Recent Research

Side effects of statins, ACE inhibitors and in-hospital outcomes for CABG, and more.


Lower energy, more exertional fatigue with statins

Statin treatment was associated with less energy and more exertional fatigue, according to a recent analysis.

Researchers used data from the University of California, San Diego Statin Study, which included 1,016 patients with low-density lipoprotein levels of 115 to 190 mg/dL and no cardiovascular disease or diabetes. The patients were randomized to daily 20-mg simvastatin, 40-mg pravastatin or placebo. The study participants rated their own change in energy and fatigue with exertion after six months of therapy. The results were published as an online research letter in the Aug. 13/27 Archives of Internal Medicine.

The study found a significantly larger drop in energy among statin users compared to placebo recipients. The authors used patients' self-ratings to create an energy/exertional fatigue score, and they found a mean drop of −0.21 (P=0.005) in statin patients. Women had an even greater decrease in their mean scores (−0.39, P=0.01). The authors explained that such a drop could indicate four in 10 statin-taking women having worsening energy or fatigue, two in 10 finding either marker to be worse or much worse, or one in 10 having much worse energy and fatigue. Simvastatin appeared to be associated with greater mean drops in the energy/fatigue score than pravastatin.

The findings support previous case reports of statin side effects, the authors concluded. These effects could be important in statin-prescribing decisions, especially for healthier patients who have less expected benefit from the drugs. Lower levels of activity and exertional tolerance could lead to other adverse effects, the authors noted. They called for long-term trials to gather additional evidence and urged physicians to be alert to statin-taking patients' reports of worsened energy and fatigue.

ACE inhibitors associated with improved in-hospital outcomes for CABG patients

Continuing angiotensin-converting enzyme (ACE) inhibitors, or adding them early after surgery, is associated with improved in-hospital outcomes for patients undergoing coronary artery bypass grafting (CABG), a study found.

In a prospective, observational study, researchers examined 4,224 patients undergoing CABG surgery. Patients were analyzed in four groups: continuation, that is, patients who were on ACE inhibitors pre- and postoperatively (21.7%, n=915); withdrawal, patients who took ACE inhibitors preoperatively but not postoperatively (21.8%, n=923); addition, patients who didn't take ACE inhibitors preoperatively but added them postoperatively (8.1%, n=343); and patients with no exposure to ACE inhibitors (48.4%, n=2,043). The primary outcome was a composite of cardiac, cerebral and renal events and in-hospital mortality. Results were published in the July 17 Circulation.

Compared to not using ACE inhibitors, continuous treatment with ACE inhibitors was associated with a significant reduction in the risk of nonfatal events (adjusted odds ratio [OR] for composite outcome, 0.69; P=0.009) and cardiovascular events (OR, 0.64; P=0.006). Adding ACE inhibitors after surgery compared to no use was also associated with a significantly lower risk of composite outcome (OR, 0.56; P=0.004) and cardiovascular events (OR, 0.63; P=0.04). Compared to withdrawal of ACE inhibitors, continuous treatment was associated with a lower risk of the composite outcome (OR, 0.50; P=0.001) as well as a decreased risk in cardiac and renal events (P<0.001 and P=0.005). There were no differences in in-hospital deaths or cerebral events based on ACE inhibitor usage.

The results indicate that withdrawing ACE inhibitors after CABG surgery is associated with nonfatal in-hospital events, while continuing ACE inhibitor treatment or adding it early after surgery is associated with better outcomes, the authors concluded. Given these findings, it is “alarming to learn that clinicians chose to acutely discontinue [ACE inhibitor] therapy in nearly 50% of patients following cardiac surgery. This pattern of practice was associated with major vascular complications. Acute withdrawal of [ACE inhibitor] therapy may be particularly harmful in the context of cardiac surgery…,” they wrote.

