By Michael Lee, MD
Faculty Peer Reviewed
In 2013, the state of New York mandated healthcare workers who do not receive influenza vaccination to wear surgical masks in healthcare settings. This historically unprecedented regulation is in part a response to the high influenza-associated morbidity and mortality witnessed during the 2012-2013 flu season, causing more than a thousand hospitalizations and five pediatric deaths in New York state alone. Although it has faced its fair share of oppositions from the healthcare workers, this new state-wide initiatiive symbolizes perhaps the most important of the four moral conducts in medicine: primum non nocere, or “first, do no harm” [1].
On a related note, JAMA this week published a meta-analysis exploring the potential cardiovascular benefit of flu vaccine in high-risk patients [2]. Historically, upper respiratory tract infections, including the flu, have been recognized as non-traditional, independent risk factors of adverse cardiovascular events, such as acute coronary syndrome (ACS). Whether flu vaccination lowers the rate of cardiovascular events, however, is unclear. Investigators of this meta-analysis identified six randomized controlled trials, which compared the effect on reducing adverse cardiovascular outcomes of standard flu vaccines against no intervention or placebo. Included studies met the selection criteria of a sample size of 50 or more participants and a followup duration of 28 days to 1 year. The subjects of these selected trials had a mean age of 67 years, 36.2% of whom had a cardiac history, and they were followed for average of 7.9 months. Two of the six trials were high quality studies demonstrating all three of the following characteristics: methods of randomization, concealment of allocation and blinding of participants, investigators and outcome assessors. One of the six trials was unpublished, and it was excluded from the primary analysis, which involved a total of 6369 subjects. The I2 statistic index measuring heterogeneity of the individual studies was a low value of 28%, denoting high consistency among the five trials.
Administration of flu vaccine was associated with a statistically significant reduction in the rate of the primary end point, defined as a composite of cardiovascular death or hospitalization for myocardial infarction, unstable angina, stroke, heart failure or urgent coronary revascularization (2.9% vs. 4.7%; Risk Ratio 0.64 [95% CI, 0.48-0.86], P=0.003, I2 = 28%). This result translates into an absolute risk reduction of 1.74%; 58 flu vaccine administrations will prevent one major cardiovascular event in this population (NNT = 58). Secondary analyses suggest the cardio-protective role of flu vaccination seen in this meta-analysis was largely driven by a subgroup of higher-risk participants who had experienced ACS within the previous one year. These findings support the current guidelines of many medical associations recommending flu vaccination to patients with cardiovascular comorbidities.
Also published in JAMA this week was a trial examining the role of risk-reduction counseling at the time of rapid HIV tests in lowering the rate of subsequent contraction of sexually transmitted infections (STIs) [3]. This parallel-group randomized controlled trial studied 5012 participants, who sought care at sexually transmitted disease clinics in the Unites States. They were block randomized into the counseling arm or the information-only arm with stratification by study site, ethnicity and gender and partner gender in order to avoid confounding variables. Participants in both arms underwent tests for STIs, including the rapid HIV-1/2 serologic testing from finger-stick blood samples, at the time of study enrollment then again after six months. Before the baseline tests were obtained at enrollment, subjects who were randomized to the counseling arm also received individualized risk-reduction counseling for a median duration of 28 minutes, followed by establishment of realistic plans to reduce the rate of future STI acquisition. Examples of topics discussed during the counseling sessions include unprotected sexual intercourse with multiple partners and sexual activity in the context of substance use. The primary outcome of this study was cumulative STI incidence during the six months of followup, and the six-month retention rate of the originally randomized participants was 86.9%. Intention-to-treat analysis revealed no significant difference in 6-month composite STI incidence between the two groups (adjusted risk ratio, 1.12; 95% CI, 0.94-1.33). The average cost per participant in the counseling group was $56, substantially greater than $23 per person in the information-only group. Interestingly, a secondary analysis on men participants who have sex with men noted an increase in STI incidence with the implementation of counseling. As stated by the author of the study, risk-reduction counseling in the setting of rapid HIV testing does not appear to be the most efficient use of limited healthcare resources.
The New England Journal of Medicine published a multicenter randomized controlled trial examining the effect of manual coronary thrombus aspiration in patients undergoing percutaneous coronary interventions for ST-segment elevation myocardial infarction [4]. A previous randomized controlled trial demonstrated improved myocardial reperfusion with thrombus aspiration, but its effect on mortality has been unknown [5]. There also existed some concern for an increased rate of neurologic complications, including stroke. This open-label trial randomized 7244 patients with ST-segment elevation myocardial infarctions, who had previous coronary angiograms and were to undergo either rescue or primary percutaneous coronary intervention. They were recruited through a pre-existing Swedish and Icelandic national registry and an additional participating coronary intervention center in Denmark. Patients on the thrombus aspiration arm received manual aspirations followed by percutaneous coronary interventions while those on the control arm only received conventional percutaneous coronary interventions. The use of intracoronary nitrates and stent placements were left to the discretion of individual physicians. The primary outcome was 30-day all-cause mortality, and no participant was lost to followup. Intention-to-treat analysis revealed no significant difference in 30-day mortality between the two groups (HR with thrombus aspiration, 0.94; 95% CI, 0.72 – 1.22; P=0.63). None of the secondary outcomes achieved statistical significance. Thrombus aspiration was not associated with higher rates of adverse outcomes, including rehospitalization due to reinfarction and neurologic complications including stroke. It is interesting to note that in this trial the median time from symptom onset to intervention was more than three hours, which is considerably longer than the currently used standard of 90 minutes. Whether a longer followup duration is required to detect mortality benefit of thrombus aspiration remains to be studied.
