Primecuts – This Week In The Journals

June 9, 2015


By: Karin Katz, MD

This past week, American Pharoah won Belmont and was the first Triple Crown winner in 37 years. “The Curious Incident of the Dog in the Night-Time” won best play at the 69th annual Tony Awards. Caitlyn Jenner made her debut on the cover of Vanity Fair. Now let’s turn our attention away from the Kardashians and back to the latest in medical news.

Not all 30-day readmissions are created equally

The Annals of Internal Medicine published a study evaluating differences between early and late hospital readmissions (1). Readmission rates are important quality metrics for hospitals, especially during the 30-days following discharge. However, a variety of both patient and provider factors can affect readmission rates. Do these factors have different impacts during different periods of this 30-day window? In a retrospective cohort analysis, Graham et al. evaluated factors contributing to readmission rates early (0 to 7 days) and late (8 to 30 days) after discharge. The study included a cohort of 13,355 admissions (representing 8,078 internal medicine patients) at a large urban teaching hospital over 2 years. Patients excluded were those who were sent to long-term acute care hospitals, as well as admissions followed by death within 30 days. The primary outcomes were early readmission and late readmission. The overall 30-day readmission rate was 19.7%, with 39.7% of readmissions occurring in the early period, and 60.3% of readmissions occurring in the late period. Not surprisingly, the sickest patients were readmitted the earliest. Early readmissions were associated with markers of the acute illness managed during a patient’s initial hospitalization. These markers included length of index hospital stay (OR for each day, 1.02, [95% CI, 1.00 to 1.03]), and whether the patient had a rapid response during the index hospitalization (OR, 1.48 [CI, 1.15 to 1.89]).

On the other hand, markers of chronic illness were associated with late readmissions. For example, being on hemodialysis was only associated with late readmissions (OR, 1.61 [1.19 to 2.17]). The authors hypothesized that readmissions in the first week after discharge were more associated with hospital care, and late readmissions were more associated with patient-specific factors. Therefore, they propose that quality metrics should reflect the heterogeneity between these two windows.

Long-term diabetes outcomes in veterans

Shifting gears from the acute inpatient setting to long-term care of patients with diabetes, the NEJM published a study evaluating intensive versus standard glycemic control on macrovascular disease in patients with type 2 diabetes (2). The Veteran Affairs Diabetes Trial (VADT) is a multisite, randomized, controlled trial of intensive compared to standard glucose control in veterans with type 2 diabetes. In both study groups, patients with a BMI of 27 kg/m2 or more were started on two oral agents, metformin plus rosiglitazone. Those with a BMI of less than 27 kg/m2 were started on glimepiride plus rosiglitazone. Patients in the intensive-therapy group were started on maximal doses, and those in the standard-therapy group were started on half of the maximal doses. For patients in the intensive-therapy group who did not achieve a glycated hemoglobin level of less than 6%, and for those in the standard-therapy group with a level of less than 9%, insulin was added.

In 2010, a study was published that reported no statistically significant differences in major cardiovascular events in patients treated with intensive-therapy compared to standard-therapy. The more recent trial in the NEJM includes 5 additional years of observational follow-up of the same study cohort. The study included 1,791 veterans with diabetes who were randomly assigned to receive either intensive or standard glucose control (3). Patients excluded from the study included those with a glycated hemoglobin level of less than 7.5%, a cardiovascular event in the last 6 months, advanced congestive heart failure, severe angina, life expectancy of less than 7 years, a body mass index (BMI) of more than 40, a serum creatinine more than 1.6 mg/dL, or an ALT more than three times the upper limit of normal.