Editorialists cautioned that, as the study was observational, one can only note associations and not assume causation, and a randomized, controlled trial is needed. “As such, we should not yet conclude that withdrawal of [ACE inhibitors] necessarily causes increased post-operative complications,” they wrote. For example, “If [ACE inhibitors] were withdrawn from patients at high risk of cardiovascular instability postoperatively, it may erroneously appear as if [ACE inhibitor] withdrawal is a cause of the postoperative cardiovascular events.” Still, they said, the study is important “in that it forces providers to re-examine the practice of routinely discontinuing [ACE inhibitors] peri-operatively. Our advice to readers is to be open minded [and] stay tuned….”

For fluid resuscitation in sepsis, lower death rates with Ringer's acetate vs. HES 130/0.4

Severe sepsis patients who received Ringer's acetate for fluid resuscitation were less likely to die at 90 days than those who received hydroxyethyl starch (HES) 130/0.4, a recent study found.

In a blinded trial, researchers screened patients from 26 general ICUs in four Nordic countries who needed fluid resuscitation and met criteria for severe sepsis within the previous 24 hours. The researchers randomly assigned 804 patients in a 1:1 ratio to fluid resuscitation with either HES 130/0.4 or Ringer's acetate. The maximum daily dose was 33 mL/kg of ideal body weight. The main composite outcome was death or dependence on dialysis 90 days after randomization. Results were published in the July 12 New England Journal of Medicine.

Of randomized patients, 798 were included in the modified intention-to-treat population. Ninety days after randomization, 51% of HES 130/0.4 patients had died (n=201 of 398 patients) compared with 43% of Ringer's acetate patients (n=172 of 400 patients; relative risk [RR], 1.17; P=0.03). HES 130/04 raised the absolute risk of death at 90 days by eight percentage points, corresponding to a number needed to harm of 13. One patient in each treatment group had end-stage kidney failure. Twenty-two percent of HES 130/0.4 patients (n=87) were treated with renal-replacement therapy compared to 16% of Ringer's acetate patients (n=65; RR, 1.35; P=0.04). HES 130/0.4 patients had fewer days alive without renal replacement therapy and fewer days alive out of the hospital.

The separation of the survival curves for the two groups occurred around day 20, indicating that late deaths were induced by HES 130/0.4, the authors noted. In the current trial and an earlier one with similar results (which was not powered to show statistically significant differences), coagulation was impaired and use of red cells increased in HES patients, “which may have later adverse effects,” the authors noted. “A high fraction of HES is taken up and deposited in tissues, where it cannot be metabolized,” they wrote. The resulting long-term toxic effects have been seen in the liver, kidney and bone marrow, they said. “Together, all these negative effects of HES may have caused the late deaths observed in our trial and in the [earlier] trial,” they wrote.

Perioperative bleeding, thrombotic event rates similar with dabigatran, warfarin

Dabigatran and warfarin are associated with similar perioperative bleeding and thrombotic complication rates, including among people having urgent or major surgery, a recent study found.

Using data from the RE-LY (Randomized Evaluation of Long-Term Therapy) trial, researchers compared rates of bleeding and thrombotic complications in patients with atrial fibrillation receiving warfarin to those of patients receiving 150 mg or 110 mg of dabigatran twice daily. Outcomes were fatal bleeding, bleeding requiring surgery, all-cause bleeding and major bleeding, with the latter defined as a reduction in hemoglobin of at least 20 grams per liter, transfusion of at least two units of blood, or symptomatic bleeding into a critical area or organ. Thromboembolic complications included ischemic stroke, systemic embolism, myocardial infarction, pulmonary embolism and death. Bleeding rates were evaluated from seven days before until 30 days after invasive procedures, with data limited to the first procedure for a patient. Results were published in the July 17 Circulation.

About a quarter of patients from the RE-LY trial had oral anticoagulation interrupted to undergo a procedure. Of these 4,591 patients, 24.7% were receiving 110 mg of dabigatran, 25.4% were receiving 150 mg of dabigatran and 25.4% were receiving warfarin. The most common procedures were pacemaker/defibrillator insertion (10.3%), dental procedures (10%), diagnostic procedures (10%), cataract removal (9.3%), colonoscopy (8.6%) and joint replacement (6.2%). Patients assigned to either dabigatran dose got the last dose of study drug 49 hours (35- to 85-hour range) before the procedure, versus 114 (87- to 144-hour range) hours for patients taking warfarin (P<0.001). Indeed, dabigatran patients were four times as likely to have their surgery within 48 hours of oral anticoagulation interruption as those on warfarin.

