Primecuts – This Week in the Journals

February 5, 2019

By Roisin Finan MD

Peer Reviewed

With medicine advancing at such a rapid pace, it is crucial for physicians to keep up with the medical literature.  This can quickly become an overwhelming endeavor given the sheer quantity and breadth of literature released on a daily basis. Primecuts helps you stay current by taking a shallow dive into recently released articles that should be on your radar. Our goal is for you to slow down and take a few small sips from the medical literature firehose.

Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes (DECLARE-TIMI) [1]

The DECLARE-TIMI trial was a randomized double-blind controlled trial that sought to investigate cardiovascular (CV) and renal outcomes in patients taking Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2 inhibitor). The study population included patients with type 2 diabetes (with HgbA1c 6.5% – 12%, and CrCl > 60 ml/min) and either established atherosclerotic CV disease (ischemic heart disease, cerebrovascular disease or peripheral artery disease) or multiple risk factors for atherosclerotic CV disease (based on age, gender, blood pressure, lipids, tobacco, among others). Participants received either Dapagliflozin 10mg daily or placebo, with the two primary outcomes measured being MACE, and a composite of CV death or hospitalization for heart failure.

Over 17,000 participants were randomized and followed for a median of 4.2 years. The use of Dapagliflozin was associated with a lower rate of hospitalization for heart failure (HR 0.73; 95% CI 0.60-0.88); however, there was no difference between groups in regards to CV death (HR 0.98; 95% CI 0.82-1.17) or MACE (HR 0.93; 95% CI 0.84-1.03). Dapagliflozin was also superior to placebo for the renal composite endpoint (HR 0.53; 95% CI 0.43-0.66). Of note, diabetic ketoacidosis and genital infections occurred at significantly higher rates in the Dapagliflozin group.

Prior studies have suggested favorable CV outcomes with the use of SGLT2 inhibitors [2, 3]. This study differed in that it included participants both with established CV disease and a risk for CV disease. Overall, SGLT2 inhibitors appear to have a place in the treatment of diabetics and in the prevention of adverse CV outcomes, specifically regarding hospitalization for heart failure. In practice, these benefits must be weighed with the increased risk of DKA and infection in a vulnerable population.

Influenza Vaccine in Heart Failure. Cumulative Number of Vaccinations, Frequency, Timing, and Survival: A Danish Nationwide Cohort Study. [4]

Using the Danish National Patient Registry, this retrospective cohort study investigated the association between the influenza vaccine and long-term survival in heart failure patients. Patients in the database over age 18 with a new diagnosis of heart failure between 2003 and 2015 were included in the study for a total of 134,048 participants. The only exclusion criterion was death within 30 days of heart failure diagnosis. The primary endpoints were all-cause death and cardiovascular death. Of note, there were differences in the baseline characteristics between those receiving at least one influenza vaccine and those receiving no influenza vaccine. The vaccine group had more males, had more medical comorbidities (cardiac and other), and took more prescribed medications.

In adjusted analysis, there was a significant reduction in all-cause death (HR 0.82; 95% CI 0.81-0.84) and cardiovascular death (HR 0.82; 95% CI 0.81-0.84) in the group receiving at least one influenza vaccine after being diagnosed with heart failure. The risk reduction was higher with more frequent vaccines (ie. yearly). In unadjusted analysis, the vaccine group had higher mortality rates, possibly due to that population being sicker at baseline.

Given that heart failure patients inherently have decreased cardiac reserve and decreased ability to compensate during times of stress, such as infection, it is critical for providers to be proactive in preventing adverse events from occurring. Encouraging administration of the flu vaccine yearly to heart failure patients appears to be a beneficial move based on this data. There is currently a clinical trial (INVESTED) investigating this question that will hopefully provide higher quality, randomized data.

A Randomized Trial of E-Cigarettes versus Nicotine-Replacement Therapy [5]

In an effort to compare the effect on tobacco cessation between e-cigarettes to nicotine replacement therapy (NRT), this UK based group designed a randomized, non-blinded, clinical trial with close to 900 participants. Current tobacco users that wished to quit smoking, but did not have a strong preference between quit mechanism were included in the trial. Participants were excluded if they were using either e-cigarettes or NRT already, or if they were pregnant or breast-feeding. Participants were given either a 3-month supply of NRT (any type) or a re-fillable e-cigarette starter pack. Additionally, both groups received behavioral therapy sessions.

The primary outcome was 1-year sustained abstinence, which occurred at a rate of 18% in the e-cigarette group and 9.9% in the NRT group (RR 1.83; 95% CI 1.3-2.58), with a NNT of 12. Among those who remained abstinent at 1 year, 80% of the e-cigarette group was still using e-cigarettes, whereas 9% of the NRT group was still using NRT. Additionally, participants subjectively rated e-cigarettes as a more satisfying method of abstinence and reported fewer withdrawal symptoms of irritability, restlessness etc. during the first week.

On the surface, this study provides encouraging data for the use of e-cigarettes with smoking cessation compared to NRT, which in prior RCT had not been the case [6]. However, prior to incorporating the use of e-cigarettes into standard practice, more data on their long-term effects is needed to ensure that any risk of continued use of e-cigarettes outweighs the benefit of tobacco cessation.

