Primecuts – This Week In The Journals

July 7, 2015

us womens soccer winBy Rina Mauricio, MD

Peer Reviewed

This past week saw the coming and going of one of the most significant and dreaded days of the year, at least within the healthcare system. July 1 signals a transition point in medical training, whether that be from student to intern, intern to resident, or resident to fellow/attending. This time last year a new class of interns bonded over the excitement of starting residency while trying to savor their last few days of summer. They soon after learned to field overnight calls, round with their teams, teach the medical students, and manage complicated patients. As they weathered this process together, frustrations were vented during happy hours and friendships grew and evolved. Now a new class of interns is standing on deck ready to begin residency with that same mixture of excitement, nervousness and fear, while others ready themselves to complete their training and move beyond residency. As we all embark upon the next step, let’s see what was in this week’s journals.

Can ezetimibe added to statin therapy reduce mortality?

The efficacy of statin therapy in decreasing the number of cardiovascular events in patients with and without cardiovascular disease is well established. However the effect on morbidity and mortality of simultaneous statin and nonstatin therapy has yet to be demonstrated.

The IMPROVE-IT investigators compared statin monotherapy and statin plus ezetimibe therapy in a double-blind, randomized controlled trial to determine any potential cardiovascular benefits. The trial enrolled over 18,000 patients with proven recent ACS whose LDL levels were already within recommendations for those with known coronary disease. Patients were followed for a median of 6 years and primary end points were a composite of death from cardiovascular disease, major coronary events, or nonfatal stroke. The authors found a 24% further reduction in LDL levels in the simvastatin-ezetimibe group compared to the simvastatin monotherapy group (p <0.001). At seven years follow-up, Kaplan-Meier event rates for the primary end points were 32.7% in the simvastatin-ezetimibe group and 34.7% in the simvastatin monotherapy group (HR 0.936, p=0.016) with the curves starting to separate after 1 year. This was driven by a decrease in risk of MI (HR 0.87, p=0.002) and ischemic stroke (HR 0.79, p=0.008). There was a higher risk of hemorrhagic stroke (HR 1.38) in the simvastatin-ezetimibe group but this was non-significant (p=0.11). There was no significant difference between the two groups with regards to rate of adverse events.

These results suggest that in patients presenting with ACS, even if their LDL levels are within guidelines, the addition of ezetimibe will have a beneficial effect on morbidity and mortality. Interestingly, patients who were on simvastatin 80mg, rosuvastatin 20mg, or atorvastatin 40mg were excluded, however patients with known CAD are often on these higher dose statins. The exclusion of these patients limits the applicability of these results to our most high-risk patients with CAD.

Can permissive underfeeding benefit critically-ill patients?

The PermiT Trial Group conducted an unblinded, pragmatic, randomized control trial in Saudi Arabia and Canada to evaluate the effect of permissive underfeeding (defined as 40-60% of calculated caloric requirements) versus standard enteral feeding (70-100% of calculated caloric requirements) in ICU patients, while keeping protein intake the same.

The trial enrolled 894 critically-ill patients to either the permissive underfeeding or standard enteral feeding arm. Patients were treated accordingly for 14 days or until discharge from the ICU, initiation of oral feeding, death, or withdrawal of nutrition as part of palliation. The primary outcome was 90-day all cause mortality. The study authors found no difference in 90-day mortality between the two groups (RR 0.95, p=0.58), as well as no difference between ICU mortality, in-hospital mortality, and 28- or 180-day mortality.

Though the overall results of the study were negative, the findings do call into question the role of standard enteral feeding in critically-ill patients. While the intention of this study was not to demonstrate non-inferiority of permissive underfeeding, it does suggest that higher caloric requirements will not have a beneficial effect on mortality. The study was powered to detect an ARR of 8 percentage points in 90-day mortality, suggesting that a smaller effect on 90-day mortality may have been missed. Furthermore, given the fixed duration of intervention, it is not known if permissive underfeeding for longer than 14 days would have an effect of mortality. This will require further investigation.