Periprocedural major bleeding rates didn't differ significantly among treatment arms (3.8% for those taking 110 mg of dabigatran, 5.1% for those taking 150 mg of dabigatran and 4.6% for those taking warfarin). Neither did rates for other bleeding outcomes, or for stroke or other thromboembolic complications—and the incidences of the latter two were low. In the subset of patients having urgent surgery, major bleeding rates didn't differ significantly, either, occurring in 17.8% of patients taking 110 mg of dabigatran (P=0.47), 17.7% of those taking 150 mg of dabigatran (P=0.44) and 21.6% taking warfarin.

Given that dabigatran lacks a direct reversal agent, it is “reassuring” that both doses of the drug are associated with similar rates of perioperative bleeding as warfarin, including in patients with urgent surgery, the authors noted. Dabigatran has the advantage of a short half-life, and thus can be discontinued 24 to 48 hours before surgery (compared to 5 days for warfarin), they wrote. This shorter interruption period helps minimize the risk of thromboembolic complications and saves on the costs of heparin bridging, they wrote.

Editorialists agreed the study suggests shorter-acting anticoagulants can simplify the interruption process for surgical procedures. They also noted the study was important because it showed how commonly patients with atrial fibrillation on oral anticoagulants have surgery or invasive procedures—about 25% in a two-year period. Unanswered questions remain, however, including the ideal duration of dabigatran interruption for specific procedures and types of patients, in order to minimize bleeding and ischemic events, they said. For now, guidance in the dabigatran package insert should be followed, they said.

Postoperative delirium associated with long-term cognitive impairment

Delirium after cardiac surgery occurred in nearly half of elderly patients and was associated with a significant cognitive decline in the year after surgery, a recent study found.

Researchers enrolled 225 patients 60 years of age or older who were planning to undergo coronary artery bypass grafting or valve replacement at two academic medical centers and one Veterans Administration hospital. Patients were assessed with the Mini-Mental State Examination (MMSE) preoperatively. They were assessed using the MMSE, Confusion Assessment Method, and other scores daily during hospitalization beginning on postoperative day 2; and at one, six and 12 months after surgery. Results appeared in the July 5 New England Journal of Medicine.

Postoperative delirium developed in 103 patients (46%), with delirium lasting one to two days in 65% and three or more days in 35%. Those who developed postoperative delirium were more likely to be older, less educated, female, and nonwhite and to have a history of stroke or transient ischemic attack, a higher average score on the Charlson comorbidity index, and a lower level of preoperative cognitive function.

Among all patients, there was a significant decline in cognitive function—4.6 points on the MMSE—from baseline to postoperative day 2 (P<0.001), followed by average increases of 1 point on the MMSE each day on days 3 to 5 (P<0.001). Improvement slowed considerably from day 6 to day 183, and then stabilized from day 184 to day 365. A higher percentage of patients with delirium than those without delirium had not returned to their preoperative baseline level at six months (40% vs. 24%, P=0.01), but the difference was not significant at 12 months (31% vs. 20%, P=0.055).

“In patients with postoperative delirium, cognitive screening at hospital discharge may identify high-risk patients who require close monitoring after discharge or tailored transitional care in order to enhance functional and clinical outcomes,” the authors noted.

Alcohol use disorder increases after bariatric surgery

Patients were more likely to report symptoms of alcohol use disorder (AUD) two years after bariatric surgery than they were presurgery, a study found.

The prospective cohort study included about 2,000 patients who underwent bariatric surgery at 10 U.S. hospitals. The prevalence of AUD was determined by the Alcohol Use Disorders Identification Test, administered preoperatively and one year and/or two years after surgery.

