed with monotherapy at 6 months, versus 35.2% and 13.7% with two-drug or multiple-drug therapy, respectively. SBP in the ITT cohort declined 22.4 (standard deviation [SD] 14.8) mmHg and DBP declined 10.5 (SD 10.3) mmHg during that time. The absolute mean Framingham score declined 2.1 (SD 3.1) points with significant age and sex variation (P<0.001) and differences between the various Framingham methods used.
Primary care physicians were able to use a strategy of BP lowering and CHD risk assessment to achieve significant reductions in BP and Framingham-assessed CHD risk. The effect size estimate of the different Framingham methods varied noticeably; reasons for those differences warrant further investigation.
PMCID: PMC3908905  PMID: 24493928
blood pressure; hypertension; angiotensin-receptor blocker; observational study
12.  Avoiding permanent atrial fibrillation: treatment approaches to prevent disease progression 
Atrial fibrillation (AF) is the most common sustained arrhythmia and a major global public health problem due to its associated morbidity, including stroke and heart failure, diminished quality of life, and increased mortality. AF often presents initially in a paroxysmal form and may progress to a more sustained form over time. Evidence from randomized controlled trials suggests that there may be no mortality benefit to using a rhythm control approach in comparison with rate control of AF. Nevertheless, sustained forms of AF may be associated with increased symptoms and cardiovascular morbidity, and consequently they remain an additional target for therapy. The present review evaluates the clinical correlates of arrhythmia progression and risk stratification techniques available to assess probability of AF progression. Further, currently available management options for arrhythmia control in AF are evaluated and their therapeutic effect and efficacy on disease progression are explored.
PMCID: PMC3872084  PMID: 24379678
atrial fibrillation; progression; permanent; prevention
14.  Experience with DPP-4 inhibitors in the management of patients with type 2 diabetes fasting during Ramadan 
A large proportion of Muslim patients with type 2 diabetes mellitus (T2DM) elect to fast during the holy month of Ramadan. For these patients hypo- and hyperglycemia constitute two major complications associated with the profound changes in food pattern during the Ramadan fast, and efficacious treatment options with a low risk of hypoglycemia are therefore needed to manage their T2DM as effectively and safely as possible. Dipeptidyl peptidase-4 (DPP-4) inhibitors modulate insulin and glucagon secretion in a glucose-dependent manner, and consequently a low propensity of hypoglycemia has consistently been reported across different patient populations with these agents. Promising data with DPP-4 inhibitors have now also started to emerge in patients with T2DM fasting during Ramadan. The objective of this review is to provide a comprehensive overview of the currently available evidence and potential role of DPP-4 inhibitors in the management of patients with T2DM fasting during Ramadan whose diabetes is treated with oral antidiabetic drugs, and to discuss the mechanistic basis for their beneficial effects in this setting.
PMCID: PMC3878957  PMID: 24391442
dipeptidyl peptidase-4; incretin; type 2 diabetes mellitus; hypoglycemia
15.  Risk of stroke associated with nonsteroidal anti-inflammatory drugs 
Nonsteroidal anti-inflammatory drugs (NSAIDs), both cyclooxygenase (COX)-2-selective and nonselective agents, have been associated with the increased risk of adverse cardiovascular events. The majority of studies have focused on myocardial infarction as the primary cardiovascular outcome. However, the association between NSAIDs and the risk of stroke events is not as clear, although an understanding of this association is important since stroke continues to be a significant cause of morbidity and mortality. Various factors may contribute to an association between NSAIDs and stroke, including hypertension and thrombosis. Additionally, the risk may vary with different NSAID types. In this review, we discuss the relevant literature assessing the possible association between NSAID use and stroke events, along with the potential mechanisms and the possible directions for future study.
Video abstract
PMCID: PMC3888349  PMID: 24421643
nonsteroidal anti-inflammatory drugs; cardiovascular; stroke; cyclooxygenase; adverse events
16.  Dabigatran and myocardial infarction: a foggy scenario 
PMCID: PMC3901777  PMID: 24476689
17.  Validation of four devices: Omron M6 Comfort, Omron HEM-7420, Withings BP-800, and Polygreen KP-7670 for home blood pressure measurement according to the European Society of Hypertension International Protocol 
Four oscillometric devices, including the Omron M6 Comfort, Omron HEM-7420, Withings BP-800, and Polygreen KP-7670, designed for self-blood pressure measurement (SBPM) were evaluated according to the European Society of Hypertension (ESH) International Protocol Revision 2010 in four separate studies.
