Blood Pressure and Hypertension in Adults Permanently Living at High Altitude: A Systematic Review and Meta-Analysis.

Aryal, Nirmal, Mark Weatherall, Yadav Kumar Deo Bhatta, and Stewart Mann. Blood pressure and hypertension in adults permanently living at high altitude: a systematic review and meta-analysis. High Alt Med Biol. 17:185-193, 2016.-The objective of this study was to estimate the associations between altitude and mean blood pressure (BP) (or prevalence of hypertension [HT]) in adults who live permanently at high altitude. A literature search was conducted in December 2014 using PubMed, Scopus, and OvidSP (MedLine and EMBASE) databases to identify relevant observational studies. Inclusion criteria were reports of studies in populations permanently living at an altitude of ≥2400 m and in those 18 years or older. Meta-regression was used to estimate the association between average BP and HT and altitude. We identified 3375 articles and inclusion criteria were met for 21 reports, which included a total of 40,854 participants. Random-effects meta-regression estimated that for every 1000 m elevation the average systolic BP (SBP) (95% confidence interval [CI]) increased by 17 mmHg (0.2 to 33.8), p = 0.05 and diastolic BP (DBP) by 9.5 mmHg (0.6 to 18.4), p = 0.04 in participants with Tibetan origin. By contrast, in participants with non-Tibetan origin, average SBP decreased by 5.9 mmHg (-19.1 to 7.3), p = 0.38 and DBP by 4 mmHg (-13 to 5), p = 0.38. The odds ratios (95% CI) for the proportion of participants with HT per 1000 m increment in the altitude were 2.01 (0.37 to 11.02), p = 0.446 and 4.05 (0.07 to 244.69), p = 0.489 for Tibetan and non-Tibetan participants, respectively. Sensitivity analysis excluding two studies with older participants (≥60 years) reversed the direction of this effect in non-Tibetans with odds ratio (95% CI) of 0.10 (0.004 to 2.22) per 1000 m, p = 0.143. Overall, this review suggests weak association between BP and altitude in Tibetan origin populations

Current trends in the cardiovascular clinical trial arena (I)

The existence of effective therapies for most cardiovascular disease states, coupled with increased requirements that potential benefits of new drugs be evaluated on clinical rather than surrogate endpoints, makes it increasingly difficult to substantiate any incremental improvements in efficacy that these new drugs might offer. Compounding the problem is the highly controversial issue of comparing new agents with placebos rather than active pharmaceuticals in drug efficacy trials. Despite the recent consensus that placebos may be used ethically in well-defined, justifiable circumstances, the problem persists, in part because of increased scrutiny by ethics committees but also because of considerable lingering disagreement regarding the propriety and scientific value of placebo-controlled trials (and trials of antihypertensive drugs in particular). The disagreement also substantially affects the most viable alternative to placebo-controlled trials: actively controlled equivalence/noninferiority trials. To a great extent, this situation was prompted by numerous previous trials of this type that were marked by fundamental methodological flaws and consequent false claims, inconsistencies, and potential harm to patients. As the development and use of generic drugs continue to escalate, along with concurrent pressure to control medical costs by substituting less-expensive therapies for established ones, any claim that a new drug, intervention, or therapy is "equivalent" to another should not be accepted without close scrutiny. Adherence to proper methods in conducting studies of equivalence will help investigators to avoid false claims and inconsistencies. These matters will be addressed in the third article of this three-part series

Primary care management for optimized antithrombotic treatment [PICANT]: study protocol for a cluster-randomized controlled trial

