Primecuts – This Week in the Journals

April 18, 2019

By Kevin P. Eaton, 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. 


Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy [1]

Type 2 diabetes is a leading cause of end-stage renal disease, and renin-angiotensin blockers are currently the main treatment for renoprotection.[2] Inhibitors of sodium-glucose cotransporter 2 (SGLT2) are a newer class of diabetic medications with recent secondary trial outcomes showing a possible improvement in renal outcomes.[3] No prior study has directly assessed the effect of SGLT2 inhibitors on renal function in patients with type 2 diabetes.

This randomized, double-blind, placebo-controlled trial included adult patients with type 2 diabetes, no worse than CKD stage 3B (GFR 30-44 mL/min), and albuminuria, already on an ACE inhibitor or angiotensin receptor blocker. A total of 4401 patients were randomized to receive either canagliflozin or placebo with a median follow-up of 2.62 years for the primary outcomes of end-stage renal disease, a sustained doubling of serum creatinine level, or death from a renal or cardiovascular cause. An intention-to-treat analysis found the event rate of the primary outcome was 30% lower in the canagliflozin group than in the placebo group (43.2 and 61.2 per 1000 patient years, respectively; hazard ratio, 0.70; 95% CI 0.59 to 0.82; p=0.00001). These effects were also consistent across each component of the primary composite outcome and not primarily driven by just one. The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, and stroke, which were secondary outcomes (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; p=0.01).

The trial was stopped early as the necessary number of primary outcome events was achieved. This certainly could have limited the power of secondary outcomes as well as potential long term adverse events. However, overall, for patients with type 2 diabetes with kidney disease, canagliflozin was found to lower the risk of renal failure (NNT of 22). Additionally, both groups had similar rates of amputation, which had previously been a noted and feared side effect. It will be interesting to await similar trial data on renal outcomes for the other SGLT2 inhibitors. Until then, many providers will likely remain hesitant to prescribe these medications given their current cost and known side effects, but this new data does help build more confidence. 

Trends in Readmissions and Length of Stay for Patients Hospitalized with Heart Failure in Canada and the United States [4] 

In October 2012, the Hospital Readmissions Reduction Program (HRRP) was implemented and included payment penalties for US hospitals with excessive readmission rates for heart failure (HF), myocardial infarction, and pneumonia.[5] Recent studies have found varying results on how this program has affected length of stay (LOS) and readmission rates for HF.[6,7] This cohort study examined the trends in LOS and readmission rates for HF in the US and in Canada, a country where no similar program exists.

The study included an analysis of adult patients discharged alive after a hospitalization for HF with data from both Canadian and US hospitals between April 1, 2005, and December 31, 2015. The outcomes were LOS and all-cause and HF-specific 30-day readmission rates. Wilcoxon rank sum tests and chi-squared analyses found that the mean LOS slightly decreased in Canada but did not change in the US over the time period. Both all-cause and HF-specific readmission rates decreased in both countries. An interrupted time-series analysis found no change in the slope between readmission rates in either country at the time of HRRP implementation. In Canada, the rate of all-cause readmissions was decreasing by 1.1% prior to implementation and 1.3% afterwards (P=0.84 for slope change). In the US, the rate was decreasing by 1.6% before and 1.8% after (P=0.60 for slope change).

This study provides the first analysis of the effects of the HRRP implementation in the US while using a different country as an external control. It is important to note, however, that the announcement of the HRRP program came in April 2010, two years before its implementation. The announcement month leading up to the time of implementation perhaps would have been an even more informative time period to analyze as most US hospital systems made system-wide changes in preparation. Regardless, this data is compelling in its suggestion that perhaps the HRRP has had less of an effect on 30-day all-cause readmission rates for HF. If that’s the case, perhaps the appropriateness of HF readmission rates as a payment penalty needs to be reconsidered. Certainly, if future studies continue to support similar findings, more effective targets for payment penalties will need to be defined.

Association of HIV Preexposure Prophylaxis with Incidence of Sexually Transmitted Infections Among Individuals at High Risk of HIV Infection [8]

The use of preexposure prophylaxis (PrEP) decreases the acquisition rate of HIV among gay and bisexual men.[9] However, the initiation of PrEP raises the concern for behavioral changes that could potentially lead to an increased rate of bacterial sexually transmitted infections (STIs) among this high-risk population.[10] This study evaluates the STI incidence as well as the changes in incidence after PrEP initiation among 2981 gay or bisexual participants who had been previously enrolled in the PrEP Expanded Study, a multicenter population intervention study in Australia.

