Recent Research

Oral fluoroquinolones and dysglycemia, metoprolol before PCI, and more.


Oral fluoroquinolones associated with increased dysglycemia risk in diabetics

Diabetic patients taking oral fluoroquinolones could have a higher risk for severe dysglycemia, according to a recent study.

Researchers performed a population-based inception cohort study of diabetic outpatients in Taiwan from January 2006 to November 2007 who were new users of oral levofloxacin, ciprofloxacin, moxifloxacin, cephalosporins and macrolides. The main outcome measures were emergency department visits or hospitalization for dysglycemia 30 days after antibiotic therapy was initiated. The study results were published in the Oct. 1 Clinical Infectious Diseases.

The study included 78,433 diabetic patients who were taking a fluoroquinolone, 12,564 taking ciprofloxacin, 4,221 taking moxifloxacin, 11,766 taking levofloxacin, 20,317 taking cephalosporins, and 29,565 taking macrolides. Two hundred fifteen hyperglycemic events and 425 hypoglycemic events occurred during the study period. Those taking moxifloxacin had an absolute risk of 6.9 per 1,000 persons for hyperglycemia and 10.0 per 1,000 persons for hypoglycemia; for those taking macrolides, the risks were 1.6 and 3.7 per 1,000 persons, respectively. Adjusted odds ratios for hyperglycemia with levofloxacin, ciprofloxacin and moxifloxacin compared to macrolides were 1.75, 1.87, and 2.48, while adjusted odds ratios for hypoglycemia were 1.79, 1.46, and 2.13, respectively. Hypoglycemia risk was significantly higher with moxifloxacin than with ciprofloxacin, as well as with moxifloxacin and concomitant insulin.

The authors noted that data on rare events were obtained from an electronic database and might therefore be incomplete. Among other limitations, they also pointed out that reverse causality could have been present, since severe infection can cause dysglycemia. However, they concluded that based on their results, diabetic patients taking fluoroquinolones, especially moxifloxacin, could potentially be at higher risk for severe dysglycemia. “Clinicians should consider these risks when treating patients with diabetes and prescribe fluoroquinolones cautiously,” the authors wrote.

Metoprolol before PCI reduces infarct size, increases LVEF in STEMI patients

In patients with ST-segment elevation myocardial infarction (STEMI) who were undergoing primary percutaneous coronary intervention (PCI), use of the beta-blocker metoprolol before reperfusion reduced infarct size and increased left ventricular ejection fraction (LVEF), a recent study found.

Patients with Killip-class ≤II anterior STEMI undergoing PCI within 6 hours of symptom onset were randomized to get intravenous metoprolol (n=131) or not (n=139) before reperfusion. Treatment group patients received up to three 5-mg boluses of metoprolol tartrate 2 minutes apart. All patients otherwise were treated per current guidelines including, when not contraindicated, receipt of oral metoprolol within 24 hours of symptom onset.

The main end point was infarct size as measured by magnetic resonance imaging (MRI) 5 to 7 days after STEMI. A major secondary safety end point was incidence of major adverse cardiac events within 24 hours after STEMI. Results were published in the Oct. 1 Circulation.

MRI was done in 220 patients (9% of study patients weren't scheduled for MRI, and another 9% of those scheduled didn't undergo MRI for various reasons, including technical problems and claustrophobia). Patients who received IV metoprolol had a smaller mean infarct size compared to control patients (25.6 g vs. 32.0 g; 95% CI, −11.39 to −1.78; P=0.012). IV metoprolol patients also had smaller infarct size as estimated by peak and area under the curve creatine-kinase release, and a higher LVEF than controls (adjusted LVEF difference 2.67%; 95% CI, 0.09% to 5.21%; P=0.045). There was no significant difference between groups in incidence of major adverse cardiac events.

Infarct size is a major determinant of mortality after STEMI, and thus it's important to limit the degree of myocardial necrosis, the authors noted. “Here we show that an inexpensive medication already approved for STEMI treatment can significantly reduce infarct size simply by being administered before reperfusion,” they wrote.

