Primecuts – This Week In The Journals

April 14, 2014

By Arnab Ghosh, MD

Peer Reviewed

With the awakening of Spring this week, the City basks in its new growth. Wandering the streets and avenues, the parks and riversides, they resemble the concord of the natural elements, whisking the bleeding cold away for another year. Punctuated by the dance of Spring showers, the vigour of the Sun’s warmth is empowering, embracing and enhancing. And so the troubles of faraway places, in Crimea, Syria, the Central African Republic, of terrible actions befalling our world, like climate change, move a little further away. Such is the joy in the season of renewal.

And as Spring arrives, the influenza season dissipates. In this light, this week’s Primecuts starts with controversy over the benefits and harms of oseltamivir (Tamiflu). Using a unique method of analysing clinical study reports (i.e. unpublished exhaustive clinical summaries of randomised controlled trials of drugs, as opposed to published trials, submitted to regulatory authorities), authors published this week in the British Journal of Medicine a systematic review of such clinical study reports of oseltamivir made available by Roche [1].

In a first in known medical literature, the authors developed a new methodology of systematic review with clinical study reports up to 900 pages. In stages, authors assessed the reports for appropriate study design, and thereafter assessed reports for their completeness, and internal and external consistency. Studies included were randomised controlled trials, either testing treatment, prophylaxis or post-exposure prophylaxis of healthy adults and children, excluding immunodeficient individuals (malignancy and HIV).

In all, 83 trials were analysed in the systematic review, with 20 included in the final meta-analysis. Of note, the study showed that in treatment of adults, oseltamivir reduced time to alleviation of symptoms of influenza to 16.7 hrs (95% confidence interval [CI] 8.4-25.1 hrs, p < 0.001). There were no differences in rates of admission to the hospital between treatment groups (relative risk [RR] 0.92, 95% CI, 0.57-1.50, I2=0). Notably however, there was a statistically significant reduction in symptomatic influenza in prophylaxis trials (RR 0.45, 95% CI 0.3-0.67, I2=0).

Interestingly, given the use of clinical study data for regulatory bodies, harms were also studied. Oseltamivir was associated with an increased risk of nausea, vomiting, and a decreased risk of diarrhoea in treatment studies; while in prophylactic studies it was associated with increased risk of headaches, psychiatric adverse events (RR 1.8, 95% CI 1.05-3.08, I2 = 0%, number-needed-to-harm [NNH] 94) and renal events.

In a first published, independent analysis of drug data, a clearer picture of the effects of common medications develops. Inherent publication bias combined with the subtle effects of pharmaceutical advertisement diminish the truth about the efficacy and harms of our commonly used medications.

The use of spironolactone in systolic heart failure is well studied, with clear mortality benefits. However its use in patients with heart failure with preserved or near normal ejection fraction is not well established. Results from the ‘Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist’ (TOPCAT) trial was published in this week’s New England Journal of Medicine in an attempt to answer this question [2].

Using a double blinded randomised study design, 3445 patients with symptomatic heart failure, with an ejection fraction of 45% or more received spironolactone (15mg or 45mg) or placebo. The primary outcome measured was a composite of cardiovascular causes, aborted cardiac arrest or hospitalisation for the management of heart failure. Participants were followed for 3.3 years.

Analysed according to an intention-to-treat protocol, the primary outcome occurred in 18.6% of the spironolactone group versus 20.4% in the placebo group (hazard ratio [HR] 0.89; 95% CI 0.77-1.04, p = 0.14). In a subgroup analysis of the composite primary outcome, only hospitalisation from heart failure was statistically significant in the spironolactone group compared to the placebo group (HR 0.83; 95% CI, 0.69-0.99, p=0.04), with neither deaths nor hospitalisations for any reason reduced compared to placebo. Interestingly, there was no significant difference in adverse events (defined as a serum creatinine of 3mg per deciliter or higher, or dialysis). And so while spironolactone appears to have considerable usage for our patients with heart failure and depressed ejection fraction, this well designed study suggests a lack of benefit for those with preserved ejection fractions.