Unadjusted and adjusted incidence rate ratios (IRR) for STI incidence from 1 year pre-enrollment to the mean study follow up of 1.1 years were calculated. The unadjusted incidence of STIs increased from a pre-enrollment rate of 69.5 per 100 person-years to 98.4 per 100 person-years during follow-up (IRR, 1.41; 95% CI, 1.29-1.56). When adjusted for the increased frequency of quarterly STI testing as part of the PrEP Expanded Study protocol, the increase in STI incidence remained significant but the magnitude decreased (adjusted IRR, 1.12; 95% CI, 1.02-1.23). However, detecting asymptomatic infections from an increased frequency of testing does not fully account for the increased STI incidence after PrEP initiation because the adjusted IRR was still significant.

There was no control group that did not receive PrEP for this study. Therefore, no causal relationship can be inferred for the increased STI incidence seen among the participants initiating PrEP for the first time. At the very least, these findings further emphasize the importance of frequent STI testing as well as counseling in this population. At most, they can help narrow the subset of patients that need to be followed more closely.

Assessment of Inpatient Time Allocation Among First-Year Internal Medicine Residents Using Time-Motion Observations [11] 

The training environment for internal medicine residents has changed over the last decade with the near universal implementation of electronic medical records. Prior recent studies have found that first-year residents (interns) now spend far less time with patients than trainees before them.[12] This study helps to describe how interns divide their time while working on inpatient medicine services. The data was collected from the iCOMPARE trial, which was a cluster-randomized trial comparing duty-hour policies.[13]

This study was a direct observational secondary analysis of interns from 6 different US university-affiliated internal medicine programs in the mid-Atlantic with a total of 194 weekday shifts observed with time motion data collected throughout daytime, nighttime, and call shifts. Mean time spent in direct and indirect patient care, education, handoffs, as well as time spent multitasking was reported. A mean of 15.9 (SD 0.7) hours was spent in indirect patient care. Only a mean of 3.0 (SD 0.1) hours was spent in direct patient care. Most of the indirect patient care time was allocated for documentation or interaction with the medical record. Direct patient care and education was most often done while multitasking with indirect patient care tasks.

Interns in internal medicine spend the majority of their time in indirect patient care rather than with patients or in educational activities. While these results might be more generalizable than prior studies, they still only reflect the distribution of time for one medical specialty and only in mid-Atlantic training programs. Additionally, the ideal educational landscape for medical residents is debatable. At the very least, this study provides a baseline for the current time allocation of interns on inpatient medicine services. And since this baseline appears overwhelmed by the requirements of documentation and the burdens of the medical record, perhaps redesigning provider workflow and shifting some of the burden of documentation away from residents needs to be considered in the future.


Association of Positive Airway Pressure Prescription with Mortality in Patients with Obesity and Severe Obstructive Sleep Apnea [14] 

Obstructive sleep apnea (OSA) is a treatable cardiovascular risk factor. This multicenter cohort study enrolled patients with obesity and severe OSA with a mean follow-up of 11.1 years comparing those with and without prescription positive airway pressure (PAP) therapy. All-cause mortality was decreased in those with PAP therapy with the mortality benefit appearing 6-7 years after initiation of therapy. 

Randomized Trial of Verubecestat for Prodromal Alzheimer’s Disease [15]

During the initial phases of development, there was much excitement around Merck’s new Alzheimer’s medication, Verubecestat, which is an inhibitor that blocks amyloid-beta production. Last year, trial data found the drug failed to prevent clinical progression of mild-moderate Alzheimer’s dementia and now has failed to improve clinical ratings of dementia among patients with even early signs of Alzheimer’s disease.[16]

Recurrent Stroke with Rivaroxaban Compared with Aspirin According to Predictors of Atrial Fibrillation [17] 

The group of patients with embolic strokes of undetermined source have not been found to benefit from rivaroxaban over aspirin.[18] Ultimately, a third of patients with this diagnosis are eventually diagnosed with atrial fibrillation after long-term cardiac monitoring.[19] This study has found that a subset of patients with embolic stroke plus other predictors of atrial fibrillation (left atrial diameter, frequent premature atrial contractions, and HAVOC score) do have a decreased risk of recurrent stroke with rivaroxaban than with aspirin therapy.

Effect of Vitamin D Supplementation on Relapse-Free Survival Among Patients with Digestive Tract Cancers [20] 

No prior studies have evaluated the use of vitamin D to improve survival in patients already diagnosed with digestive tract cancers. This was a double-blind, placebo-controlled trial of 417 patients with the primary outcome of relapse-free survival, which was ultimately found not to be improved at 5 years. 