The four devices measure brachial blood pressure (BP) using the oscillometric method. The Withings BP-800 has to be connected to an Apple® iOS device such as an iPhone®, iPad®, or iPod®. The ESH International Protocol Revision 2010 includes a total number of 33 subjects. The difference between observer and device BP values was calculated for each measure. Ninety-nine pairs of BP differences were classified into three categories (≤5 mmHg, ≤10 mmHg, ≤15 mmHg). The protocol procedures were followed precisely in each of the four studies.
All four tested devices passed the validation process. The mean differences between the device and mercury readings were: −1.8±5.1 mmHg and −0.4±2.8 mmHg for systolic and diastolic BP, respectively, using the Omron M6 Comfort device; 2.5±4.6 mmHg and −1.2±4.3 mmHg for the Omron HEM-7420 device; −0.2±5.0 mmHg and 0.4±4.2 mmHg for the Withings BP-800 device; and 3.0±5.3 mmHg and 0.3±5.2 mmHg for the Polygreen KP-7670 device.
Omron M6 Comfort, Omron HEM-7420, Withings BP-800, and Polygreen KP-7670 readings differing by less than 5 mmHg, 10 mmHg, and 15 mmHg fulfill the ESH International Protocol Revision 2010 requirements, and therefore are suitable for use by patients for SBPM, if used correctly.
Video abstract
PMCID: PMC3897354  PMID: 24476688
Omron M6 Comfort; Omron HEM-7420; Withings BP-800; Polygreen KP-7670; self-blood pressure measurement; validation; European Society of Hypertension International Protocol Revision
18.  Is higher body temperature beneficial in ischemic stroke patients with normal admission CT angiography of the cerebral arteries? 
Low body temperature is considered beneficial in ischemic stroke due to neuroprotective mechanisms, yet some studies suggest that higher temperatures may improve clot lysis and outcomes in stroke patients treated with tissue plasminogen activator (tPA). The effect of increased body temperature in stroke patients treated with tPA and with normal computed tomography angiography (CTA) on admission is unknown. We hypothesized a beneficial effect of higher body temperature in the absence of visible clots on CTA, possibly due to enhanced lysis of small, peripheral clots.
Patients with ischemic stroke admitted to our Stroke Unit between February 2006 and April 2013 were prospectively registered in a database (Bergen NORSTROKE Registry). Ischemic stroke patients treated with tPA with normal CTA of the cerebral arteries were included. Outcomes were assessed by the modified Rankin Scale (mRS) after 1 week. An excellent outcome was defined as mRS=0, and a favorable outcome as mRS=0–1.
A total of 172 patients were included, of which 48 (27.9%) had an admission body temperature ≥37.0°C, and 124 (72.1%) had a body temperature <37.0°C. Body temperature ≥37.0°C was independently associated with excellent outcomes (odds ratio [OR]: 2.8; 95% confidence interval [CI]: 1.24–6.46; P=0.014) and favorable outcomes (OR: 2.8; 95% CI: 1.13–4.98; P=0.015) when adjusted for confounders.
We found an association between higher admission body temperature and improved outcome in tPA-treated stroke patients with normal admission CTA of the cerebral arteries. This may suggest a beneficial effect of higher body temperature on clot lysis in the absence of visible clots on CTA.
PMCID: PMC3905091  PMID: 24482573
acute ischemic stroke; body temperature; thrombolysis; tissue plasminogen activator
19.  Increased prevalence of coronary artery disease risk markers in patients with chronic hepatitis C – a cross-sectional study 
Chronic hepatitis C is a global health problem and has been associated with coronary artery disease. Our aim was to examine the prevalence of coronary artery disease risk markers including endothelial biomarkers in patients with chronic hepatitis C and matched comparisons without manifest cardiovascular disease or diabetes in a cross-sectional design.
Sixty patients with chronic hepatitis C (mean age 51 years) were recruited from the Department of Infectious Diseases at Copenhagen University Hospital, and compared with 60 age-matched non-hepatitis C virus-infected individuals from a general population survey. We examined traditional coronary artery disease risk factors, metabolic syndrome, carotid intima media thickness, and a range of endothelial biomarkers.
Patients with chronic hepatitis C had more hypertension (40% versus 25%, prevalence ratio [PR] 1.6; 95% confidence interval [CI] 0.9–2.7) and smoked more (53% versus 38%, PR 1.4; 95% CI 0.9–2.1). The two groups had similar body mass index (mean 25.0 versus 25.7 kg/m2), whereas those with chronic hepatitis C had less dyslipidemia (including significantly lower low-density lipoprotein and cholesterol/high-density lipoprotein ratio), higher glycosylated hemoglobin level (mean 6.2 versus 5.7, difference of means 0.5; 95% CI 0.3–0.8), and a higher prevalence of metabolic syndrome (28% versus 18%, PR 1.6; 95% CI 0.8–3.0). Increased carotid intima media thickness above the standard 75th percentile was seen more frequently in chronic hepatitis C (9% versus 3%, PR 1.7; 95% CI 0.4–6.7), though difference of means was only 0.04 mm (95% CI 0.00–0.10). Patients with chronic hepatitis C had increased hsCRP (high-sensitivity C-reactive protein), sICAM-1 (soluble intercellular adhesion molecule-1), sVCAM-1 (soluble vascular cell adhesion molecule-1), and soluble E-selectin, but lower levels of tPAI-1 (tissue-type plasminogen activator inhibitor-1), MMP9 (matrix metallopeptidase 9), and MPO (myeloperoxidase) than their comparisons.
Our findings indicate that patients with chronic hepatitis C have increased prevalence of several coronary artery disease risk markers. These results may be important when evaluating the appropriateness of screening for coronary artery disease and its risk factors in chronic hepatitis C.
PMCID: PMC3905100  PMID: 24482574
risk factors; atherosclerosis; endothelial dysfunction; biomarkers; metabolic syndrome; intima media thickness
20.  Serum lipid profile and correlates in newly presenting Nigerians with arterial hypertension 
Arterial hypertension and dyslipidemia are modifiable cardiovascular risk factors. The multiplicative effect of these risk factors may worsen the atherogenic index of an individual. The objective of this study was to determine the pattern and prevalence of dyslipidemia in newly presenting Nigerians with arterial hypertension, as well as determine some of its correlates.
This cross-sectional study compared 115 newly presenting, age- and sex-matched individuals with arterial hypertension with 115 normotensive individuals. Fasting lipids, total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and fasting plasma glucose were estimated.
Patients with arterial hypertension had higher body mass index (t=7.64; P=0.000), TC (t=2.95; P=0.006), and HDL-C (t=−5.18; P=0.000). The most common dyslipidemia was low HDL-C, found in both the hypertensive (44.3%) and normotensive (20.9%) patients. The prevalence of dyslipidemia in hypertensives and controls was 64% and 39%, respectively. In hypertensive patients, TC correlated positively to diastolic blood pressure (r=0.218; P=0.0019). Other positive correlates include LDL-C and age (r=0.217; P=0.020) and fasting plasma glucose (r=0.202; P=0.030) and body mass index (r=0.209; P=0.025). Among normotensive controls, TC correlated positively with LDL-C (r=0.63; P=0.000) but correlated negatively with tri glycerides (r=−0.30; P=0.001).
Lipid abnormalities are common in newly presenting Nigerians with arterial hypertension. Screening of these risk factors, promotion of healthy lifestyle, and the institution of therapy is desirable to reduce their multiplicative effects.
PMCID: PMC3857265  PMID: 24348044
healthy lifestyle; screening; high-density lipoprotein cholesterol; cardiovascular; atherogenic index
21.  Vitamin E tocotrienol supplementation improves lipid profiles in chronic hemodialysis patients 
Chronic hemodialysis patients experience accelerated atherosclerosis contributed to by dyslipidemia, inflammation, and an impaired antioxidant system. Vitamin E tocotrienols possess anti-inflammatory and antioxidant properties. However, the impact of dietary intervention with Vitamin E tocotrienols is unknown in this population.
Patients and methods
A randomized, double-blind, placebo-controlled, parallel trial was conducted in 81 patients undergoing chronic hemodialysis. Subjects were provided daily with capsules containing either vitamin E tocotrienol-rich fraction (TRF) (180 mg tocotrienols, 40 mg tocopherols) or placebo (0.48 mg tocotrienols, 0.88 mg tocopherols). Endpoints included measurements of inflammatory markers (C-reactive protein and interleukin 6), oxidative status (total antioxidant power and malondialdehyde), lipid profiles (plasma total cholesterol, triacylglycerols, and high-density lipoprotein cholesterol), as well as cholesteryl-ester transfer protein activity and apolipoprotein A1.
TRF supplementation did not impact any nutritional, inflammatory, or oxidative status biomarkers over time when compared with the baseline within the group (one-way repeated measures analysis of variance) or when compared with the placebo group at a particular time point (independent t-test). However, the TRF supplemented group showed improvement in lipid profiles after 12 and 16 weeks of intervention when compared with placebo at the respective time points. Normalized plasma triacylglycerols (cf baseline) in the TRF group were reduced by 33 mg/dL (P=0.032) and 36 mg/dL (P=0.072) after 12 and 16 weeks of intervention but no significant improvement was seen in the placebo group. Similarly, normalized plasma high-density lipoprotein cholesterol was higher (P<0.05) in the TRF group as compared with placebo at both week 12 and week 16. The changes in the TRF group at week 12 and week 16 were associated with higher plasma apolipoprotein A1 concentration (P<0.02) and lower cholesteryl-ester transfer protein activity (P<0.001).