The percentage of patients with AUD symptoms one year after surgery was about the same as before surgery (7.3% vs. 7.6%) and the U.S. average (8.5%, or 6.5% if adjusted to match the mostly female study population). However, two years after surgery, the percentage with AUD was significantly higher: 9.6%. This increase was mostly seen among patients who received Roux-en-Y gastric bypass; they had double the risk of AUD compared to patients who had laparoscopic adjustable gastric banding.

Several other risk factors for AUD after surgery were also identified: male sex; younger age; smoking, regular alcohol consumption or recreational drug use before surgery; and lower sense of belonging. Preoperative AUD was also a predictor of postoperative AUD, but more than half of patients who had the disorder after surgery did not report it preoperatively. The results were published in the June 20 Journal of the American Medical Association.

The researchers acknowledged that their cutoff for AUD was lower than some commonly used criteria: Patients were considered to have the disorder if they reported at least one symptom of alcohol-related harm or alcohol dependence. The authors also expressed concern about the levels of drinking reported by even patients who didn't have AUD—1 in 6 patients reported alcohol consumption at a potentially hazardous level by year two.

The authors speculated that increased alcohol sensitivity following Roux-en-Y surgery (as well as resumption of heavier drinking) could be responsible for the increase in AUD. Clinicians should educate potential bariatric surgery patients about the risk of AUD and conduct alcohol screening, and if necessary should refer for treatment, they said. The authors also called for longer-term research on AUD in bariatric surgery patients and investigation of the disorder's relationship to postoperative weight control.

Thrombolysis safe in stroke patients on warfarin with INR at or below 1.7

Thrombolysis doesn't appear to raise the risk of intracranial hemorrhage in ischemic stroke patients taking warfarin who have an international normalized ratio (INR) of 1.7 or lower, a study found.

Researchers used data from the Get With The Guidelines (GWTG)-Stroke Registry to analyze outcomes of 23,437 patients with ischemic stroke and an INR of 1.7 or lower who were treated with intravenous tissue plasminogen activator (IV-tPA). Patients came from 1,203 hospitals and were treated between April 2009 and June 2011. The primary outcome measure was symptomatic intracranial hemorrhage (sICH); secondary end points included life-threatening or serious systemic hemorrhage, any IV-tPA complication and in-hospital death. Results were published in the June 27 Journal of the American Medical Association.

Nearly 8% of ischemic stroke patients (n=1,802) who were given IV-tPA were taking warfarin prior to admission. Warfarin patients had more severe strokes and comorbid conditions and were older. While the unadjusted sICH rate was higher in warfarin patients than non-warfarin patients (5.7% vs. 4.6%; P<0.001), these differences weren't significantly different after adjustment for baseline clinical factors. There were also no significant differences between warfarin and non-warfarin patients in secondary outcomes. In warfarin-treated patients with INRs of 1.7 or lower, the degree of anticoagulation wasn't statistically significantly associated with sICH risk, though there was a trend toward increased risk as INR increased.

Up to 48.6% of warfarin-treated patients who met American Heart Association/American Stroke Association guidelines eligibility criteria for IV-tPA didn't receive it. Among eligible warfarin patients, those who did receive IV-tPA were less likely to have a history of previous stroke and more likely to present with greater stroke severity. The authors noted that while the study supports the safe use of IV-tPA at an INR at or below 1.7, it's unclear how high the INR value could be for IV-tPA to remain safe. Their exploratory analysis suggested an INR of 2.0 or lower may be safe, though the results “should be interpreted with caution,” they said. They also noted there is little experience with—and no guidelines for—use of IV-tPA in patients taking newer anticoagulants like dabigatran and rivaroxaban.

An editorialist cautioned that results may not be generalizable to hospitals that aren't part of the GWTG-Stroke Registry, as the GWTG hospitals may be more likely to have well-developed protocols for the use of IV-tPA. Still, he noted the “salient finding” that many eligible stroke patients taking warfarin didn't receive IV-tPA. “Extrapolating this finding to the 5,000 acute care hospitals in the United States suggests that perhaps at least 4,000 to 5,000 patients who might have been eligible for intravenous tPA every two years were not treated, for unclear reasons,” he wrote.