Oral versus Intravenous Antibiotics for Bone and Joint infection (OVIVA) [7]

Traditionally, patients with complex bone and joint infections, such as osteomyelitis or prosthetic joint infections have required long courses of intravenous (IV) antibiotics, which come with its own list of risks and burdens to a patient [8]. This randomized, controlled, non-inferiority trial aimed to compare outcomes in bone and joint infections with traditional IV antibiotics versus oral antibiotics. Enrolled patients had either osteomyelitis or joint infection (native or prosthetic joint) that would have ordinarily been treated with at least 6 weeks of IV antibiotics (based on an attending’s opinion). Antibiotic regimens were left to the discretion of the provider team. The primary outcome was definitive treatment failure within 1 year.

Approximately 900 patients were analyzed in the study, with definitive treatment failure occurring in 14.6% of the IV group and 13.2% of the oral group. The risk margin between therapies met the pre-defined non-inferiority criteria for the study. Additionally, there were no significant differences between groups regarding c. difficile infection or number of adverse events noted. The oral group notably had a shorter hospital course and fewer catheter associated complications.

While antibiotic regimens will continue to be a highly individualized decision based on infection type, isolated organism and local resistant patterns, this study suggests that we can consider oral courses to be non-inferior to IV courses. This will be particularly relevant to patients for which home IV infusions are not possible, as an oral regimen could rid the need to remain in the hospital or be transferred to a subacute rehab center.


Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis [9]

This is a randomized, non-inferiority, controlled trial that compares typical practice IV antibiotics to IV antibiotics for 10 days followed by an oral course, in patients with left sided endocarditis. Non-inferiority to standard treatment was met by the partial oral treatment group, with the primary outcome looking at a composite of mortality, unplanned surgery, embolic events or bacteremia.

Open-Label Randomized Trial Comparing Oral Anticoagulation With and Without Single Antiplatelet Therapy in Patients With Atrial Fibrillation and Stable Coronary Artery Disease Beyond 1 Year After Coronary Stent [10]

This study looked at patients with stable CAD and atrial fibrillation one year after last cardiac stent placement, and investigated if anticoagulation alone was non-inferior to anticoagulation with an antiplatelet in terms of death, MI and stroke. After 2.5 years, non-inferiority was not met by the anticoagulation alone group; however, the study was underpowered due to premature enrollment termination (due to slow enrollment), and further studies are needed.

Effect of Supplemental Oxygen on Blood Pressure in Obstructive Sleep Apnea (SOX) [11]

This randomized, double-blinded, crossover trial tried to distinguish whether the intermittent hypoxia or the recurrent arousals associated with OSA was the cause of elevated blood pressure often seen in patients with OSA. Based on positive blood pressure responses to supplemental O2 – that had no effect on number of arousals – the trial suggests that OSA associated hypoxia is linked to HTN.

Dr. Roisin Finan is an internal medicine specialist at NYU Langone Health

Peer reviewed by David Kudlowitz, MD, Internal Medicine, NYU Langone Health

Image courtesy of Wikimedia Commons


[1] Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019; 380:347-57. DOI: 10.1056/NEJMoa1812389.

[2] Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015; 373:2117-2128. DOI:10.1056 /NEJMoa1504720. https://www-nejm

[3] Neal B, Perkovic V, Mahaffev KW et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017; 377:644-757. DOI: 10.1056/NEJMoa1611925.

[4] Modin D, Jorgenses ME, Gislason G, et al. Influenza Vaccine in Heart Failure. Cumulative Number of Vaccinations, Frequency, Timing, and Survival: A Danish Nationwide Cohort Study. Circulation. 2019; 139:575-586. DOI: 10.1161/CIRCULATIONAHA.118.036788.

[5] Hajek P, Phillips-Waller A, Przulj D, et al. A Randomized Trial of E-Cigarettes versus Nicotine-Replacement Therapy. N Engl J Med. 2019. Jan 30 Online before print. DOI: 10.1056/NEJMoa1808779. https://www-nejm

[6] Bullen C, Howe C, Laugesen M, et al. Electronic Cigarettes for Smoking Cessation: a Randomised Controlled Trial. Lancet. 2013; 382: 1629-1637.

[7] Li H-K, Rombach I, Zambellas R, et al. Oral versus Intravenous Antibiotics for Bone and Joint Infection. N Engl J Med. 2019; 380:425-36. DOI: 10.1056/NEJMoa1710926.

[8] Lew DP, Waldvogel FA. Osteomyelitis. Lancet 2004;364:369-79.

[9] Iversen K, Ihlemann N, Gill S, et al. Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis. N Engl J Med. 2019; 380: 415-24. DOI: 10.1056/NEJMoa1808312.

[10] Matsmura-Nakano Y, Shizuta S, Komasa A, et al. Open-Label Randomized Trial Comparing Oral Anticoagulation With and Without Single Antiplatelet Therapy in Patients With Atrial Fibrillation and Stable Coronary Artery Disease Beyond 1 Year After Coronary Stent Implantation. Circulation. 2019;139:604–616. DOI: 10.1161/CIRCULATIONAHA.118.036768.

[11] Turnbull C, Sen D, Kohler M, Petousi N, and Stradling J. Effect of Supplemental Oxygen on Blood Pressure in Obstructive Sleep Apnea. Am J Respir Crit Care Med. 2019; 199:211-19. DOI: 10.1164/rccm.201802-0240OC.