Participants from the original study were followed through a national data registry. The primary outcome was the time to the first major cardiovascular event. The patients had a mean age of 60 years, and had diabetes for a mean of 11.5 years. More than 40% of patients had a previous cardiovascular event. The differences in the glycated hemoglobin between the intensive and standard-therapy group averaged 1.5 percentage points during the trial, and then decreased to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over about 10 years, the intensive-therapy group had a significantly lower risk of a major cardiovascular event than the standard-therapy group (hazard ratio, 0.83; 95% CI, 0.70 to 0.99, p=0.04), with an absolute reduction in risk of 8.6 major CV events per 1000 person-years. However, the intensive-therapy group did not have reduced cardiovascular mortality (hazard ratio, 0.88; 95% CI, 0.64 to 1.20; p=0.42).

Most randomized clinical trials to date have not shown a benefit of intensive therapy on macrovascular outcomes in patients with type 2 diabetes. In extrapolating the data of this study to patients, it is important to consider the homogeneity of the patient population, mostly older men with chronic and not newly diagnosed diabetes. In addition, the use of drugs in the thiazolidinedione class would not likely be used in a similar study started today, and novel therapeutic approaches to diabetes management could impact cardiovascular morbidity and mortality in the long-term.

Lipid-lowering therapy in acute coronary syndromes

Also in the NEJM this week, a new study evaluated different approaches to lipid-lowering therapy in the management of acute coronary syndrome (ACS). Cannon et al. evaluated the effect of ezetimibe combined with simvastatin, compared to simvastatin alone, in patients with ACS (4). Patients included men and women, at least 50 years of age, with an LDL level of 50 mg/dL or higher who were hospitalized for ACS in the last 10 days. The study included 18,144 patients followed over a median of 6 years. Those patients on long-term lipid-lowering therapy could have a maximum LDL level of 125 mg/dL prior to enrollment in the study. For patients not on lipid-lowering therapy, the maximum LDL level for eligibility in the study was 100 mg/dL. Patients were randomly assigned to receive simvastatin 40mg plus ezetimibe 10mg daily, or simvastatin monotherapy. Of note, for patients in either study group with an LDL level greater than 79 mg/dL on two consecutive measurements, the simvastatin dose was increased to 80mg in a double-blind fashion. Then, in 2011, when the FDA limited the use of this high dose of simvastatin, many patients had their dose reduced. The primary efficacy end point was a composite of death from cardiovascular disease, a major coronary event, or nonfatal stroke. The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group. This was compared to a Kaplan-Meier event rate of 34.7% in the simvastatin monotherapy group (hazard ratio, 0.936; 95% CI, 0.89 to 0.99, p=0.016). No major differences in adverse events between the two groups were reported. There were many limitations to this study. This trial was conducted based on the now outdated practice guidelines of using lipid-lowering therapy to target LDL goals. Is the study still applicable? The number needed to treat in the simvastatin-ezetimibe group to achieve the primary end point was 50. However, many patients were on a dose of simvastatin no longer used. Also of note, 42% of patients discontinued the study medication prematurely (equally in both groups). Although this study, supported by Merck, suggests a possible benefit of using both statin and nonstatin therapy adjunctively in the treatment of the acute coronary syndrome, more research is needed. The study does not discuss the cost of including ezetimibe in the treatment of acute coronary syndrome. This study also did not demonstrate differences in the rates of death from cardiovascular causes and from any cause in the two groups.