TRF supplementation improved lipid profiles in this study of maintenance hemodialysis patients. A multi-centered trial is warranted to confirm these observations.
PMCID: PMC3849001  PMID: 24348043
vitamin; tocotrienol-rich fraction; lipid profiles; hemodialysis; end-stage renal disease; nutrition intervention
22.  Visceral obesity is not an independent risk factor of mortality in subjects over 65 years 
The aim of the study was to determine the role of obesity evaluated by body mass index (BMI), waist circumference (WC), and their combined effect on all-cause mortality according to age and related risk factors. This study included 119,090 subjects (79,325 men and 39,765 women), aged from 17 years to 85 years, who had a general health checkup at the Centre d’Investigations Préventives et Cliniques, Paris, France. The mean follow-up was 5.6±2.4 years. The prevalence of obesity, defined by WC and BMI categories, was determined according to age groups (<55, 55–65, >65 years). All-cause mortality according to obesity and age was determined using Cox regression analysis, adjusted for related risk factors and previous cardiovascular events. For the entire population, WC adjusted for BMI, an index of central obesity, was strongly associated with mortality, even after adjustment for hypertension, dyslipidemia, and diabetes. The prevalence of obesity increased with age, notably when defined by WC. Nonetheless, the association between WC adjusted for BMI and mortality was not observed in subjects >65 years old (hazard ratio [HR] =1.010, P=NS) but was found in subjects <55 (HR =1.030, P<0.0001) and 55–65 years old (HR =1.023, P<0.05). By contrast, hypertension (HR =1.31, P<0.05), previous cardiovascular events (HR =1.98, P<0.05), and smoking (HR =1.33, P<0.05) remained associated with mortality even after age 65. In conclusion, WC adjusted for BMI is strongly and independently associated with all-cause mortality before 65 years of age, after taking into account the associated risk factors. This relationship disappears in subjects >65 years of age, suggesting a differential impact of visceral fat deposition according to age.
PMCID: PMC3839799  PMID: 24294003
abdominal; aging; body mass index; hypertension; smoking
23.  Vitamin D deficiency is associated with development of subclinical coronary artery disease in HIV-infected African American cocaine users with low Framingham-defined cardiovascular risk 
Chronic cocaine use may lead to premature atherosclerosis, but the prevalence of and risk factors for coronary artery disease (CAD) in asymptomatic cocaine users have not been reported. The objective of this study was to examine whether vitamin D deficiency is associated with the development of CAD in human immunodeficiency virus (HIV)-infected African American cocaine users with low CAD risk.
In this prospective follow-up study, we investigated 169 HIV-infected African American cocaine users with low Framingham risk at baseline. The main outcome measures were incidence of subclinical CAD and development of subclinical CAD.
Fifty of the 169 African Americans had evidence of subclinical disease on the initial cardiac computed tomography. A second cardiac computed tomography was performed on the 119 African Americans without disease on the first scan. The total sum of person-years of follow-up was 289.6. Subclinical CAD was detected in 11 of these, yielding an overall incidence of 3.80/100 person-years (95% confidence interval 1.90–6.80). Among the factors investigated, only vitamin D deficiency was independently associated with development of subclinical CAD. The study did not find significant associations between CD4 count, HIV viral load, or antiretroviral treatment use and the incidence of subclinical CAD. This study appears to suggest that there is a threshold level of vitamin D (10 ng/mL) above which the effect of vitamin D on subclinical CAD is diminished.
The incidence of subclinical CAD in HIV-infected African American cocaine users with low CAD risk is high, especially in those with vitamin D deficiency. Well designed randomized clinical trials are warranted to confirm the role of vitamin D deficiency in the development of CAD in HIV-infected African American cocaine users with low CAD risk.
PMCID: PMC3833705  PMID: 24265555
vitamin D deficiency; subclinical coronary artery disease; cocaine use; prospective follow-up study; African Americans
24.  Changes in LDL-C levels and goal attainment associated with addition of ezetimibe to simvastatin, atorvastatin, or rosuvastatin compared with titrating statin monotherapy 
Many high-risk coronary heart disease (CHD) patients on statin monotherapy do not achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals, and combination lipid-lowering therapy may be considered for these individuals. The effect of adding ezetimibe to simvastatin, atorvastatin, or rosuvastatin therapy versus titrating these statins on LDL-C changes and goal attainment in CHD or CHD risk-equivalent patients was assessed in a large, managed-care database in the US.