Editorialists wrote that the results are “important and stimulating” and inspire “great hope in clinical benefit.” Their stated concerns about the trial include the lack of a placebo control group and exclusion of patients with Killip-class III and IV STEMI (who have large infarctions) and of patients with inferior infarction. Overall, they concluded, the study's results are “expected to be clinically relevant,” but since infarct size is only a surrogate of outcomes, clinical practice shouldn't be changed until the results are confirmed in randomized trials powered for hard clinical end points like mortality.

Prasugrel not helpful in certain ACS patients scheduled for catheterization

In patients with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS) scheduled to undergo catheterization, pretreatment with prasugrel at diagnosis didn't reduce the rate of major ischemic events and increased the rate of major bleeding complications, a recent industry-funded study found.

Researchers studied 4,033 patients from 171 centers with NSTE ACS and elevated troponin levels. All patients were scheduled to have coronary angiography, and percutaneous coronary intervention (PCI) if needed, within 2 to 48 hours after study randomization. They were randomized to pretreatment with prasugrel or matching placebo (control group).

The pretreatment group received a 30-mg loading dose of prasugrel before coronary angiography, with an additional 30 mg given at the time of PCI if the angiography confirmed PCI was indicated. Control group patients got placebo before angiography and, if they needed PCI, a 60-mg loading dose of prasugrel after angiography. Patients whose angiography results indicated CABG or medical treatment was best didn't get the second dose (i.e., 30 mg in the pretreatment group and 60 mg in the control group).

The main efficacy end point was a composite of death from cardiovascular causes, stroke, urgent revascularization or glycoprotein IIb/IIa inhibitor rescue therapy through day 7. This outcome didn't differ between the treatment and control groups, including in the individual components of the end point.

The main safety end point of major bleeding episodes through day 7 was higher in the pretreatment group (hazard ratio, 1.90; 95% CI, 1.19 to 3.02; P=0.006), with rates of major bleeding and life-threatening bleeding increased by factors of 3 and 6, respectively. Bleeding events were mainly associated with PCI or coronary artery bypass grafting (CABG) and happened early in patients who had PCI. All results remained the same at 30 days and held for prespecified subgroups, including the elderly and patients with diabetes.

It's become common to use clopidogrel pretreatment in patients with NSTE ACS, and the practice “has often been extended to new oral P2Y12 antagonists,” the researchers wrote. But the current study results support the use of prasugrel only “when the coronary anatomy is known and after PCI is selected as the treatment strategy,” they wrote. In this study, 32% of the patients didn't end up needing pretreatment at all because they underwent CABG or had medical treatment with or without further P2Y12 inhibition, they noted.

Enrollment in the study was suspended just before completion due to the safety issues, but the power of the trial wasn't affected, the researchers noted. Results were published in the Sept. 12 New England Journal of Medicine. The trial was sponsored by Daiichi Sankyo, which developed prasugrel, and Eli Lilly, which markets prasugrel in the U.S.

Procalcitonin can help guide antibiotic therapy in ICU patients

Procalcitonin can help guide antibiotic management, including when to discontinue therapy, in ICU patients, a recent meta-analysis found.

Researchers searched MEDLINE, EMBASE and the Cochrane Controlled Trials register for comparative studies and systematic reviews on using procalcitonin-guided antibiotic therapy in patients with infections. Specifically, they sought data from randomized, controlled trials that compared using procalcitonin versus clinical criteria to guide initiation, intensification or discontinuation of antibiotic therapy. Outcomes were antibiotic usage, morbidity and mortality. The results were published in the September Journal of Hospital Medicine.

Data from the 18 qualified studies were pooled into 5 clinically similar groups. In adult ICU patients, using procalcitonin to guide antibiotic discontinuation lowered the duration of antibiotic use by 2.05 days (95% CI, −2.59 to −1.52) without increasing morbidity or mortality. However, using procalcitonin as an indicator of need for antibiotic intensification led to greater antibiotic usage and morbidity, including longer length of stay and more days on mechanical ventilation. In adults with respiratory tract infections, guidance with procalcitonin significantly reduced antibiotic duration by 2.35 days (95% CI, −4.38 to −0.33) and antibiotic prescription rate by 22% (95% CI, −41% to −4%); it also decreased total antibiotic exposure and didn't affect morbidity or mortality.

