Friday, February 15, 2019

Limitations of clinical trials with surrogate endpoints


Background Surrogate endpoint trials test strategies more efficiently but are accompanied by uncertainty about the relationship between changes in surrogate markers and clinical outcomes.

Methods and Results We identified cardiovascular trials with primary surrogate endpoints published in the New England Journal of Medicine, Lancet, and JAMA: Journal of the American Medical Association from 1990 to 2011 and determined the trends in publication of surrogate endpoint trials and the success of the trials in meeting their primary endpoints. We tracked for publication of clinical outcome trials on the interventions tested in surrogate trials. We screened 3016 articles and identified 220 surrogate endpoint trials. From the total of 220 surrogate trials, 157 (71.4%) were positive for their primary endpoint. Only 59 (26.8%) surrogate trials had a subsequent clinical outcomes trial. Among these 59 trials, 24 outcomes trial results validated the positive surrogates, whereas 20 subsequent outcome trials were negative following positive results on a surrogate. We identified only 3 examples in which the surrogate trial was negative but a subsequent outcomes trial was conducted and showed benefit. Findings were consistent in a sample cohort of 383 screened articles inclusive of 37 surrogate endpoint trials from 6 other high‐impact journals.

Conclusions Although cardiovascular surrogate outcomes trials frequently show superiority of the tested intervention, they are infrequently followed by a prominent outcomes trial. When there was a high‐profile clinical outcomes study, nearly half of the positive surrogate trials were not validated. Cardiovascular surrogate outcome trials may be more appropriate for excluding benefit from the patient perspective than for identifying it.

Thursday, February 14, 2019

A prediction tool for early recognition of spinal epidural abscess

Psychological benefits of a single exercise session

Systematic review here.

Smart Mat technology can detect diabetic foot ulcers a month in advance

From a report in Diabetes Care. There were a lot of false positives.

Wednesday, February 13, 2019

The yield of sputum cultures in hospital acquired pneumonia

Despite the fact that the new guidelines advocate for sputum cultures, the yield was low:

The clinical predictors of positive sputum culture have not been previously reported in hospital-acquired pneumonia (HAP), and data on yield of sputum culture in this setting are scant. Current Infectious Disease Society of America guidelines for HAP recommend noninvasive sputum sampling, though the data for this practice are limited. We assessed the yield of sputum culture in HAP cases at an academic medical center from January 2007 to July 2013. HAP cases were identified by International Classification of Diseases, Ninth Revision-Clinical Modification codes for bacterial pneumonia and all cases were validated by chart review. Our cohort had 1172 hospitalizations with a HAP diagnosis. At least 1 sputum specimen was collected noninvasively and sent for bacterial culture after hospital day 2 and within 7 days of HAP diagnosis in 344 of these hospitalizations (29.4%), with a total of 478 sputum specimens, yielding 63 (13.2%) positive, 109 (22.8%) negative, and 306 (64.0%) contaminated cultures..

Spontaneous bacterial peritonitis

Severe carisoprodol withdrawal

Monday, February 11, 2019

Stool PCR panels

The stool PCR panel can detect a wide variety of pathogens. Here is some info from Mayo Clinic Labs with algorithms for appropriate use.

Saturday, February 09, 2019

Spinal epidural abscess and diagnostic errors



With this study, we set out to identify missed opportunities in diagnosis of spinal epidural abscesses to outline areas for process improvement.


Using a large national clinical data repository, we identified all patients with a new diagnosis of spinal epidural abscess in the Department of Veterans Affairs (VA) during 2013. Two physicians independently conducted retrospective chart reviews on 250 randomly selected patients and evaluated their records for red flags (eg, unexplained weight loss, neurological deficits, and fever) 90 days prior to diagnosis. Diagnostic errors were defined as missed opportunities to evaluate red flags in a timely or appropriate manner. Reviewers gathered information about process breakdowns related to patient factors, the patient–provider encounter, test performance and interpretation, test follow-up and tracking, and the referral process. Reviewers also determined harm and time lag between red flags and definitive diagnoses.


Of 250 patients, 119 had a new diagnosis of spinal epidural abscess, 66 (55.5%) of which experienced diagnostic error. Median time to diagnosis in error cases was 12 days, compared with 4 days in cases without error (P less than .01). Red flags that were frequently not evaluated in error cases included unexplained fever (n = 57; 86.4%), focal neurological deficits with progressive or disabling symptoms (n = 54; 81.8%), and active infection (n = 54; 81.8%). Most errors involved breakdowns during the patient–provider encounter (n = 60; 90.1%), including failures in information gathering/integration, and were associated with temporary harm (n = 43; 65.2%).


