Archive for October, 2016

Supplemental Oxygen Therapy in Patients with COPD and moderate hypoxemia.

The Long-Term Oxygen Treatment Trial Research Group report a randomized clinical trial of long term oxygen therapy in patients with COPD and moderate resting and/or exercise hypoxemia. There was no difference between groups with respect to the primary end-point of time to death or first hospitalization. The editorial is available here.



Long-term treatment with supplemental oxygen has unknown efficacy in patients with stable chronic obstructive pulmonary disease (COPD) and resting or exercise-induced moderate desaturation.


We originally designed the trial to test whether long-term treatment with supplemental oxygen would result in a longer time to death than no use of supplemental oxygen among patients who had stable COPD with moderate resting desaturation (oxyhemoglobin saturation as measured by pulse oximetry [Spo2], 89 to 93%). After 7 months and the randomization
of 34 patients, the trial was redesigned to also include patients who had stable COPD with moderate exercise-induced desaturation (during the 6-minute walk test, Spo2 ≥80% for ≥5 minutes and <90% for ≥10 seconds) and to incorporate the time to the first hospitalization for any cause into the new composite primary outcome. Patients were randomly assigned, in a 1:1 ratio, to receive long-term supplemental oxygen (supplementaloxygen group) or no long-term supplemental oxygen (no-supplemental-oxygen group). In the supplemental-oxygen group, patients with resting desaturation were prescribed 24-hour oxygen, and those with desaturation only during exercise were prescribed oxygen during exercise and sleep. The trial-group assignment was not masked.


A total of 738 patients at 42 centers were followed for 1 to 6 years. In a time-to-event analysis, we found no significant difference between the supplemental-oxygen group and the no-supplemental-oxygen group in the time to death or first hospitalization (hazard ratio, 0.94; 95% confidence interval [CI], 0.79 to 1.12; P = 0.52), nor in the rates of all hospitalizations (rate ratio, 1.01; 95% CI, 0.91 to 1.13), COPD exacerbations (rate ratio, 1.08; 95% CI, 0.98 to 1.19), and COPD-related hospitalizations (rate ratio, 0.99; 95% CI, 0.83 to 1.17). We found no consistent between-group differences in measures of quality of life, lung function, and the distance walked in 6 minutes.


In patients with stable COPD and resting or exercise-induced moderate desaturation, the prescription of long-term supplemental oxygen did not result in a longer time to death or first hospitalization than no long-term supplemental oxygen, nor did it provide sustained benefit with regard to any of the other measured outcomes.




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Calcium and Vitamin D intake and Cardiovascular Effects

Chung et al report an updated systematic review of the cardiovascular effects of calcium intake with or without vitamin D. The authors find no harmful or beneficial effect on for cardiovascular and cerebrovascular disease, mortality, or all-cause mortality for generally health people. The The National Osteoporosis Foundation and
American Society for Preventive Cardiology position statement is available here.




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Brief Primary Care Intervention for Obesity

Aveyard et al report a randomized clinical trial of a brief physician intervention versus control of physician informing patient the benefits of weight loss. The authors found the active intervention was associated with greater meaningful weight loss. This was achieved was similar rates of patient acceptance.



Background Obesity is a common cause of non-communicable disease. Guidelines recommend that physicians screen
and off er brief advice to motivate weight loss through referral to behavioural weight loss programmes. However,
physicians rarely intervene and no trials have been done on the subject. We did this trial to establish whether physician
brief intervention is acceptable and eff ective for reducing bodyweight in patients with obesity.


In this parallel, two-arm, randomised trial, patients who consulted 137 primary care physicians in England
were screened for obesity. Individuals could be enrolled if they were aged at least 18 years, had a body-mass index of at
least 30 kg/m² (or at least 25 kg/m² if of Asian ethnicity) , and had a raised body fat percentage. At the end of the
consultation, the physician randomly assigned participants (1:1) to one of two 30 s interventions. Randomisation was
done via preprepared randomisation cards labelled with a code representing the allocation, which were placed in opaque
sealed envelopes and given to physicians to open at the time of treatment assignment. In the active intervention, the
physician off ered referral to a weight management group (12 sessions of 1 h each, once per week) and, if the referral was accepted, the physician ensured the patient made an appointment and off ered follow-up. In the control intervention, the physician advised the patient that their health would benefi t from weight loss. The primary outcome was weight change at 12 months in the intention-to-treat population, which was assessed blinded to treatment allocation. We also assessed asked patients’ about their feelings on discussing their weight when they have visited their general practitioner for other reasons. Given the nature of the intervention, we did not anticipate any adverse events in the usual sense, so safety outcomes were not assessed. This trial is registered with the ISRCTN Registry, number ISRCTN26563137.