Preventing acute kidney injury during cardiac surgery

Acute kidney injury after cardiac surgery is associated with morbidity and mortality, and is quite common. Up to 30% of patients may develop acute kidney injury after cardiac surgery. In a multicenter, double blind, randomized trial, 240 patients enrolled between August 2013 and June 2014 at hospitals in Germany were randomized to receive remote ischemic preconditioning, or a sham procedure, prior to cardiac surgery (5). In remote ischemic preconditioning, brief episodes of ischemia and reperfusion are applied to distant tissues, in order to protect the myocardium from a lethal episode of ischemia and reperfusion, although the mechanisms of this are not completely understood. Several trials have provided evidence that remote ischemic preconditioning can reduce myocardial injury during coronary bypass surgery. This study evaluated whether or not ischemic preconditioning can also prevent acute kidney injury during surgery. Patients were followed up to 30 days post-operatively. Patients in the intervention group had remote ischemic preconditioning, which consisted of 3 cycles of 5-minute inflation of a blood pressure cuff to 200 mm Hg (or at least 50 mm Hg higher than the systolic arterial pressure) to one upper arm after anesthesia induction. Then, patients had a 5-minute reperfusion with the cuff deflated. Patients in the control group had a sham remote ischemic preconditioning. This included 3 cycles of low pressure, 5-minute blood pressure cuff inflation and a 5-minute cuff deflation. The primary outcome of this study was the rate of acute kidney injury within the first 72 hours after cardiac surgery. In an intention-to-treat analysis, acute kidney injury was significantly reduced with remote ischemic preconditioning (45 of 120 patients [37.5%] compared with control (63 of 120 patients [52.5%]; absolute risk reduction, 15%; 95% CI, 2.56% to 27.44%; p=0.02). This corresponds to a NNT of 7. Interestingly, fewer patients receiving remote ischemic preconditioning received renal replacement therapy (7 [5.8%] versus 19 [15.8%]; absolute risk reduction, 10%; 95% CI, 2.25% to 17.75%; p=0.01). The mechanisms of ischemic preconditioning, and its pathophysiologic relationship to acute kidney injury, are incompletely understood. One hypothesis is that damage-associated molecules released from ischemic tissue during this process provoke self-protective mechanisms in the kidney. Ischemic preconditioning also decreased the post-cardiopulmonary bypass expression of biomarkers of acute kidney injury which were measured in the study, such as HMGB-1. There were no significant effects of this intervention on myocardial infarction, stroke or mortality. Even though there was no mortality benefit, the prospect of saving patients from needing hemodialysis is enticing. On the other hand, this is a small study, and it is important to consider other factors in the operating room that may affect the results. This includes estimated blood loss during surgery, as well as the type of anesthetic used. The benefit of this intervention is that it is low cost and easily applicable.

Also in the news…

A phase 1 trial was published on the safety and immunogenicity of a low-dose adenovirus type-5 vector-based Ebola vaccine, or high-dose vaccine on healthy adults in China. (6)

A review of alternative therapies marketed to treat Lyme disease was published in Clinical Infectious Diseases. More than 30 alternative treatments were found, including oxygen therapy, nutritional therapy, chelation, and even stem cell transplantation. Review of the medical literature did not substantiate these treatments (7).

Dr. Karin Katz is Chief Resident, Internal  Medicine at the VA Medical Center

Peer reviewed by Matthew Dallos, MD, a 3rd year resident at NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

1. Graham KL, Wilker EH, Howell MD, Davis RB, Marcantonio ER. Differences between early and late readmissions among patients: a cohort study. Ann Intern Med 2015;162:741-749. http://annals.org.ezproxy.med.nyu.edu/article.aspx?articleid=2299852

2. Hayward RA, Reaven PD, Wiitala WL, Bahn GD, Reda DJ, Ge L, McCarren M, et al. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;372:2197-2206. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMoa1414266#t=articleDiscussion

3. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129-139. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMoa0808431#t=articleDiscussion

4. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1410489

5. Zarbock A, Schmidt C, Van Aken H, Wempe C, Martens S, Zahn PK, Wolf B, et al. Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial. JAMA 2015;313:2133-2141. http://jama.jamanetwork.com.ezproxy.med.nyu.edu/article.aspx?articleid=2299339

6. Zhu FC, Hou LH, Li JX, Wu SP, Liu P, Zhang GR, Hu YM, et al. Safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in China: preliminary report of a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet 2015. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60553-0/abstract

7. Lantos PM, Shapiro ED, Auwaerter PG, Baker PJ, Halperin JJ, McSweegan E, Wormser GP. Unorthodox alternative therapies marketed to treat lyme disease. Clin Infect Dis 2015;60:1776-1782. http://cid.oxfordjournals.org/content/60/12/1776