Background: Antithrombotic treatment is a continuous therapy that is often performed in general practice and requires careful safety management. The aim of this study is to investigate whether a best practice model that applies major elements of case management, including patient education, can improve antithrombotic management in primary health care in terms of reducing major thromboembolic and bleeding events. Methods: This 24-month cluster-randomized trial will be performed in 690 adult patients from 46 practices. The trial intervention will be a complex intervention involving general practitioners, health care assistants and patients with an indication for oral anticoagulation. To assess adherence to medication and symptoms in patients, as well as to detect complications early, health care assistants will be trained in case management and will use the Coagulation-Monitoring-List (Co-MoL) to regularly monitor patients. Patients will receive information (leaflets and a video), treatment monitoring via the Co-MoL and be motivated to perform self-management. Patients in the control group will continue to receive treatment-as-usual from their general practitioners. The primary endpoint is the combined endpoint of all thromboembolic events requiring hospitalization, and all major bleeding complications. Secondary endpoints are mortality, hospitalization, strokes, major bleeding and thromboembolic complications, severe treatment interactions, the number of adverse events, quality of anticoagulation, health-related quality of life and costs. Further secondary objectives will be investigated to explain the mechanism by which the intervention is effective: patients' assessment of chronic illness care, self-reported adherence to medication, general practitioners' and health care assistants' knowledge, patients' knowledge and satisfaction with shared decision making. Practice recruitment is expected to take place between July and December 2012. Recruitment of eligible patients will start in July 2012. Assessment will occur at three time points: baseline (T0), follow-up after 12 (T1) and after 24 months (T2). Discussion: The efficacy and effectiveness of individual elements of the intervention, such as antithrombotic interventions, self-management concepts in orally anticoagulated patients and the methodological tool, case-management, have already been extensively demonstrated. This project foresees the combination of several proven instruments, as a result of which we expect to profit from a reduction in the major complications associated with antithrombotic treatment

Elevated Ratio of Urinary Metabolites of Thromboxane and Prostacyclin Is Associated with Adverse Cardiovascular Events in ADAPT

Results from prevention trials, including the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT), have fueled discussion about the cardiovascular (CV) risks associated with non-steroidal anti-inflammatory drugs (NSAIDs). We tested the hypotheses that (i) adverse CV events reported among ADAPT participants (aged 70 years and older) are associated with increased ratio of urine 11-dehydrothromboxane B2 (Tx-M) to 2′3-donor–6-keto-PGF1 (PGI-M) attributable to NSAID treatments; (ii) coincident use of aspirin (ASA) would attenuate NSAID-induced changes in Tx-M/PGI-M ratio; and (iii) use of NSAIDs and/or ASA would not alter urine or plasma concentrations of F2-isoprostanes (IsoPs), in vivo biomarkers of free radical damage. We quantified urine Tx-M and PGI-M, and urine and plasma F2-IsoPs from 315 ADAPT participants using stable isotope dilution assays with gas chromatography/mass spectrometry, and analyzed these data by randomized drug assignment and self-report compliance as well as ASA use. Adverse CV events were significantly associated with higher urine Tx-M/PGI-M ratio, which seemed to derive mainly from lowered PGI-M. Participants taking ASA alone had reduced urine Tx-M/PGI-M compared to no ASA or NSAID; however, participants taking NSAIDs plus ASA did not have reduced urine Tx-M/PGI-M ratio compared to NSAIDs alone. Neither NSAID nor ASA use altered plasma or urine F2-IsoPs. These data suggest a possible mechanism for the increased risk of CV events reported in ADAPT participants assigned to NSAIDs, and suggest that the changes in the Tx-M/PGI-M ratio was not substantively mitigated by coincident use of ASA in individuals 70 years or older

How to use implantable loop recorders in clinical trials and hybrid therapy

Epidemiological studies show that atrial fibrillation (AF) is associated with a doubling of mortality, even after adjustment for confounders. AF can be asymptomatic, but this does not decrease the thromboembolic risk of the patient. Office ECGs, occasional 24-h Holter recordings and long-term ECG event recording might not be sensitive and accurate enough in patients with AF, especially in those with paroxysmal episodes. In one study, 7 days of continuous monitoring with event recorders detected paroxysmal AF in 20 of 65 patients with a previous negative 24-h Holter recording. Over the last decade, enormous improvements have been made in the technology of implantable devices, which can now store significant information regarding heart rhythm. The first subcutaneous implantable monitor (Reveal XT, Medtronic) was validated for continuous AF monitoring by the XPECT study. The dedicated AF detection algorithm uses irregularity and incoherence of R–R intervals to identify and classify patterns in ventricular conduction. Its sensitivity in identifying patients with AF is >96%. Numerous clinical data from continuous monitoring of AF have recently been published. The first applications of this technology have been in the field of surgical and catheter AF ablation. With regard to cryptogenic stroke, an international randomized trial is ongoing to compare standard care with standard care plus the implantable cardiac monitor for AF detection in patients discharged with the diagnosis of cryptogenic stroke: the Crystal AF trial. Continuous AF monitoring provides an optimal picture of daily AF burden, both symptomatic and asymptomatic. Implantable cardiac monitors have high sensitivity, enable better assessment of therapy success and may guide further AF therapy