The authors noted that, despite some differences between this and previous reviews, the conclusion is the same: Procalcitonin-guided decision making reduces use of antibiotics without changing morbidity and mortality, as compared to clinical criteria-guided decision making. However, procalcitonin shouldn't be used to guide intensification of antibiotics in adult ICU patients, they added, and there's not enough evidence to recommend procalcitonin-guided therapy in postoperative patients at risk for infection.

Many patients don't understand discharge summaries

A week after hospital discharge, even patients who claim to have understood their discharge summaries often have difficulty describing their diagnosis and follow-up plan, a recent study found.

Researchers at Yale-New Haven Hospital enrolled 395 patients age 65 and older who had been hospitalized for acute coronary syndrome, heart failure or pneumonia between May 2009 and April 2010. The patients' medical records were reviewed and they were contacted by phone for an interview within a week after discharge. Results were published by JAMA Internal Medicine on Aug. 19.

Almost all of the patients (95.6%) reported that they understood the reason for their hospitalization, and 90.3% said they had received written instructions prior to discharge, which more than 85% reported were easy to read and understand. But when researchers compared patients' explanations of their hospitalizations to the medical records, they found that only 59.6% fully understood their diagnosis and an additional 32.2% could at least describe their symptoms. Thirty patients (8.2%) showed no understanding. About a quarter of discharge summaries did not describe the patient's diagnosis in lay language, the researchers found.

They also looked at patients' preparation for discharge and found that 30% reported receiving less than a day's advance notice before discharge and that 66.1% had been asked whether they would receive sufficient support at home. According to the records, 32.6% had a follow-up outpatient appointment scheduled before discharge, but only 43.9% of those patients could recall the details of the appointment during the phone interview.

Despite patients' positive reviews of their discharge experiences, discharge practices and patient comprehension are suboptimal, the researchers concluded, noting that asking patients about their understanding does not seem to be a good way to gauge the effectiveness of discharge preparation. “To better assess what was actually done, questions should be constructed to ask about practice rather than perceived understanding,” they wrote. Other potential solutions include patient teach-back or a “universal precautions” approach of treating every patient as if he had cognitive impairment or low health literacy.

Among other limitations, the study was conducted at a single site and did not routinely assess caregivers' understanding, the researchers cautioned. Still, the inclusion of only patients who were discharged to home and could respond to interview questions by telephone may indicate that these results are a best-case scenario, with a more functional patient population than those typically admitted with the studied conditions.

Cangrelor may improve periprocedural outcomes after PCI

Cangrelor may reduce periprocedural thrombotic complications in patients undergoing percutaneous coronary intervention (PCI), a recent industry-funded analysis indicates.

Researchers performed a prespecified pooled analysis of patient-level data from the phase III trials CHAMPION-PCI, CHAMPION-PLATFORM and CHAMPION-PHOENIX, all of which compared cangrelor with a control drug, clopidogrel or placebo, for prevention of periprocedural thrombotic complications related to PCI. Men and nonpregnant women were eligible for the trials if they were at least 18 years of age and required PCI. All 3 CHAMPION trials were funded by The Medicines Company, which manufactures IV cangrelor.

CHAMPION-PCI and CHAMPION-PHOENIX enrolled patients with stable angina, non-ST-segment elevation acute coronary syndrome or ST-segment elevation myocardial infarction (STEMI), while CHAMPION-PHOENIX did not enroll patients who had STEMI. Patients who took a P2Y12 inhibitor or abciximab in the 7 days before randomization were excluded from CHAMPION-PHOENIX and from CHAMPION-PLATFORM, but clopidogrel before randomization was allowed in CHAMPION-PCI. Patients taking eptifibatide, tirofiban or fibrinolytic therapy within 12 hours of randomization were excluded from all 3 trials.