Dr. Kevin Eaton is a Hospitalist at NYU Langone Health. 

Peer reviewed by Neil Shapiro, MD, Editor-in-Chief, Clinical Correlations.

Image courtesy of Wikimedia Commons


[1] Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. NEJM. Published online April 14, 2019. doi:10.1056/NEJMoa1811744. Available at:

[2] Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. NEJM. 2001; 345:851-60. Available at:

[3] Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS program randomized clinical trials. Lancet Diabetes Endocrinology. 2018;6:691-704. Available at:

[4] Samsky MD, Ambrosy AP, Youngson E, et al. Trends in readmissions and length of stay for patients hospitalized with heart failure in Canada and the United States. JAMA Cardiology. Published online April 10, 2019. doi:10.1001/jamacardio.2019.0766. Available at:

[5] McIlvennan CK, Eapen ZJ, Allen LA. Hospital Readmissions Reduction Program. Circulation. 2015;131(20);1796-1803. Available at:

[6] Eapen ZJ, Reed SD, Li Y, et al. Do countries or hospitals with longer hospital stays for acute heart failure have lower readmission rates? Findings from ASCEND-HF. Circ Heart Fail. 2013;6(4):727-32. Available at:

[7] Khan H, Greene SJ, Fonarow GC, et al. Length of hospital stay and 30-day readmission following heart failure hospitalization: Insights from EVEREST trail. Eur J Heart Fail. 2015;17(10):1022-31. Available at:

[8] Traeger MW, Cornelisse VJ, Asselin J, et al. Association of HIV preexposure prophylaxis with incidence of sexually transmitted infections among individuals at high risk of HIV infection. JAMA. Published online April 9, 2019.  doi:10.1001/jama.2019.2947. Available at:

[9] Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. NEJM. 2010;363(27):2587-99. Available at:

[10] Blumenthal J, Haubrich RH. Will risk compensation accompany pre-exposure prophylaxis for HIV? Virtual Mentor. 2014;16(11):909-15. Available at:

[11] Chaiyachati KH, Shea JA, Asch DA, et al. Assessment of inpatient time allocation among first-year Internal Medicine residents using time-motion observations. JAMA Intern Med. Published online April 15, 2019. doi:10.1001/jamainternmed.2019.0095. Available at:

[12] Guarisco S, Oddone E, Simel D. Time analysis of a general medicine service: Results from a random work sampling study. J Gen Intern Med. 1994:9(5):272-7. Available at:

[13] Desai SV, Asch DA, Bellini LM, et al. Education outcomes in a duty-hour flexibility trial in Internal Medicine. NEJM. 2018;378:1494-1508. Available at:

[14] Lisan Q, Van Sloten T, Marques Vidal P, Haba Rubio J, Heinzer R, Empana JP. Association of positive airway pressure prescription with mortality in patients with obesity and severe obstructive sleep apnea: The Sleep Heart Health Study. JAMA Otolaryngol Head Neck Surg. Published online April 11, 2019. doi:10.1001/jamaoto.2019.0281. Available at:

[15] Egan MF, Kost J, Voss T, et al. Randomized trial of Verubecestat for prodromal Alzheimer’s disease. NEJM. 2019;380:1408-20. doi:10.1056/NEJMoa1812840. Available at:

[16] Egan MF, Kost J, Tariot PN, et al. Randomized trial of Verubecestat for mild-to-moderate Alzheimer’s disease. NEJM. 2018;378:1691-1703. Available at:

[17] Healey JS, Gladstone DJ, Swaminathan B, et al. Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: Secondary analysis of the NAVIGATE ESUS randomized clinical trial. JAMA Neurol. Published online April 08, 2019. doi:10.1001/jamaneurol.2019.0617. Available at:

[18] Kasner SE, Lavados P, Sharma M, et al. Characterization of patients with embolic strokes of undetermined source in NAVIGATE ESUS randomized trial. J Stroke Cerebrovasc Dis. 2018;27(6):1673-1682. Available at:

[19] Gladstone DJ, Spring M, Dorian P, et al. Atrial fibrillation in patients with cryptogenic stroke. NEJM. 2014;370(26):2467-2477. Available at:

[20] Urashima M, Ohdaira H, Akutsu T, et al. Effect of Vitamin D supplementation on relapse-free survival among patients with digestive tract cancers: The AMATERASU Randomized Clinical Trial. JAMA.2019;321(14):1361–1369. doi:10.1001/jama.2019.2210. Available at: