Recent Research

Macrolide antibiotics may be associated with cardiovascular complications, deaths

Macrolide antibiotics were associated with increased risk for sudden cardiac death (SCD), ventricular tachyarrhythmia (VTA), and cardiovascular death but not increased all-cause mortality, a meta-analysis found.

The analysis included 33 studies from the literature involving more than 20 million participants. Eleven of the studies (3 randomized controlled trials, 5 cohort studies, and 3 case-control studies) with data for more than 6.6 million people and more than 5,800 events reported risk estimates for SCD or VTA. Twelve studies (6 randomized controlled trials and 6 cohort studies), involving more than 17 million participants and almost 4,200 events, were included for the outcome of cardiovascular death. Results appeared in the Nov. 17/24, 2015, Journal of the American College of Cardiology.

Patients taking macrolides, compared with those who took no macrolides, had an increased risk of SCD or VTA (relative risk [RR], 2.42; 95% CI, 1.61 to 3.63), SCD (RR, 2.52; 95% CI, 1.91 to 3.31), and cardiovascular death (RR, 1.31; 95% CI, 1.06 to 1.62). No association was found between macrolides use and all-cause death. The RRs associated with SCD or VTA were 3.40 for azithromycin, 2.16 for clarithromycin, and 3.61 for erythromycin. RRs for cardiovascular death were 1.54 for azithromycin and 1.48 for clarithromycin. No association was noted between roxithromycin and adverse cardiac outcomes. Treatment with macrolides is associated with an absolute risk increase of 118.1 additional SCDs or VTAs and 38.2 additional cardiovascular deaths per 1 million treatment courses, the authors calculated.

“Interpretation of the clinical importance of this finding is delicate,” they wrote. “The estimates for additional SCDs and cardiac deaths per 1 million treatment courses are remarkably close, suggesting that most VTA observed in the macrolide groups might not result in fatal outcomes. The absolute risks for SCD and cardiac death are small, so this finding should probably have limited effect on prescribing practice in individual patients. However, given that macrolides are 1 of the more commonly used antibiotic groups in many countries and that millions of patients are prescribed these drugs annually, the total number of excess SCD or VTAs and cardiac deaths may not be negligible.”

An editorial noted that “roughly 1:8,500 patients treated with a macrolide antibiotic is expected to develop a serious arrhythmic event, and 1:30,000 could die suddenly, because of our treatment.” They also expressed concern that discontinuing production of macrolides “would be unfortunate because macrolides are first-line agents for community-acquired pneumonia, legionellosis, sexually transmitted infections, and peptic ulcer caused by Helicobacter pylori infection.” Other treatments have their own drawbacks, and risks for drug-induced long QT syndromes can be further reduced by screening for well-recognized risk factors, the editorialists said. They called for development of guidelines on the topic.

Central thermometers preferred to peripheral when temperature could influence diagnosis, treatment

Peripheral thermometers used orally or under the arm do not have clinically acceptable accuracy and should not be used when accurate measurement of body temperature might influence clinical decisions, a meta-analysis found.

Researchers reviewed 75 published prospective studies comparing the accuracy of tympanic membrane, temporal artery, axillary, or oral thermometers with pulmonary artery catheter, urinary bladder, esophageal, or rectal thermometers. The results of the systematic evidence review and meta-analysis were published Nov. 16, 2015, by Annals of Internal Medicine.

Peripheral thermometers had poor clinical accuracy and poor sensitivity for detecting low-grade fever compared with central thermometers, the researchers noted. Compared with central thermometers, peripheral thermometers had pooled 95% limits of agreement (random-effects meta-analysis) outside the predefined clinically acceptable range (± 0.5 °C), especially among patients with fever (−1.44 °C to 1.46 °C for adults; −1.49 °C to 0.43 °C for children) and hypothermia (−2.07 °C to 1.90 °C for adults; no data for children). For detection of fever, the peripheral thermometers' sensitivity was low (64%; 95% CI, 55% to 72%; I2 = 95.7%; P<0.001) but specificity was high (96%; 95% CI, 93% to 97%; I2 = 96.3%; P<0.001).

Researchers suggested that clinicians consider using central thermometers when accurate measurement of a patient's temperature will influence diagnosis and management. Rectal thermometers could be used for most of these patients, and bladder thermometers could be used for those requiring a bladder catheter. When a central thermometer is best avoided, such as in neutropenia, electronic oral thermometers (for adults) or tympanic membrane thermometers (for adults or children) that are calibrated before use seem to be the best alternative, they said.

“At extremes of body temperature, peripheral temperature measurements may be as much as 1 to 2 degrees higher or lower than actual body temperature,” the authors wrote. “Peripheral thermometers therefore represent a poor screening tool for detecting temperature abnormalities. In contrast, nonvascular central thermometers show excellent agreement with the gold standard, the pulmonary artery catheter, which confirms their clinical utility. Taken together with previous meta-analyses in children, our study provides clinically meaningful insight into the most appropriate means of monitoring a vital sign.”

Acute kidney injury risk factors identified in orthopedic patients

Researchers developed a risk score that accurately predicted risk of acute kidney injury among orthopedic surgery patients, according to a recent British study.

They used a cohort of adult Scottish patients who underwent orthopedic surgery between 2005 and 2011. Their model was developed in 6,220 patients at 2 hospitals and validated in 4,395 patients from another hospital. Results were published by the BMJ on Nov. 11, 2015.

Within a week of surgery, acute kidney injury occurred in 672 (10.8%) of the patients in the development cohort and 295 (6.7%) in the validation cohort. Older age, male sex, diabetes, number of prescribed drugs, lower estimated glomerular filtration rate, use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and higher American Society of Anesthesiologists grade were all independent predictors of acute kidney injury. A model based on those 7 factors showed good discrimination in both cohorts and good calibration in the development cohort, as well as the validation cohort after recalibration. Only the highest risks were over-predicted, the authors noted.

The study also looked at differences in survival and found that patients with acute kidney injury (including of the lowest severity) had a significant increase in mortality risk, with an adjusted hazard ratio (HR) of 1.53 (95% CI, 1.38 to 1.70) compared to those without kidney injury. The risk diminished over time, from a 90-day adjusted HR of 2.36 (95% CI, 1.94 to 2.87) to 1.40 (95% CI 1.10 to 1.79) in a year to 1.28 (95% CI, 1.10 to 1.48) after a year (median follow-up, 4.58 years).

There are few risk scores available for predicting acute kidney injury in noncardiac surgery patients, the authors noted. This study differs from a previous study that similarly investigated kidney injury by defining the condition more stringently as an increase in serum creatinine level of more than 0.3 mg/dL (26.4 µmol/L) based on the Kidney Disease Improving Global Outcomes criteria. Predicting these lower-severity cases seems important, given the notable difference in survival, they said. The risk factors should be validated in other geographic cohorts, but after that's done, the score could be used to guide perioperative management and motivate interventions such as frequent renal function monitoring, avoidance of nephrotoxins, and optimization of fluid balance, they suggested.

Radial artery access for catheterization may produce better outcomes than femoral access

During cardiac catheterization of patients with acute coronary syndrome (ACS), radial artery access reduced the risk of all-cause mortality and other adverse outcomes compared with femoral artery access, according to a recent study.

The meta-analysis examined 4 multicenter randomized trials comparing radial and femoral artery access in patients with ACS. Results were published online Nov. 10, 2015, by Annals of Internal Medicine. The trials, which reported clinical outcomes at 30 days, included 17,133 patients: 8,552 randomly assigned to radial access and 8,581 randomly assigned to femoral access.

Compared with femoral access, radial access was associated with reductions in all-cause death (risk ratio [RR], 0.73; 95% CI, 0.59 to 0.90; P=0.003); major adverse cardiac events (RR, 0.86; 95% CI, 0.75 to 0.98; P=0.025); access-site bleeding (RR, 0.36; 95% CI, 0.28 to 0.47; P<0.001); and major bleeding (RR, 0.57; 95% CI, 0.37 to 0.88; P=0.011). There were no significant differences between access points on the outcomes of myocardial infarction (MI) and stroke.

In the studies that included duration of procedure, radial procedures lasted slightly longer than femoral procedures (standardized mean difference, 0.11 minutes; 95% CI, 0.04 to 0.18 minutes; P=0.002). Radial access was also associated with a 4-fold higher risk of access-site crossover (6.3% vs. 1.7%, P<0.001).

The study's authors noted limitations to their analysis, such as how 2 trials enrolled only patients with ST-segment elevation MI (STEMI) and the other 2 that enrolled non-STEMI patients came to conflicting conclusions. They also could not assess whether the definitions of MI used in the trials satisfy modern criteria for adjudication of “clinically relevant” events. In addition, there was no standardized definition of major bleeding across studies.

“This study adds to the mounting evidence of the clinical benefits of radial access, and hopefully it will spur U.S. cardiologists to catch up to their international colleagues in greater adoption of this approach,” said an accompanying editorial. However, given the limitations of the study, the editorialists wrote that radial access should not be considered the “default strategy” for cardiac catheterization in patients with ACS, as the study authors suggest. Rather, cardiologists should increase their utilization of the radial approach and attain proficiency in both routes in order to provide the best care for their patients, according to the editorial.

30-day readmissions after MI declined over past decade

A recent study found a decline in 30-day readmissions after acute myocardial infarction (MI) from 2001 to 2011 and identified a few risk factors that may predict such readmissions.

The study included 4,810 patients treated for acute MI at 3 central Massachusetts hospitals between 2001 and 2011. All of the studied patients survived to hospital discharge, their average age was 69 years, and 92% were white. Results were published by the Journal of the American Heart Association on Nov. 3, 2015.

The percentage of patients being readmitted within 30 days declined from 20.5% in 2001-2003 to 15.8% in 2009–2011. After adjustment, the odds ratio for being readmitted in the latest period was 0.74 (95% CI, 0.61 to 0.91) compared to the earliest period. MI was the cause of only 8% of the readmissions, while 38% of them were for a noncardiovascular cause. Over the whole period, 36% of 30-day readmissions occurred within a week of discharge, which confirms other similar research and suggests that focusing on improving transitional care and early follow-up could reduce readmissions, the authors said.

They identified several patient factors that were associated with increased risk of readmission, including female sex, previously diagnosed heart failure or chronic kidney disease, and in-hospital development of cardiogenic shock or heart failure. “Although most of these factors are not modifiable, these findings suggest that health care providers should pay extra attention to these high-risk groups…when planning hospital discharge and postdischarge management,” the authors said.

Overall, the trend of declining readmissions is encouraging, according to the study authors, who expressed hope that their findings would “lead to better development of innovative, patient-centered intervention strategies that can improve in-hospital management and follow-up care.” They noted that the study's generalizability was limited by its population, who were treated at only 3 hospitals in a single geographic area.

Endovascular thrombectomy improved functional outcomes

Endovascular thrombectomy was associated with improved functional outcomes but no difference in 90-day mortality compared to standard stroke care, a recent meta-analysis found.

The analysis included 8 randomized clinical trials that compared endovascular therapy (with mechanical thrombectomy) to standard medical care including intravenous tissue plasminogen activator (tPA). There were 2,423 studied patients, including 1,313 receiving endovascular thrombectomy and 1,110 receiving standard care. Results were published in the Nov. 3, 2015, Journal of the American Medical Association.

Thrombectomy was associated with significant proportional treatment benefit in modified Rankin scale scores at 90 days (odds ratio [OR] 1.56; 95% CI 1.14 to 2.13; P=0.005). The thrombectomy groups were also more likely to be functionally independent at 90 days (44.6% vs. 31.8%; risk difference, 12% [95% CI, 3.8% to 20.3%]; OR, 1.71 [95% CI, 1.18 to 2.49]; P=0.005). However, angiographic revascularization within 24 hours was also more likely with thrombectomy (75.8% vs. 34.1%; OR, 6.49; 95% CI, 4.79 to 8.79; P<0.001).

The groups had no significant differences in 90-day rates of symptomatic intracranial hemorrhage or all-cause mortality. The authors noted that the existing research on thrombectomy is very heterogenous, with the initial studies of the technique failing to find significant benefit. The more recent studies, with positive findings, improved on the intervention in several ways, including more use of vascular imaging and tPA and more advanced mechanical devices. In the analysis, stent retrievers appeared to be associated with the most favorable outcomes, but there are still a number of open research questions about the application of this new technology, the authors said.

An accompanying editorial highlighted a number of those questions about thrombectomy, including which patients should get it, how late they can be treated, and which hospitals and which clinicians should perform it.

Expedited shocks, without prolonged compressions, had best outcomes in inpatient VF/VT arrest

Patients who had in-hospital, witnessed ventricular fibrillation/ventricular tachycardia (VF/VT) arrest were more likely to survive if they received stacked shocks instead of chest compressions before each shock, a study found.

The retrospective, observational study included all patients at 1 hospital who had a VF/VT arrest between July 2005 and June 2013 that was either witnessed by hospital staff or occurred while on cardiac monitoring. From 2005 to 2008, hospital protocol called for administration of 3 expedited stacked shocks with a brief pause between each single defibrillation attempt to confirm sustained VF/VT and before administering chest compressions. From 2008 to 2011, the protocol was changed to include a 2-minute period of chest compressions prior to each single defibrillation. Then, in 2011–2013, the hospital switched back to 3 expedited stacked shocks for monitored VF/VT arrest, with compressions between shocks if they did not interfere with rhythm analysis. However, patients who suffered unmonitored arrest were given 2 minutes of chest compressions prior to each defibrillation.

During the study period, 106 patients had VF/VT arrest (102 while monitored). Survival to hospital discharge was 58% during the initial stacked-shock period, 18% during the chest compression period, and 71% during the final period (P<0.01 for difference). Rates of return of spontaneous circulation were also better during the stacked shock periods, leading the study authors to conclude that inpatients who have monitored VF/VT should undergo expeditious defibrillation with use of stacked shocks.

They noted that in 2005, the American Heart Association changed recommendations for VF/VT defibrillation from 3 stacked shocks to a single shock followed by 2 minutes of chest compressions between defibrillation attempts, but that this advice was directed primarily at out-of-hospital arrests. The results of this study support the theory that the changing energy status of the heart in the minutes after arrest affects the success of shocks versus chest compressions, the authors noted.

“Our findings suggest that there is no ‘one size fits all’ approach to chest compression and defibrillation strategy. Instead, we suggest that factors including whether the arrest occurred while monitored or not aid with decision making and timing of defibrillation,” they wrote. The study was published by the Journal of Hospital Medicine on Oct. 28, 2015.

Treatment of post-thrombolysis hemorrhage fails to reduce mortality, hematoma growth

Treatment of post-thrombolysis symptomatic intracerebral hemorrhage (sICH) did not significantly reduce in-hospital mortality or hematoma expansion in a recent study.

Of 3,894 patients at 10 large U.S. stroke centers who received intravenous recombinant tissue plasminogen activator (rtPA) within 4.5 hours of symptom onset of ischemic stroke between Jan. 1, 2009, and April 30, 2014, 128 (3.3%) had sICH (median age, 74 years). Researchers studied these patients' treatment, time to treatment, and outcomes, and results of the retrospective analysis were published online on Oct. 26, 2015, by JAMA Neurology.

In 110 of the 128 patients (85.9%), clinicians made a diagnosis of sICH more than 2 hours after initiation of rtPA. The median time from initiation of rtPA therapy to sICH diagnosis was 470 minutes (range, 30 to 2,572 minutes), and the median time from diagnosis to treatment of sICH was 112 minutes (range, 12 to 628 minutes).

Researchers identified a nonsignificant suggestion (P=0.06) of lower in-hospital mortality in patients receiving any treatment for sICH versus no treatment. The association between lower in-hospital mortality and surgical treatment versus nonsurgical treatment was also nonsignificant (P=0.10).

“We found significant delays in the time to diagnosis and treatment for sICH, which could explain the lack of efficacy of these treatments,” the study's authors wrote. Of the various hemostatic agents used to treat sICH, the most common was cryoprecipitate (31.3% [40 of 128]).

A total of 49 of 128 patients (38.2%) received any treatment for sICH. Thirty-seven of the 128 patients (28.9%) had code status change to comfort care within the first 24 hours after sICH diagnosis, and they were more likely to die in the hospital.

Receipt of endovascular neurointerventional procedure (20.9% [14 of 67] of patients who died vs. 6.6% [4 of 61] of those who survived, P=0.02) and a higher median hematoma volume (29 vs. 16 mL, P=0.02) were the only other statistically significant factors associated with a higher in-hospital mortality rate.

The study's authors noted limitations to their analysis, such as its retrospective nature and the wide variations in management and treatment protocols used by participating stroke centers. These diverse treatments may have contributed to their neutral results, they noted. They also acknowledged that the effects of therapy may be underestimated because few patients received each of the sICH treatments.

Even with these limitations, this study highlights the complexity of the patient population, treatment options, and differences in clinical practice for sICH across the U.S., according to an accompanying editorial. “In addition, the variability in treatment for sICH is guided by each individual clinical situation,” the editorialist wrote. “An attempt to standardize treatment may be warranted and, ultimately, would help in determining whether treatment for sICH is actually beneficial.”

No mortality benefit with corticosteroids for CAP, but reductions in ARDS and LOS

Using corticosteroids to treat community-acquired pneumonia (CAP) doesn't affect mortality but may decrease risk of acute respiratory distress syndrome (ARDS) and shorten length of stay (LOS), according to a recent meta-analysis.

Researchers examined 9 randomized controlled trials (with 1,667 patients) and 6 cohort studies (with 4,095 patients) evaluating the use of corticosteroids in adult patients with CAP. The mean corticosteroid dose was methylprednisolone, 30 mg/d for 7 days. Results were published online in CHEST on Oct. 22, 2015.

In patients with CAP, corticosteroids did not have a statistically significant effect on mortality (relative risk [RR], 0.72; 95% CI, 0.43 to 1.21; evidence rank: low). The same was true among severe CAP patients (in randomized controlled trials: RR, 0.72; 95% CI, 0.43 to 1.21; evidence rank: low/in cohort studies: RR, 1.00; 95% CI, 0.86 to 1.17). Corticosteroids were associated with a significant decrease in ARDS (RR, 0.21; 95% CI, 0.08 to 0.59).

The analysis also looked at length of hospital and ICU stay, duration of intravenous antibiotic treatment, and time to clinical stability. The data were not sufficiently detailed to do a pooled analysis on these outcomes, but “nearly all included studies show that corticosteroid treatment tended to reduce” them, the authors reported. There was also no apparent increase in adverse events with corticosteroids.

The lack of mortality benefit (found regardless of whether patients had high or low inflammatory response and short- or long-term steroid treatment) might be due to insufficient doses of corticosteroids, rebound of inflammatory response after corticosteroid discontinuation, or side effects of corticosteroids, the authors speculated. Still, they concluded that short-term treatment with corticosteroids is safe, may reduce the risk of ARDS, and could shorten the duration of illness in CAP patients.

PPIs may benefit post-MI patients when NSAIDs cannot be avoided

Use of proton-pump inhibitors (PPIs) was independently associated with a decreased risk of gastrointestinal bleeding in post-myocardial infarction (MI) patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) along with antithrombotics, a Danish study found.

Researchers conducted a nationwide cohort study based on linked administrative registry data from all hospitals in Denmark between 1997 and 2011. The study included patients aged 30 years and over admitted with a first MI who survived at least 30 days after discharge. Of the 82,955 study patients (mean age, 67.4 years; 64% men) who were taking single or dual antithrombotic therapy, 42.5% filled at least 1 prescription for NSAIDs, 45.5% received PPIs, and 12.8% had concurrent NSAID and PPI exposure.

Results were published by BMJ on Oct. 19, 2015.

Over a mean follow-up of 5.1 years, 3,229 gastrointestinal bleeds occurred in the overall patient population, 282 (8.7%) of which were fatal. The crude incidence rate of gastrointestinal bleeding among patients on NSAID treatment was 2.1 (95% CI, 1.8 to 2.4) events per 100 person-years in those not on PPIs and 1.8 (95% CI, 1.4 to 2.4) events per 100 person-years in those receiving concurrent PPI treatment. The researchers concluded that PPI use was associated with a significantly lower risk of gastrointestinal bleeding (hazard ratio, 0.72; 95% CI, 0.54 to 0.95).

They also looked at NSAIDs by group (selective cyclooxygenase-2 inhibitors, non-selective NSAIDs, other NSAIDs) and found that PPIs were associated with similar adjusted hazard ratios and crude incidence rates with all types. Individual PPIs (omeprazole, pantoprazole, lansoprazole, and esomeprazole) were also associated with reduced bleeding risks. For individual NSAIDs (rofecoxib, celecoxib, diclofenac, ibuprofen, naproxen), hazard ratios for bleeding were lower with concurrent PPI use than without, but not significantly so, likely because of small numbers of events.

The authors noted that guidelines currently recommend concomitant PPIs for patients at high risk of gastrointestinal bleeding who are on antithrombotic and NSAID treatment. “The results suggest that PPI treatment probably has a beneficial effect regardless of underlying gastrointestinal risk and that when NSAIDs cannot be avoided in post-myocardial infarction patients, physicians might prescribe a PPI as well,” they wrote. “The study does not clarify whether PPIs might be safely omitted in specific subgroups of patients with a low risk of gastrointestinal bleeding.”