Patients in all 3 trials received an IV and an oral study drug. The IV drug was given as a bolus (cangrelor, 30 µg/kg, or matching placebo), then an infusion (cangrelor, 4 µg/kg per min, or matching placebo). The infusion was continued for a minimum of 2 hours or until the index PCI concluded. Patients in the cangrelor group received 600 mg of clopidogrel when the infusion was completed. The control group in CHAMPION-PCI received 600 mg of clopidogrel when PCI began, while the control group in CHAMPION-PLATFORM received 600 mg when PCI ended. The control group in CHAMPION-PHOENIX received 300 or 600 mg of clopidogrel at the start or end of PCI, according to the standard of care at the study site.

The primary composite outcome for efficacy in the modified intention-to-treat sample was death, myocardial infarction, revascularization due to ischemia and stent thrombosis at 48 hours, while the primary safety outcome was severe or life-threatening bleeding at 48 hours that was not related to coronary artery bypass grafting. The study results were published online Sept. 3 by Lancet.

About 25,000 patients each were included in the efficacy and safety analyses, half controls and half receiving cangrelor. Overall, in the efficacy analysis, 57.4% of patients had non-ST-segment elevation acute coronary syndrome, 31% had stable angina and 11.6% had STEMI. The mean patient age was 63 years, 85.8% were white, and 72.3% were men. The primary outcome occurred in 3.8% of the cangrelor patients and 4.7% of the controls (odds ratio, 0.81; P=0.0007); stent thrombosis occurred in 0.5% versus 0.8%, respectively (odds ratio, 0.59; P=0.0008). All-cause death, myocardial infarction and revascularization related to ischemia occurred in 3.6% of cangrelor patients and 4.4% of controls (odds ratio, 0.81; P=0.0014). Benefits in the cangrelor group remained at 30 days. Rates of the primary safety outcome, moderate bleeding, and transfusion did not differ between groups, but mild bleeding was more common with cangrelor (16.8% vs. 13%; P<0.0001).

The authors noted that the control groups, definitions of certain outcome events, and populations studied differed among the 3 trials and that follow-up was short, among other limitations. However, they concluded that IV cangrelor at PCI significantly reduced risk for periprocedural events at 48 hours and 30 days compared with oral clopidogrel and with placebo plus deferred clopidogrel, as well as risk for complications associated with angiography. In addition, cangrelor did not increase risk for severe bleeding events or transfusion but did increase risk for minor bleeding, the authors said.

The author of an accompanying editorial pointed out that the CHAMPION trials did not compare cangrelor with an optimal antiplatelet regimen or with ticagrelor or prasugrel, both of which outperform clopidogrel in PCI for acute coronary syndrome. He noted that cangrelor could be advantageous in certain clinical situations but stressed that its potential cost-effectiveness is questionable and remains to be determined. However, he wrote, “Despite these considerations, its favourable pharmacodynamic profile and effectiveness in reducing periprocedural events makes cangrelor a useful and welcome agent for interventional cardiologists and their patients.”

Haloperidol doesn't decrease delirium duration in critically ill

Though it's safe and can help with acute agitation, haloperidol doesn't reduce the overall duration of delirium in critically ill patients, a recent study found.

Critically ill adults who needed mechanical ventilation within 72 hours of admission were enrolled in a placebo- controlled trial in a single ICU in the United Kingdom. Patients were randomized to receive 2.5 mg of haloperidol (n=71) or 0.9% saline placebo (n=70) intravenously every 8 hours, regardless of delirium or coma status. The drug was stopped upon discharge from the ICU, once a patient was delirium- and/or coma-free for 2 straight days, or after a maximum of 14 days of treatment, whichever came first. Researchers used the Confusion Assessment Method for the ICU (CAM-ICU) to assess delirium. The main outcome was days free of delirium and coma.

Patients in the haloperidol group spent a median of 5 days alive without delirium or coma, compared to 6 days in the placebo group—a nonsignificant difference. There were no differences between groups in secondary outcomes like ventilator-free days, length of ICU stay or hospital stay, or 28-day mortality. The most common adverse events were oversedation (11 patients in the haloperidol group vs. 6 in the placebo group) and QTc prolongation (7 in the haloperidol group vs. 6 in the placebo group). No patients had serious adverse events related to the study drug. Results were published in the September Lancet Respiratory Medicine.