In other news, with the release of new guidelines for lipid and blood pressure management recently released, more evidence has come to the fore regarding the effect of these guidelines on the population management of these conditions.

Published last week in JAMA, authors used the National Health and Nutrition Exmaination Survey (NHANES) data between 2005-2010 and the new guidelines provided by the 8th Joint National Committee guidelines to estimate the proportion of US adults affected [3].

The study used descriptive techniques weighted for the sampling techniques, and examining the proportion of adults requiring to be medicated with antihypertensives. In total, 16,732 participants were studied. Using JNC 8 guidelines, patients between the ages of 18-59 years with treatment-eligible hypertension were 19.2% (95% CI, 18.1%-20.4%) compared with the 20.3% (95% CI, 19.1%-21.4%) for JNC7 guidelines. These differences were more appreciated for those patients over the age of 60 years. Compared to JNC 7, 20.4% (95% CI, 18.8% – 22.0%) of adult population over the age of 60 years were now at goal using the JNC 8 guidelines. These findings are in concordance with the general relaxation of the blood pressure guidelines related to JNC 8.

A similar study was published this week in the New England Journal of Medicine, which examined the effects of the 2013 American College of Cardiology/American Heart Association (ACC-AHA) guidelines for treatment of cholesterol. Authored by the same group, the study employed a similar methodology as described above [4].

Compared to the Third Adult Treatment Panel (ATP III) guidelines, those adults eligible for statin therapy increased from 43.2 million (37.5%) to 56 million (48.6%), with the majority of increases according for those without cardiovascular disease. Most of this increase would be driven by adults aged between 60-75 years, with the increase in men in this age range being eligible for statin treatment from 30.4% to 87.4%, and for women 21.2 to 53.6%. In contrast to the new blood pressure guidelines, the 2013 ACA-AHA guidelines increase their sensitivity for future cardiovascular events, particularly in the older generation, while decreasing the specificity. Only further realtime data about how these guidelines are uptaken by the physician community will help answer the question of whether doctors feel this is a worthy change.

A quick review of the literature:

1. Comparing the use of albumin to crystalloid in septic shock in an open label, multicenter trial, it appears that albumin compared to crystalloid does not change mortality at either 28 days (RR 1, 95% 0.87-1.14, p = 0.94) nor 90 days (RR 0.94; 95% CI, 0.85-1.05,p=0.29) for patients in septic shock [5].

2. A meta-analysis of data suggesting vegetarianism is related to lower blood pressure was undertaken using 7 clinical trials and 32 observational studies. Of 311 participants, consumption of vegetarian diets was associated with lower mean systolic blood pressure (approximately 4.8mmHg; 95% CI,-6.6 to -3.1; p < 0.001, I2 = 0) [6].

Dr. Arnab Ghosh is a contributing Editor, Clinical Correlations

Dr. Matthew Vorsanger is an associate editor, Clinical Correlations

Image Courtesy of wikimedia Commons


1. Jefferson et al. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014;348:g2545.

2. Pitt et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014 Apr 10;370(15):1383-92.

3. Navar-Boggan et al. Proportion of US adults potentially affected by the 2014 hypertension guideline. JAMA. 2014 Apr 9;311(14):1424-9.

4. Pencina et al. Application of new cholesterol guidelines to a population-based sample. N Engl J Med. 2014 Apr 10;370(15):1422-31.

5. Caironi et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014 Apr 10;370(15):1412-21.

6. Yokoyama Y, Nishimura K, Barnard ND, Takegami M, Watanabe M, Sekikawa A,Okamura T, Miyamoto Y. Vegetarian Diets and Blood Pressure: A Meta-analysis. JAMA Intern Med. 2014 Apr 1;174(4):577-87.