Guidelines on peripheral vascular ultrasound and physiologic testing

Recent guidelines describe the appropriate uses of arterial ultrasound and physiological testing for patients with known or suspected peripheral vascular disorders.

The criteria, which were released by a collaboration of several medical societies and published in the July Journal of the American College of Cardiology, described 255 clinical scenarios. Of these, 117 were judged to be appropriate uses of noninvasive vascular testing, 84 were rated as uncertain, and 54 were found to be inappropriate. The scenarios cover non-coronary arterial disorders including atherosclerotic occlusive disease (i.e., carotid artery stenosis, lower- and upper-extremity peripheral arterial disease, renal and mesenteric artery occlusive disease), abdominal aortic aneurysms, fibromuscular dysplasia, vasospasm, arterial dissection and arterial trauma.

In general, testing was found to be appropriate when indicated by clinical signs and symptoms, as well as to establish a baseline after revascularization. Follow-up studies for patients with normal findings were generally rated as inappropriate.

The criteria are intended to help clinicians maximize use of the noninvasive vascular laboratory, identify evidence gaps in the field, and serve as a reference for policymakers, the authors said, acknowledging that many potential indications for testing are not included. They noted that this document included more indications for surveillance than appropriate use criteria for other cardiovascular imaging modalities, because optimal clinical management of peripheral vascular disorders requires periodic imaging surveillance.

The criteria were titled “Part I,” and the authors wrote that appropriateness criteria for venous ultrasound and physiological testing are currently under development. The criteria were jointly released by the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American College of Radiology, American Institute of Ultrasound in Medicine, American Society of Echocardiography, American Society of Nephrology, Intersocietal Commission for the Accreditation of Vascular Laboratories, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Interventional Radiology, Society for Vascular Medicine, Society for Vascular Surgery, American Academy of Neurology, American Podiatric Medical Association, Society for Clinical Vascular Surgery, Society for Cardiovascular Magnetic Resonance and Society for Vascular Ultrasound.

Delirium linked to adverse outcomes in hospitalized patients with Alzheimer's disease

Patients with Alzheimer's disease who develop delirium during hospitalization are more likely to have adverse outcomes, according to a study.

Researchers performed a prospective cohort study of patients with Alzheimer's disease who were enrolled in the Massachusetts Alzheimer's Disease Research Center patient registry from 1991 to 2006. The goal of the study was to determine the association between hospitalization and delirium and risks for institutionalization, cognitive decline and death. The authors defined cognitive decline as a decrease of at least four points on the Blessed Information-Memory-Concentration test score. Adjusted relative risks (RRs) were calculated by using multivariate analysis. The study results appeared in the June 19 Annals of Internal Medicine.

A total of 771 patients at least 65 years of age (mean age, 77.2 years) with a diagnosis of Alzheimer's disease were included in the study. Fifty-seven percent were women, and 95% were white. Over the study period, 367 patients (48%) were hospitalized and 194 (25%) developed delirium. Risks for death and institutionalization were higher in hospitalized patients than in nonhospitalized patients (adjusted RRs, 4.7 and 6.9, respectively) and were increased further in hospitalized patients who developed delirium (adjusted RRs, 5.4 and 9.3, respectively). Hospitalized patients who developed delirium also had an adjusted RR of 1.6 for cognitive decline. Overall, 21% of cognitive decline, 15% of institutionalizations, and 6% of deaths in hospitalized patients were determined to be associated with delirium.

The authors acknowledged that their study was nonrandomized, that some data were missing, and that ethnic minorities were not well represented, among other limitations. However, they concluded that delirium during hospitalization will lead to at least one adverse outcome in approximately one in eight patients with Alzheimer's disease. “Further investigation is greatly needed to determine whether prevention of hospitalization and delirium can decrease the attributable risk for death, institutionalization, and cognitive impairment in the vulnerable and increasing population of persons with [Alzheimer's disease],” the authors wrote.