Though the study wasn't powered to show this difference between groups, the results suggest haloperidol might decrease the need for sedatives, the authors noted, although this ultimately had no effect on days in delirium or coma. Most clinicians use haloperidol for agitation, and indeed, the study confirmed it is useful for this indication, though it ultimately appears not to affect how long a person has delirium or coma, they concluded.

Updated guidelines issued on post-HIV-exposure prophylaxis

Health care workers with any occupational exposure to HIV should immediately use a post-exposure prophylaxis regimen comprising 3 or more antiretroviral drugs, according to updated guidelines from the United States Public Health Service.

Previously, the guidelines recommended assessing the level of risk associated with individual exposures in order to determine how many drugs to use for post-exposure prophylaxis (PEP). The guidelines also recommend taking a full 4-week PEP regimen and undergoing close follow-up HIV testing that includes counseling and monitoring for drug toxicity. Follow-up appointments should start within 72 hours of exposure. These guidelines update the 2005 version and were published online Aug. 6 by Infection Control and Hospital Epidemiology.

If a newer, fourth-generation combination HIV p24 antigen-HIV antibody test is used for follow-up testing, the testing can be finished 4 months after exposure, the guidelines said. If a newer testing platform is not available, however, follow-up testing should continue until 6 months after exposure.

When a health care worker is exposed to HIV, he or she should seek expert consultation, though not at the expense of delaying treatment, the guidelines said. Consultation can be made with local experts or by calling the National Clinicians' Post-Exposure Prophylaxis Hotline at 888-448-4911. Situations in which expert consultation is especially recommended include when an exposure report occurs ≥72 hours after exposure; when the exposure source is unknown; when the exposed person is pregnant, breastfeeding or has a serious illness; when the source virus is known or suspected to be resistant to antiretrovirals; and when the exposed person experiences toxicity from the initial PEP regimen.

The guidelines were developed by an interagency Public Health Service working group comprising representatives from the Centers for Disease Control, National Institutes of Health, Food and Drug Administration and the Health Resources and Services Administration, in consultation with an external expert panel. They apply to a wide range of workers, including laboratory personnel, physicians, technicians, pharmacists, nurses, students, trainees, volunteers and emergency medical personnel.

Guidance on perioperative antiplatelet management in stent patients lacking, review finds

For patients with stents undergoing noncardiac surgery, most recommendations on perioperative antiplatelet therapy are based on expert opinions that don't always agree, a review found.

Researchers reviewed clinical practice guidelines related to this specific population of patients. They sought to answer 4 questions: when elective surgery should be done in this patient population; which antiplatelets should be stopped or continued around the time of surgery; which antiplatelets should be stopped and resumed before and after surgery; and whether bridging therapy is needed around the time of surgery. Results were published online Aug. 8 by Chest.

The researchers found 2,766 potentially relevant articles, which were eventually narrowed down to 11 practice guidelines included in the review. Most guidelines recommended delaying elective noncardiac surgery for at least 4 to 6 weeks after bare-metal stent implantation, though 1 guideline said a 2-week delay was sufficient and another said a 12-week delay was optimal. Nine guidelines advised delaying elective noncardiac surgery for at least 12 months after drug-eluting stent implantation; the other 2 advised delaying at least 6 months.

Most guidelines advised continuing acetylsalicylic acid (ASA) therapy around the time of surgery when possible and continuing dual antiplatelet therapy in patients at highest risk for stent thrombosis—unless this was limited by the risk of bleeding associated with the surgery. Four guidelines advised discontinuing ASA/clopidogrel at least 5 days before surgery if antiplatelet therapy needs to be interrupted, while 2 guidelines recommended discontinuing 7 to 10 days before surgery in this case. Eight guidelines advised resuming antiplatelets promptly after surgery, with 3 of them saying it should be done 24 hours after surgery. Five guidelines offered advice on perioperative bridging during antiplatelet interruption, but the advice differed.

Strengths of the review included its comprehensiveness and the high degree of agreement among reviewers, the reviewers wrote. However, the review was limited by the lack of good evidence, as most guidelines were based on low-quality studies or expert opinion, they wrote. High-quality, prospective studies are needed to assess management strategies in this population of patients, they concluded.

