Primecuts-This Week in the Journals

September 16, 2015

Oscillometre sphygmometrique 9558.jpgBy: Miguel A. Saldivar

Last week, the National Institutes of Health (NIH), in conjunction with the National Heart, Lung and Blood Institute (NHLBI) announced the premature ending of what is now being dubbed a landmark study: the Systolic Blood Pressure Intervention Trial (SPRINT) [1]. Preliminary results showed that, in adults over the age of 50, a target systolic blood pressure of 120 mm Hg could reduce the risk of cardiovascular events by almost a third and the risk of death by almost a quarter. But as promising as they are, these results are preliminary and were only announced as part of a press release; the full analysis and publication of the data is still pending (including data on potential side effects of aggressive therapy) and no formal recommendations have been issued. Nevertheless, this didn’t stop the media from announcing the preliminary results with enthusiasm, including headlines such as “Federal researchers urge older adults to aim for much lower blood pressure” [2], “Aggressive treatment of high blood pressure pays off for patients, study finds” [3], and “Lower Blood Pressure Guidelines Could Be ‘Lifesaving,’ Federal Study Says” [4]. This serves us as a reminder of the importance of the appropriate use of the available evidence, as well as the importance of gathering all the relevant evidence before drawing potentially practice-changing conclusions. With this in mind, we begin this edition of Primecuts with an article on a trial for a new oral influenza vaccine.

An Oral Tablet Vaccine Against Influenza A H1N1

In Lancet Infectious Diseases, the results of a phase I, randomized, double-blind, placebo controlled, single-site study was published that assessed the safety and efficacy of an influenza A H1N1 vaccine in an oral form [5]. The primary endpoint was the safety of the tablet vaccine, and the secondary endpoint was its immunogenicity. A total of 24 subjects were were enrolled. Twelve of them received the vaccine, while the other 12 received a placebo. Eligibility criteria included an initial hemagglutination inhibition titer of no more than 1:20, age 18-49 years, and “good health”. Exclusion criteria included a history of influenza vaccine in the past two years and H1 influenza positivity by hemagglutination inhibition assay, among many others. Of note, the definition of “good health” was not clarified, but people with certain specific conditions were excluded, including immunodeficiency, HIV positivity, history of chronic alcohol consumption, and many more.

The results were promising: of the 12 participants who received the vaccine, 9 seroconverted and reached seroprotective concentrations, compared to zero in the placebo group. Furthermore, this response was maintained at the 180-day mark, and reported side effects were minimal. It should be noted, however, that the study has certain limitations. Among these is the fact that the number of participants (n=24) is rather small and only included healthy, young people. Furthermore, a discrepancy was noted among the rate of vaccine-recipients who had a significant increase in hemagglutination titer (92%) compared to those who seroconverted to protective levels (~75%), a finding which remained unexplained. Thus, while these initial results appear promising, further research will be needed before the vaccine’s efficacy is confirmed and it becomes available to the public.
Observed patterns in Takotsubo Cardiomyopathy

Although Takotsubo cardiomyopathy is a disease that is recognized worldwide, it remains poorly understood. The New England Journal of Medicine brings us an article that seeks to identify some of its clinical features, assess its clinical course and outcomes, and define its prognostic predictors [6]. The authors established the International Takotsubo Registry at the University Hospital Zurich in collaboration with 25 cardiovascular centers spanning across nine countries. The analysis focuses on two aspects: to identify disease patterns in patients with a diagnosis of takotsubo cardiomyopathy (as defined by the Mayo Clinic diagnostic criteria), and to compare the outcomes of 455 patients with this disease with a second group of age and gender-matched patients with a diagnosis of acute coronary syndrome (ACS). The analysis resulted in several interesting findings. Of 1750 patients with takotsubo cardiomyopathy, nearly 90% were women, and almost 80% were older than 50 years of age. Physical triggers where most common (36%), followed by emotional triggers (27.7%). As compared with patients with ACS, patients with takotsubo had higher rates of pre-existing neuropsychiatric disorders (21.7% compared to13.8% for neurologic disorders, and 36.6% compared to 13.6% for psychiatric disorders).

The article, however, has some limitations, including that the diagnosis of takotsubo, especially in the emergency room, remains challenging. When eligibility of patients for inclusion into the study was uncertain (likely due to an uncertain diagnosis), cases were reviewed by investigators to reach a consensus, creating the potential for biases by including these individuals in the study. It is interesting to note, however, that while previous studies have suggested emotional triggers as causes for takotsubo’s cardiomyopathy, this study demonstrated that physical triggers are actually more commonly the culprit, such as acute respiratory failure, fractures, infection, malignancy, or “other” physical triggers as described in the supplementary appendix of the article.

Information Sharing Preferences among the Elderly

Last week, JAMA Internal Medicine presented the results of a qualitative study that investigated the topic of information-sharing preferences among the elderly and their caregivers [7]. The authors sought to identify how patients 75 years of age or older approach the sharing of their health information with caregivers, and whether “patient portals” (secured websites which provide access to an individual’s health data) may be able to facilitate information sharing. By conducting moderated focus groups, audiotaping/transcribing the sessions and analyzing the contents, the authors were able to identify two main themes surrounding the consequences of sharing information, and regarding the dynamic control of information sharing. For example, patients often expressed their wish to avoid becoming a “burden” to their families and thus preferred retaining control of their health data. In addition, they largely appeared to recognize that, as they aged further, their data would be more likely to be shared with their caregivers. Patients and caregivers appeared to agree that the patient’s autonomy should be retained for as long as possible. The authors concluded that these and other findings could have significant impact on the future design of online patient portals.