Is there a new, readily effective way to reverse dabigatran?

The novel anticoagulants are increasingly being favored over warfarin. However, their use has been limited by the lack of reversal agents. In RE-VERSE AD, investigators are conducting a prospective cohort study to determine the safety of idarucizumab (an antibody to dabigatran) and its ability to reverse the drug in patients with serious bleeding or who require an urgent procedure. This trial published its preliminary results from the first 90 patients enrolled.

Enrolled patients were divided into those with overt, uncontrollable, life-threatening bleeding and those requiring surgery or other invasive procedures that could not be delayed at least 8 hours. Both groups received 5mg of idarucizumab, and the primary end point was the maximum percentage reversal of dabigatran. Idarucizumab completely reversed the anticoagulant effect of dabigatran in 88-98% of patients with elevated clotting times at baseline within minutes. Only 1 of the 90 patients had a thrombotic event in the subsequent 72 hours. Interestingly, the plasma levels of dabigatran, which were undetectable immediately after idarucizumab infusion, were again detected 12 hours after idarucizumab infusion in 6 patients and 24 hours after in 16 patients.

This study demonstrated efficacy of idarucizumab in reversing dabigatran, however it does so in a small population of patients studied for only 24 hours. The detection of dabigatran in plasma 12-24 hours after idarucizumab infusion suggests that the drug has a temporary effect. Further studies must be done on more patients and for a prolonged period of time to determine how idarucizumab can best be used in clinical practice.

Elsewhere in the journals…

Shibata et al. studied coronary artery embolism, an often recognized but ill-characterized cause of acute myocardial infarction (AMI). In 1,776 patients, coronary artery embolism was the etiology of 2.9% of AMIs (with atrial fibrillation as the most common cause of coronary artery embolism, 73%), with a significantly higher incidence of cardiac death (p<0.001).

Hezode et al. studied an interferon-free regimen (ombitasvir plus paritaprevir plus ritonavir with or without ribavirin) in patients with genotype 4 chronic Hepatitis C virus infection. In previously untreated patients, sustained virologic response was 100% in the regimen containing ribavirin and 90.9% in the ribavirin-free regimen. All treatment-experienced patients achieved sustained virologic response.

Hill et al. studied the efficacy of fall prevention education programs for patients and staff in rehabilitation units. There were fewer falls (p=0.03), injurious falls (p=0.006) and fallers (p=0.003), suggesting that a dedicated fall prevention education program could have a significant effect on patient safety in the hospital setting.

Whiting et al. conducted a meta analysis on the benefits and adverse effects of cannabinoids and there was moderate evidence to support the use of cannabinoids in treating chronic pain and spasticity. However cannabinoids were associated with a risk of short-term adverse events.

Dr. Rina Mauricio is a 2nd year resident at NYU Langone Medical Center

Peer reviewed by Anish B. Parikh, MD, chief resident, NYU Langone Medical Center


1.  Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. The New England journal of medicine 2015;372:2387-97.

2.  Arabi YM, Aldawood AS, Haddad SH, et al. Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults. The New England journal of medicine 2015;372:2398-408.

3.  Pollack CV, Jr., Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal. The New England journal of medicine 2015.

4.  Shibata T KS, Noguchi T, et al. Prevalence, Clinical Features, and Prognosis of Acute Myocardial Infarction Due to Coronary Artery Embolism Circulation 2015.

5.  Hezode C, Asselah T, Reddy KR, et al. Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. Lancet 2015;385:2502-9.

6.  Hill AM, McPhail SM, Waldron N, et al. Fall rates in hospital rehabilitation units after individualised patient and staff education programmes: a pragmatic, stepped-wedge, cluster-randomised controlled trial. Lancet 2015;385:2592-9.

7.  Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. Jama 2015;313:2456-73.