Between June 4, 2013, and Dec 23, 2014, we screened 8403 patients, of whom 2728 (32%) were obese. Of these
obese patients, 2256 (83%) agreed to participate and 1882 were eligible, enrolled, and included in the intention-to-treat
analysis, with 940 individuals in the support group and 942 individuals in the advice group. 722 (77%) individuals
assigned to the support intervention agreed to attend the weight management group and 379 (40%) of these individuals
attended, compared with 82 (9%) participants who were allocated the advice intervention. In the entire study population,
mean weight change at 12 months was 2·43 kg with the support intervention and 1·04 kg with the advice intervention,
giving an adjusted diff erence of 1·43 kg (95% CI 0·89–1·97). The reactions of the patients to the general practitioners’
brief interventions did not diff er signifi cantly between the study groups in terms of appropriateness (adjusted odds
ratio 0·89, 95% CI 0·75–1·07, p=0·21) or helpfulness (1·05, 0·89–1·26, p=0·54); overall, four (<1%) patients thought
their intervention was inappropriate and unhelpful and 1530 (81%) patients thought it was appropriate and helpful.


A behaviourally-informed, very brief, physician-delivered opportunistic intervention is acceptable to
patients and an eff ective way to reduce population mean weight.




Cardiovascular Events with Distance Running

Gerardin et al report on the Paris RACE registry. The authors quantify and determine correlates of case fatality with long distance running events. The authors also present a meta-analysis. Acute myocardial ischemia was the major underlying aetiology identified. However, non-shockable rhythm and non-ischemic heart disease were predictors of case fatality.



Long distance running races are associated with a low risk of life-threatening events much often attributed to hypertrophic  cardiomyopathy. However, retrospective analyses of aetiology lack consistency.

Methods and results

Incidence and aetiology of life-threatening/fatal events were assessed in long distance races in the prospective Registre  des Accidents Cardiaques lors des courses d’Endurance (RACE Paris Registry) from October 2006 to September 2012.
Characteristics of life-threatening/fatal events were analysed by interviewing survivors and reviewing medical records including post-mortem data of each case. Seventeen life-threatening events were identified of 511 880 runners of which two were fatal. The vast majority were cardiovascular events (13/17) occurring in experienced male runners [mean
(+SD) age 43+10 years], with infrequent cardiovascular risk factors, atypical warning symptoms prior to the race or negative treadmill test when performed. Acute myocardial ischaemia was the predominant aetiology (8 of 13) and led to immediate myocardial revascularization. All cases with initial shockable rhythm survived. There was no
difference in event rate according to marathons vs. half-marathons and events were clustered at the end of the race. A meta-analysis of all available studies including the RACE Paris registry (n ¼ 6) demonstrated a low prevalence of life threatening
events (0.75/100 000) and that presentation with non-shockable rhythm [OR ¼ 29.9; 95% CI (4.0–222.5), P ¼ 0.001] or non-ischaemic aetiology [OR ¼ 6.4; 95% CI (1.4–28.8), P ¼ 0.015] were associated with case-fatality.


Life-threatening/fatal events during long distance races are rare, most often unpredictable and mainly due to acute myocardial ischaemia. Presentation with non-shockable rhythm and non-ischaemic aetiology are the major determinant of case fatality.


Pulmonary Embolism and First Syncope Presentation

Prandoni et al report an Italian multi-centre trial of systematic investigation for pulmonary embolism in patients with first presentation of syncope. The prevalence of pulmonary embolism including cases with alternative diagnoses is highlighted.



The prevalence of pulmonary embolism among patients hospitalized for syncope
is not well documented, and current guidelines pay little attention to a diagnostic workup for pulmonary embolism in these patients.


We performed a systematic workup for pulmonary embolism in patients admitted
to 11 hospitals in Italy for a first episode of syncope, regardless of whether there were alternative explanations for the syncope. The diagnosis of pulmonary embolism was ruled out in patients who had a low pretest clinical probability, which was defined according to the Wells score, in combination with a negative d-dimer assay. In all other patients, computed tomographic pulmonary angiography or ventilation–perfusion lung scanning was performed.


A total of 560 patients (mean age, 76 years) were included in the study. A diagnosis of pulmonary embolism was ruled out in 330 of the 560 patients (58.9%) on the basis of the combination of a low pretest clinical probability of pulmonary embolism and negative d-dimer assay. Among the remaining 230 patients, pulmonary embolism was identified in 97 (42.2%). In the entire cohort, the prevalence of pulmonary embolism was 17.3% (95% confidence interval, 14.2 to 20.5). Evidence of an embolus in a main pulmonary or lobar artery or evidence of perfusion defects larger than 25% of the total area of both lungs was found in 61 patients. Pulmonary embolism was identified in 45 of the 355 patients (12.7%) who had an alternative explanation for syncope and in 52 of the 205 patients (25.4%) who did not.


Pulmonary embolism was identified in nearly one of every six patients hospitalized for a first episode of syncope.

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Caffeine Ingestion in Patients with Heart Failure

Zuchinali et al report a randomized double blind placebo controlled trial of short term high dose (500 mg caffeine over 5 hours) in patients with moderate to severe left ventricular systolic dysfunction. The primary end-point was frequency of ventricular premature beats on continuous electrocardiographic monitoring. Caffeine was not associated with an increase in the primary end-point or other measured outcomes.