A recent issue of JAMA Internal Medicine features a double-blind randomized controlled trial examining the effect of vitamin D3 supplementation in improving isolated systolic hypertension in the elderly [6]. Many of the conventional antihypertensive medications are not well tolerated in the aged population, and previous studies have noted, albeit inconsistently, an association between low 25-hydroxyvitamin D levels and cardiovascular diseases including hypertension. This trial examined the potential blood pressure-lowering effect of cholecalciferol in elderly Caucasian men. The 159 participants had an average age of 76.8 years and isolated systolic hypertension with a mean baseline blood pressure of 163/78 mmHg. They were taking two antihypertensive medications on average at the time of study enrollment, including beta-blockers, calcium channel blockers, diuretics, angiotensin converting enzyme inhibitors and angiotensin receptor blockers. Those in the intervention arm received 100,000 units of oral cholecalciferol every three months for one year, and the subjects in the control arm received placebo at equivalent intervals. Despite the increase in the average 25-hydroxyvitamin D level by 8 ng/mL in the treatment group at one year, cholecalciferol supplementation did not lead to a significant reduction in blood pressure. Using a modified intention-to-treat analysis, the study’s primary outcome showed no difference in supine systolic blood pressure between the two groups after three months (-0.7 mmHg, 95% CI -5.2 to 3.8 mmHg, P= 0.76). Furthermore no treatment effect was seen at the six-month, nine-month and one-year marks in either supine office blood pressure or 24-hour daytime blood pressure measurements.
Read below for more interesting articles from this week:
The New England Journal of Medicine published two original articles on the recent nation-wide outbreak of injectable methylprednisolone fungal contamination [7, 8]. The main culprit of this outbreak was the fungus species, Exserohilum rostratum. Both studies described the clinical disease spectrum and presented epidemiologic data on reported cases of outbreak-associated fungal infection, including fungal meningitis. Of note, the importance of established, real-time epidemiological surveillance was highlighted by the authors.
The British Medical Journal features a simulation study, which calculates the cardiovascular benefit expected to result from a 20% increase in tax on palm oil in India [9]. The study speculates that a tax increase of this magnitude on palm oil will prevent as many as 421,000 deaths over next twenty years due to replacement of palm oil with other types of oil rich in polyunsaturated fat.
Annals of Internal Medicine published a phase 3 randomized controlled trial looking at the effect of extracorporeal liver assistance on the six-month mortality of 102 patients with acute liver failure [10]. Albumin dialysis conferred no mortality benefit in this study, possibly due to the short median delay of 16.2 hours between randomization and liver transplantation.
Dr. Michael Lee is a 1st year resident at NYU Langone Medical Center
Peer reviewed by Arnab Ghosh, MD, 3rd year resident at NYU Langone Medical Center
Image courtesy of Wikimedia Commons
References
1. Caplan et al. Managing the Human Toll Caused by Seasonal Influenza: New York State’s Mandate to Vaccinate or Mask. JAMA. Epub 2013 Oct 1. http://jama.jamanetwork.com/article.aspx?articleid=1746248
2. Udell et al. Association between Influenza Vaccination and Cardiovascular Outcomes in High-Risk Patients: A Meta-Analysis. JAMA. 2013;310(16):1711-1720. http://jama.jamanetwork.com/article.aspx?articleid=1758749
3. Metsch et al. Effect of Risk-Reduction Counseling with Rapid HIV Testing on Risk of Acquiring Sexually Transmitted Infections: The AWARE Randomized Clinical Trial. JAMA. 2013;310(16):1701-1710. http://jama.jamanetwork.com/article.aspx?articleid=1758751
4. Fröbert et al. Thrombus Aspiration during ST-Segment Elevation Myocardial Infarction. N Engl J Med. 2013; 369:1587-1597. http://www.nejm.org/doi/full/10.1056/NEJMoa1308789
5. Svilaas et al. Thrombus Aspiration during Primary Percutaneous Coronary Intervention. N Engl J Med. 2008; 358:557-567. http://www.nejm.org/doi/full/10.1056/NEJMoa0706416
6. Witham et al. Cholecalciferol Treatment to Reduce Blood Pressure in Older Patients With Isolated Systolic Hypertension: The VitDISH Randomized Controlled Trial. JAMA Intern Med. 2013;173(18):1672-1679. http://archinte.jamanetwork.com/article.aspx?articleid=1754360
7. Smith et al. Fungal Infections Associated with Contaminated Methylprednisolone Injections. N Engl J Med. 2013; 369:1598-1609. http://www.nejm.org/doi/full/10.1056/NEJMoa1213978
8. Chiller et al. Clinical Findings for Fungal Infections Caused by Methylprednisolone Injections. N Engl J Med. 2013; 369:1610-1619. http://www.nejm.org/doi/full/10.1056/NEJMoa1304879
9. Basu et al. Palm Oil Taxes and Cardiovascular Disease Mortality in India: Economic-Epidemiologic Model. BMJ. 2013;347:f6048. http://dx.doi.org/10.1136/bmj.f6048
10. Saliba et al. Albumin Dialysis With a Noncell Artificial Liver Support Device in Patients with Acute Liver Failure: A Randomized, Controlled Trial. Ann Intern Med. 2013;159(8): 522-531. http://annals.org/article.aspx?articleid=1748843