CKD guidelines may lead to overdiagnosis, overtreatment

The current definition of chronic kidney disease (CKD) based on estimated glomerular filtration rate (eGFR) has led to 1 in 8 people being labeled as having the condition, compared to the actual treatment rate of 1 person for every 3,000 to 5,000 for end-stage renal disease (ESRD), a study found.

The result is overdiagnosis and overtreatment of people unlikely to ever progress to ESRD, reviewers said in an analysis published online July 30 in BMJ.

A 2002 guideline defined CKD by eGFR based on serum creatinine or cystatin C levels and an assessment of kidney damage most commonly derived from albuminuria. The reviewers noted that, by these criteria, anyone with an eGFR below 60 mL/min/1.73 m2 for 3 months or longer could be diagnosed as having CKD of stage 3A or greater, even if they have no other signs of kidney disease.

The goal had been to capture patients who progressed all the way to ESRD unchecked, especially in the African-American community, the authors wrote. This definition has resulted in almost 14% of U.S. adults being labeled as having CKD. A third of the people who meet the definition of CKD also meet the definition of stage 3A. Most are older than 65, and many have an eGFR that falls within the 5th to 95th percentile for their age. About 75% have no urine markers of kidney damage, such as albuminuria.

Reviewers suggested several ways for clinicians to improve CKD management:

  • Share uncertainty about diagnostic thresholds and measurements with patients.
  • Look for potential evidence of anemia, abnormal urinalysis results or abnormalities on renal ultrasonography.
  • Be aware of the variability of results when testing eGFR and albuminuria and of the need to repeat the tests, soon after the first test and again after 3 months.
  • Avoid the label of CKD for people age 65 years and older with eGFR stage 3A without albuminuria.
  • Recognize that older people with stable but modestly reduced eGFR of 45 to 59 mL/min/1.73 m2 are unlikely to have a high risk unless they have persistent overt albuminuria.

Noninfectious catheter-associated complications as common as CAUTIs

Noninfectious catheter-associated complications are as common as catheter-associated urinary tract infections (CAUTIs), though the former receive less research attention, a meta-analysis concluded.

Researchers searched electronic databases of published literature as well as collections of conference abstracts and other unpublished work, for studies assessing noninfectious complications of indwelling urethral catheters among adults through July 2012. They sorted studies into 3 categories: short-term catheterization in patients without spinal cord injury, long-term catheterization in those without spinal cord injury, and catheterization in patients with spinal cord injury. Results were published in the Sept. 17 Annals of Internal Medicine.

In the 37 studies pooled, minor complications were common. The pooled frequency of urine leakage, for example, ranged from 10.6% in short-term catheterization cohorts to 52.1% among outpatients with long-term indwelling catheters. In short-term catheterization patients, other common complications were gross hematuria (4.7%), accidental removal (4.0%), and catheter blockage (5.0%, in 1 study). Urethral strictures occurred in 3.4% of patients with short-term catheterization.

In patients catheterized longer than 3 weeks, results varied by whether they were inpatient or outpatient. Accidental catheter removal was more common among inpatients (70.2% vs.7.3%), as was catheter blockage (44.4% vs. 28.7%), though frequency of leakage or incontinence was higher in outpatients (52.1%). For spinal cord injury patients, 13.5% had gross hematuria and 1.0% developed bladder cancer.

Meta-regression for catheter duration implied that frequency of gross hematuria was significantly higher with a longer duration of catheterization, though duration didn't seem to affect frequency of catheter blockage, accidental removal, urine leakage or urethral stricture. On the whole, 30% of patients with long-term catheters and/or catheters in conjunction with spinal cord injury had several noninfectious complications.

Study limitations include the variability in study quality and the fact that some outcomes (like blockage and leakage) may have been associated with UTIs. The authors concluded that “considering the frequency with which urethral catheters are used in the hospital setting, we believe it is imperative to consider not only CAUTI but also noninfectious complications as a key area of possible harm and, thus, a vital target for future prevention efforts.”