The presumed proarrhythmic action of caffeine is controversial. Few studies have assessed the effect of high doses of caffeine in patients with heart failure due to left ventricular systolic dysfunction at high risk for ventricular arrhythmias.


To compare the effect of high-dose caffeine or placebo on the frequency of supraventricular and ventricular arrhythmias, both at rest and during a symptom-limited exercise test.


Double-blinded randomized clinical trial with a crossover design conducted at the heart failure and cardiac transplant clinic of a tertiary-care university hospital. The trial included patients with chronic heart failure with
moderate-to-severe systolic dysfunction (left ventricular ejection fraction <45%) and New York Heart Association functional class I to III between March 5, 2013, and October 2, 2015.


Caffeine (100mg) or lactose capsules, in addition to 5 doses of 100 mL decaffeinated coffee at 1-hour intervals, for a total of 500mg of caffeine or placebo during a 5-hour protocol. After a 1-week washout period, the protocol was repeated.
MAIN OUTCOMES AND MEASURES Number and percentage of ventricular and supraventricularpremature beats assessed by continuous electrocardiographic monitoring.


We enrolled 51 patients (37 [74%] male; mean [SD] age, 60.6 [10.9] years) with predominantly moderate-to-severe left ventricular systolic dysfunction (mean [SD] left ventricular ejection fraction, 29% [7%]); 31 [61%] had an implantable cardioverterdefibrillator device. No significant differences between the caffeine and placebo groups were
observed in the number of ventricular (185 vs 239 beats, respectively; P = .47) and supraventricular premature beats (6 vs 6 beats, respectively; P = .44), as well as in couplets, bigeminal cycles, or nonsustained tachycardia during continuous electrocardiographic monitoring. Exercise test–derived variables, such as ventricular and supraventricular
premature beats, duration of exercise, estimated peak oxygen consumption, and heart rate, were not influenced by caffeine ingestion.We observed no increases in ventricular premature beats (91 vs 223 vs 207 beats, respectively) in patients with higher levels of plasma caffeine concentration compared with lower plasma levels (P = .91) or with the placebo group (P = .74).


AND RELEVANCE Acute ingestion of high doses of caffeine did not induce arrhythmias in patients with systolic heart failure and at high risk for ventricular arrhythmias.


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FRISC II 15 Year Follow-up

Professor Wallentin et al report on the 15 year follow-up of the FRISC II study. Sustained benefit in reduction of non-fatal cardiovascular events and a modest mortality benefit were observed. The editorial is available here.



The FRISC-II trial was the first randomised trial to show a reduction in death or myocardial infarction
with an early invasive versus a non-invasive treatment strategy in patients with non-ST-elevation acute coronary
syndrome. Here we provide a remaining lifetime perspective on the effects on all cardiovascular events during
15 years’ follow-up.


The FRISC-II prospective, randomised, multicentre trial was done at 58 Scandinavian centres in Sweden,
Denmark, and Norway. Between June 17, 1996, and Aug 28, 1998, we randomly assigned (1:1) 2457 patients with
non-ST-elevation acute coronary syndrome to an early invasive treatment strategy, aiming for revascularisation within
7 days, or a non-invasive strategy, with invasive procedures at recurrent symptoms or severe exercise-induced
ischaemia. Plasma for biomarker analyses was obtained at randomisation. For long-term outcomes, we linked data
with national health-care registers. The primary endpoint was a composite of death or myocardial infarction.
Outcomes were compared as the average postponement of the next event, including recurrent events, calculated as
the area between mean cumulative count-of-events curves. Analyses were done by intention to treat.


At a minimum of 15 years’ follow-up on Dec 31, 2014, data for survival status and death were available for
2421 (99%) of the initially recruited 2457 patients, and for other events after 2 years for 2182 (89%) patients. During
follow-up, the invasive strategy postponed death or next myocardial infarction by a mean of 549 days (95% CI 204–888;
p=0·0020) compared with the non-invasive strategy. This eff ect was larger in non-smokers (mean gain 809 days,
95% CI 402–1175; pinteraction=0·0182), patients with elevated troponin T (778 days, 357–1165; pinteraction=0·0241), and
patients with high concentrations of growth diff erentiation factor-15 (1356 days, 507–1650; pinteraction=0·0210). The
diff erence was mainly driven by postponement of new myocardial infarction, whereas the early diff erence in mortality
alone was not sustained over time. The invasive strategy led to a mean of 1128 days (95% CI 830–1366) postponement
of death or next readmission to hospital for ischaemic heart disease, which was consistent in all subgroups (p<0·0001).


During 15 years of follow-up, an early invasive treatment strategy postponed the occurrence of death or
next myocardial infarction by an average of 18 months, and the next readmission to hospital for ischaemic heart
disease by 37 months, compared with a non-invasive strategy in patients with non-ST-elevation acute coronary
syndrome. This remaining lifetime perspective supports that an early invasive treatment strategy should be the
preferred option in most patients with non-ST-elevation acute coronary syndrome.


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