Nut consumption and risk of atrial fibrillation in the Physicians' Health Study

<p>Abstract</p> <p>Background</p> <p>Atrial Fibrillation is highly prevalent in clinical practice affecting approximately 2.3 million people in USA and 4.5 million people in European Union. The aim of the study was to examine the association between nut consumption and incident atrial fibrillation.</p> <p>Methods</p> <p>Prospective cohort of 21,054 male participants of Physicians' Health Study I. Nut consumption was estimated using food frequency questionnaire and incident atrial fibrillation was ascertained through yearly follow-up questionnaires. Cox regression was used to estimate relative risks of atrial fibrillation.</p> <p>Results</p> <p>The average age was 54.6 ± 9.5 years (40.7-87.1). During a mean follow up of 20 years (median 24 years), 3,317 cases of atrial fibrillation occurred. The crude incidence rate was 7.6, 7.4, 8.2, 7.9, and 6.8 cases/1000 person-years for people reporting nut consumption of rarely/never, 1-3/month, 1/per week, 2-6/week, and ≥ 7/week, respectively. Multivariable adjusted hazard ratios (95% CI) for incident atrial fibrillation were 1.00 (ref), 1.00 (0.90-1.11), 1.09 (0.97-1.21), 1.07 (0.95-1.21), and 0.91 (0.70-1.17) for nut consumption from the lowest to the highest category of nut consumption (p for trend 0.26). No statistically significant association between nut consumption and atrial fibrillation was found when stratified by body mass index (BMI < 25 vs ≥ 25 kg/m²) or age (< 65 vs. ≥ 65 years).</p> <p>Conclusions</p> <p>Our data did not show an association between nut consumption and incident atrial fibrillation among US male physicians.</p

Carotid intimal-media thickness as a surrogate for cardiovascular disease events in trials of HMG-CoA reductase inhibitors

BACKGROUND: Surrogate measures for cardiovascular disease events have the potential to increase greatly the efficiency of clinical trials. A leading candidate for such a surrogate is the progression of intima-media thickness (IMT) of the carotid artery; much experience has been gained with this endpoint in trials of HMG-CoA reductase inhibitors (statins). METHODS AND RESULTS: We examine two separate systems of criteria that have been proposed to define surrogate endpoints, based on clinical and statistical arguments. We use published results and a formal meta-analysis to evaluate whether progression of carotid IMT meets these criteria for HMG-CoA reductase inhibitors (statins). IMT meets clinical-based criteria to serve as a surrogate endpoint for cardiovascular events in statin trials, based on relative efficiency, linkage to endpoints, and congruency of effects. Results from a meta-analysis and post-trial follow-up from a single published study suggest that IMT meets established statistical criteria by accounting for intervention effects in regression models. CONCLUSION: Carotid IMT progression meets accepted definitions of a surrogate for cardiovascular disease endpoints in statin trials. This does not, however, establish that it may serve universally as a surrogate marker in trials of other agents

Predicting clinically unrecognized coronary artery disease: use of two- dimensional echocardiography