Eligible patients (n = 17,830), initially on statin monotherapy who were ≥18 years with baseline and follow-up LDL-C values, no concomitant use of other lipid-lowering therapy, and on lipid-lowering therapy for ≥42 days, were identified between November 1, 2002 and September 30, 2009. The percent change from baseline in LDL-C levels and the odds ratios for attainment of LDL-C <1.8 and <2.6 mmol/L (70 and 100 mg/dL) were estimated using an analysis of covariance and logistic regression, respectively, adjusted for various baseline factors.
LDL-C reductions from baseline and goal attainment improved substantially in patients treated with ezetimibe added onto simvastatin, atorvastatin, or rosuvastatin therapy (n = 2,312) versus those (n = 13,053) who titrated these statins. In multivariable models, percent change from baseline in LDL-C was −13.1% to −14.8% greater for those who added ezetimibe onto simvastatin, atorvastatin, or rosuvastatin versus those who titrated. The odds of attaining LDL-C <1.8 and <2.6 mmol/L (70 and 100 mg/dL) increased by 2.6–3.2-fold and 2.5–3.1-fold, respectively, in patients who added ezetimibe onto simvastatin, atorvastatin, or rosuvastatin versus titrating statins.
CHD/CHD risk-equivalent patients in a large US managed-care database, who added ezetimibe onto simvastatin, atorvastatin, or rosuvastatin, had greater LDL-C reductions and goal attainment than those who uptitrated these statin therapies. Our study suggests that high-risk CHD patients in need of more intensive LDL-C lowering therapy may benefit by adding ezetimibe onto statin therapy.
PMCID: PMC3833706  PMID: 24265554
low-density lipoprotein cholesterol goal; ezetimibe; atorvastatin; rosuvastatin
25.  Efficacy and safety of insulin glargine added to a fixed-dose combination of metformin and a dipeptidyl peptidase-4 inhibitor: results of the GOLD observational study 
For patients with type 2 diabetes who are uncontrolled on a combination of two oral antidiabetic agents, addition of the long-acting basal insulin glargine is a well established treatment option. However, data on the efficacy and safety of a combination of metformin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and insulin glargine are limited in real-world settings. Therefore, the aim of this study was to analyze blood glucose control, rates of hypoglycemia and body weight in a large cohort of patients with type 2 diabetes treated with this combination therapy in real practice.
This noninterventional, multicenter, prospective, observational trial with a follow-up of 20 weeks enrolled insulin-naïve patients who had been on a stable fixed dose of metformin and a DPP-4 inhibitor for at least 3 months, and had a glycosylated hemoglobin (HbA1c) between 7.5% and 10%. Patients were selected at the investigators’ discretion for initiation of insulin glargine at baseline. A total of 1,483 patients were included, of whom 1,262 were considered to be the efficacy set. Primary efficacy parameters were HbA1c and fasting plasma glucose. Secondary outcome measures included achievement of glycemic targets, body weight, rates of hypoglycemia, and other safety parameters, as well as resource consumption.
Upon initiation of insulin glargine, mean HbA1c decreased from 8.51% to 7.36% (−1.15%±0.91%; 95% confidence interval [CI] −1.20 to −1.10). An HbA1c level <6.5% was achieved in 8.2% of patients and a level <7.0% in 31.5%. Mean fasting plasma glucose decreased from 174±47 mg/dL to 127±31 mg/dL (−47.3±44.1 mg/dL; 95% CI −49.8 to −44.8). In 11.9% of patients, a fasting plasma glucose level <100 mg/dL was achieved. Bodyweight decreased on average by 0.98±3.90 kg (95% CI 1.19–0.76). Hypoglycemia (blood glucose ≤70 mg/dL) was observed in 29 patients (2.30%), of whom six (0.48%) had nocturnal hypoglycemia and four (0.32%) had documented severe events (blood glucose <56 mg/dL).
The results of this observational study show that insulin glargine, when added to a fixed-dose combination of metformin and a DPP-4 inhibitor, resulted in a significant and clinically relevant improvement of glycemic control. Importantly, this intervention did not interfere with the action of the DPP-4 inhibitors, resulting in neutral effects on weight and low rates of hypoglycemia. We conclude that this treatment intensification approach may be useful, efficient, and safe in daily clinical practice for patients with type 2 diabetes.
PMCID: PMC3833837  PMID: 24259985
diabetes; dipeptidyl dipeptidase-4 inhibitors; metformin; insulin glargine

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