Limitations of the study include the fact that the patient population was small (n=30) and that all participants were from the same senior health care organization. This resulted in a very homogeneous population, 87% of the population was female, more than 97% were Caucasian, and more than 75% were at least college-educated. This limits the ability to reliably apply this data to larger, more heterogenous populations.

Pulmonary Embolism Diagnosis in Primary Care

Most (if not all) non-invasive prediction models for the diagnosis of pulmonary embolus have been developed for the inpatient and/or acute setting. With this in mind, the British Medical Journal brings us a systematic review of different prediction models followed by a validation study to assess their transportability to the primary care setting [8]. Ten published models were initially identified. Of these, five were excluded from analysis on the basis of predictors that are not easily obtained in primary care (e.g., arterial blood gas, advanced electrocardiography interpretation, chest x-ray). Five models were deemed to have the highest transportability as follows: the three versions of the Wells Score (original, modified and simplified revised), the revised Geneva model, and the simplified revised Geneva model. The study proceeded to compare diagnostic accuracy measures, with interesting results.

Sensitivity in the three Wells models ranged from 95-96%, and specificity from 49-51%. Sensitivity in the Geneva models ranged from 88-90%, with specificities of 48-53%. Positive predictive values were similar among all five models (range 20-21%), as were negative predictive values (97-99%). Failure rates, however, were higher in the Geneva scores (range 2.7-3.1%, compared to 1.2-1.5% for the Wells scores). Based on these numbers, the authors concluded that the three Wells models appear to be the most reliable for use in primary care.

However, it should be noted that even though at first glance the diagnostic accuracy measures appear to favor the Wells models, there is significant overlap among the reported confidence intervals, which raises the question of whether the Wells models are equally reliable when compared to the studied versions of the Geneva model. Furthermore, the study took place in the Netherlands, a country where primary care doctors function as gatekeepers and are strong drivers of the initial patient-doctor interaction, which may make the results less generalizable to healthcare settings such as that in the U.S., where care is sometimes more heavily driven by subspecialists, E.R. visits, and many other factors.


— An article in Nature raises the question of whether Alzheimer’s disease is a transmissible disease [9].

— The BMJ presents an observational study that compares different quality metrics among physician-owned and non-physician-owned hospitals [10].

— The NEJM presents a review article on the use of cannabinoids in the treatment of epilepsy [11].

— An article in JAMA puts an old tool to the test: assessment of the CHA2DS2-VASc score in predicting stroke, thromboembolism and death in patients with heart failure, with and without the presence of atrial fibrillation [12].

Miguel A. Saldivar, MD is a 3rd year resident at NYU Langone Medical Center

Peer Reviewed by Karin Katz, MD, Associate Editor, Clinical Correlations


1. NIH Press Release: Landmark NIH study shows intensive blood pressure management may save lives. September 11, 2015.
2. Bernstein, L. Federal researchers urge older adults to aim for much lower blood pressure. The Washington Post. September 12, 2015.
3. 11. Kaplan, K. Aggressive treatment of high blood pressure pays off for patients, study finds. Los Angeles Times. September 11, 2015.
4. 12. Kolata, G. The New York Times. September 11, 2015. Lower Blood Pressure Guidelines Could Be ‘Lifesaving,’ Federal Study Says.
5. Liebowitz D, Lindbloom JD, Brandl J, et al. High titre neutralising antibodies to influenza after oral tablet immunisation: a phase 1, randomised, placebo-controlled trial. Lancet Infect Dis. 2015 Sep;15(9):1041-8. doi: 10.1016/S1473-3099(15)00266-2. PMID 26333337.
6. Templin C, Ghadri JR, Diekmann J, et al. Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy. N Engl J Med. 2015 Sep 3;373(10):929-38. doi: 10.1056/NEJMoa1406761. PMID: 26332547.
7. Crotty BH, Walker J, Dierks M, et al. Information Sharing Preferences of Older Patients and Their Families. JAMA Intern Med. 2015;175(9):1492-1497. doi:10.1001/jamainternmed.2015.2903.
8. Hendriksen JM, Geersing GJ, Lucassen WA, et al. Diagnostic prediction models for suspected pulmonary embolism: systematic review and independent external validation in primary care. BMJ. 2015 Sep 8;351:h4438. doi: 10.1136/bmj.h4438.
9. Abbott, A. Autopsies reveal signs of Alzheimer’s in growth-hormone patients. Nature 525, 165–166, (10 September 2015). doi:10.1038/525165a.
10. Blumenthal, DM, Orav, EJ, Jena AB, et al. Access, quality, and costs of care at physician owned hospitals in the United States: observational study. BMJ 2015;351:h4466.
11. Friedman, D, Devinsky, O. Cannabinoids in the Treatment of Epilepsy. N Engl J Med 2015; 373:1048-1058. September 10, 2015DOI: 10.1056/NEJMra1407304.
12. Melgaard L, Gorst-Rasmussen A, Lane DA, et al. Assessment of the CHA2DS2-VASc Score in Predicting Ischemic Stroke, Thromboembolism, and Death in Patients With Heart Failure With and Without Atrial Fibrillation. JAMA. 2015;314(10):1030-1038. doi:10.1001/jama.2015.10725.