<p>Abstract</p> <p>Background</p> <p>2-D Echo is often performed in patients without history of coronary artery disease (CAD). We sought to determine echo features predictive of CAD.</p> <p>Methods</p> <p>2-D Echo of 328 patients without known CAD performed within one year prior to stress myocardial SPECT and angiography were reviewed. Echo features examined were left ventricular and atrial enlargement, LV hypertrophy, wall motion abnormality (WMA), LV ejection fraction (EF) < 50%, mitral annular calcification (MAC) and aortic sclerosis/stenosis (AS). High risk myocardial perfusion abnormality (MPA) was defined as >15% LV perfusion defect or multivessel distribution. Severe coronary artery stenosis (CAS) was defined as left main, 3 VD or 2VD involving proximal LAD.</p> <p>Results</p> <p>The mean age was 62 ± 13 years, 59% men, 29% diabetic (DM) and 148 (45%) had > 2 risk factors. Pharmacologic stress was performed in 109 patients (33%). MPA was present in 200 pts (60%) of which, 137 were high risk. CAS was present in 166 pts (51%), 75 were severe. Of 87 patients with WMA, 83% had MPA and 78% had CAS. Multivariate analysis identified age >65, male, inability to exercise, DM, WMA, MAC and AS as independent predictors of MPA and CAS. Independent predictors of high risk MPA and severe CAS were age, DM, inability to exercise and WMA.</p> <p>2-D echo findings offered incremental value over clinical information in predicting CAD by angiography. (Chi square: 360 vs. 320 p = 0.02).</p> <p>Conclusion</p> <p>2-D Echo was valuable in predicting presence of physiological and anatomical CAD in addition to clinical information.</p

Carotid plaque regression following 6-month statin therapy assessed by 3T cardiovascular magnetic resonance: comparison with ultrasound intima media thickness

<p>Abstract</p> <p>Background</p> <p>Cardiovascular magnetic resonance (CMR) allows volumetric carotid plaque measurement that has advantage over 2-dimensional ultrasound (US) intima-media thickness (IMT) in evaluating treatment response. We tested the hypothesis that 6-month statin treatment in patients with carotid plaque will lead to plaque regression when measured by 3 Tesla CMR but not by IMT.</p> <p>Methods</p> <p>Twenty-six subjects (67 ± 2 years, 7 females) with known carotid plaque (> 1.1 mm) and coronary or cerebrovascular atherosclerotic disease underwent 3T CMR (T1, T2, proton density and time of flight sequences) and US at baseline and following 6 months of statin therapy (6 had initiation, 7 had increase and 13 had maintenance of statin dosing). CMR plaque volume (PV) was measured in the region 12 mm below and up to 12 mm above carotid flow divider using software. Mean posterior IMT in the same region was measured. Baseline and 6-month CMR PV and US IMT were compared. Change in lipid rich/necrotic core (LR/NC) and calcification plaque components from CMR were related to change in PV.</p> <p>Results</p> <p>Low-density lipoprotein cholesterol decreased (86 ± 6 to 74 ± 4 mg/dL, p = 0.046). CMR PV decreased 5.8 ± 2% (1036 ± 59 to 976 ± 65 mm³, p = 0.018). Mean IMT was unchanged (1.12 ± 0.06 vs. 1.14 ± 0.06 mm, p = NS). Patients with initiation or increase of statins had -8.8 ± 2.8% PV change (p = 0.001) while patients with maintenance of statin dosing had -2.7 ± 3% change in PV (p = NS). There was circumferential heterogeneity in CMR plaque thickness with greatest thickness in the posterior carotid artery, in the region opposite the flow divider. Similarly there was circumferential regional difference in <it>change </it>of plaque thickness with significant plaque regression in the anterior carotid region in region of the flow divider. Change in LR/NC (R = 0.62, p = 0.006) and calcification (R = 0.45, p = 0.03) correlated with PV change.</p> <p>Conclusions</p> <p>Six month statin therapy in patients with carotid plaque led to reduced plaque volume by 3T CMR, but ultrasound posterior IMT did not show any change. The heterogeneous spatial distribution of plaque and regional differences in magnitude of plaque regression may explain the difference in findings and support volumetric measurement of plaque. 3T CMR has potential advantage over ultrasound IMT to assess treatment response in individuals and may allow reduced sample size, duration and cost of clinical trials of plaque regression.</p