Despite wide availability of clinical data, errors in diagnosis of spinal epidural abscesses are common and involve inadequate history, physical examination, and test ordering. Solutions should include renewed attention to basic clinical skills.

If the patient’s using a smart phone on rounds they may be close to discharge

File this one under “tell me something I don’t already know.”

Sleep apnea update

This topic was reviewed in JACC. The full text is only available to subscribers but the audio summary is open access.

Here are a few points of interest:

Obstructive sleep apnea (OSA) is common in the general population.

Central sleep apnea (CSA) is largely confined to patients who already have cardiovascular disease, largely heart failure. It is particularly associated with heart failure with reduced ejection fraction. It is also associated with stroke and atrial fibrillation.

OSA is a cause of multiple cardiovascular disorders. CSA, though a result of certain cardiovascular disorders, can in turn contribute to further cardiovascular dysfunction, resulting in a vicious cycle of reciprocal cause and effect.

Although OSA is largely a disorder of obesity, in which fatty deposits in the upper airway are contributory, 20-30% of OSA is in non-obese individuals. In such cases upper airway dilator muscle dysfunction is believed to be at play.

Among the many consequences of sleep apnea are the metabolic effects of hypoxemia, increased sympathetic output, cytokine activation, endothelial dysfunction, insulin resistance, systemic and pulmonary hypertension and atrial fibrillation.

Friday, February 08, 2019

Fighting C diff: the case for gastric acid suppressant stewardship

Postural tachycardia syndrome (POTS), inappropriate sinus tachycardia (IST) and vasovagal syncope (VVS)

Regional thrombolysis with adjunctive mechanical interventions and post thrombotic syndrome



The post-thrombotic syndrome frequently develops in patients with proximal deep-vein thrombosis despite treatment with anticoagulant therapy. Pharmacomechanical catheter-directed thrombolysis (hereafter "pharmacomechanical thrombolysis") rapidly removes thrombus and is hypothesized to reduce the risk of the post-thrombotic syndrome.


We randomly assigned 692 patients with acute proximal deep-vein thrombosis to receive either anticoagulation alone (control group) or anticoagulation plus pharmacomechanical thrombolysis (catheter-mediated or device-mediated intrathrombus delivery of recombinant tissue plasminogen activator and thrombus aspiration or maceration, with or without stenting). The primary outcome was development of the post-thrombotic syndrome between 6 and 24 months of follow-up.


Between 6 and 24 months, there was no significant between-group difference in the percentage of patients with the post-thrombotic syndrome (47% in the pharmacomechanical-thrombolysis group and 48% in the control group; risk ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.11; P=0.56). Pharmacomechanical thrombolysis led to more major bleeding events within 10 days (1.7% vs. 0.3% of patients, P=0.049), but no significant difference in recurrent venous thromboembolism was seen over the 24-month follow-up period (12% in the pharmacomechanical-thrombolysis group and 8% in the control group, P=0.09). Moderate-to-severe post-thrombotic syndrome occurred in 18% of patients in the pharmacomechanical-thrombolysis group versus 24% of those in the control group (risk ratio, 0.73; 95% CI, 0.54 to 0.98; P=0.04). Severity scores for the post-thrombotic syndrome were lower in the pharmacomechanical-thrombolysis group than in the control group at 6, 12, 18, and 24 months of follow-up (P less than 0.01 for the comparison of the Villalta scores at each time point), but the improvement in quality of life from baseline to 24 months did not differ significantly between the treatment groups.


Among patients with acute proximal deep-vein thrombosis, the addition of pharmacomechanical catheter-directed thrombolysis to anticoagulation did not result in a lower risk of the post-thrombotic syndrome but did result in a higher risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute and others; ATTRACT number, NCT00790335 .).

The conclusion sentence is simplistic. You were equally likely to get ANY degree of post-thrombotic syndrome no matter what treatment you got. But moderate to severe post-thrombotic syndrome was less likely with intervention. Quality of life was equal across the board but that’s going to differ from one patient to another and becomes a matter of preference and value.

First, second and third generation cephalosporins cause delirium while cefepime and quinolones do not. Really?