Recent Research

Perioperative aspirin, clonidine don't reduce AKI risk

Taking aspirin or clonidine before or after noncardiac surgery isn't associated with a lower risk of acute kidney injury (AKI), a study found.

Researchers studied 6,905 patients undergoing noncardiac surgery from 88 centers in 22 countries. Approximately half took 200 mg of aspirin or placebo 2 to 4 hours before surgery, then 100 mg of aspirin or placebo daily up to 30 days after surgery. The other half took 0.2 mg of oral clonidine or placebo 2 to 4 hours before surgery, then wore a transdermal clonidine patch (0.2 mg of clonidine/d) or a placebo patch until 72 hours after surgery. Researchers defined AKI as an increase in serum creatinine compared to preoperative concentration of either 0.3 mg/dL or more within 48 hours of surgery or an increase of 50% of more within 7 days of surgery.

Neither aspirin nor clonidine reduced the percentage of patients who had AKI (aspirin vs. placebo, 13.4% vs. 12.3%; adjusted relative risk [ARR], 1.10; clonidine vs. placebo, 13.0% vs. 12.7%; ARR, 1.03). Aspirin did increase the risk of major bleeding, and in a post hoc analysis, major bleeding was associated with a higher risk of subsequent AKI (23.3% AKI with bleeding present vs. 12.3% with bleeding absent; ARR, 2.20). Clonidine increased the risk of clinically important hypotension, which, in post hoc analysis, was associated with a higher risk of subsequent AKI (14.3% AKI with hypotension present vs. 11.8% with hypotension absent); ARR, 1.34). Results were published in the Dec. 3, 2014, Journal of the American Medical Association.

About 20 million adults who undergo major noncardiac surgery each year develop AKI, which is associated with long hospitalizations, poor outcomes, and high costs, the authors noted. Editorialists said the results were “sobering and constitute a setback to finding effective interventions to prevent AKI and the burden of its consequences.” They did, however, praise the genesis of the study itself, which involved partnering with investigators of large cardiovascular trials and proposing ancillary studies relevant to kidney research. “It is almost unfathomable that funding agencies would have funded a stand-alone trial of interventions for the primary prevention of acute kidney injury of the size and scope of [this study],” they noted.

Longer surgeries associated with higher clot risk

The duration of surgery was directly associated with the risk of postoperative venous thromboembolism, a large study found.

Researchers used retrospective cohort data from the American College of Surgeons National Surgical Quality Improvement Program to assess rates of deep venous thrombosis and pulmonary embolism in more than 1.4 million patients who had surgery at 315 U.S. hospitals between 2005 and 2011. Any venous thromboembolism (VTE) within 30 days was counted, and surgical duration was standardized across CPT codes. Results were published in JAMA Surgery on Dec. 3, 2014.

Overall, 0.96% of the patients had a VTE within 30 days of surgery (0.71% deep venous thrombosis and 0.33% pulmonary embolism). The risk of VTE increased with surgery duration in a stepwise fashion. Patients with the longest procedures had a 1.27-fold increased risk for VTE compared to those with average-length surgeries (95% CI, 1.21 to 1.34). The shortest surgeries were associated with a lower risk of a clot than an average surgery (adjusted odds ratio, 0.86; 95% CI, 0.83 to 0.88).

The finding of a direct association between surgical duration and VTE risk confirms a widely held, but not previously proven, belief and should inform perioperative decision making, the study authors concluded. Physicians could target chemoprophylaxis strategies and better inform patients of the risks of surgery based on risk stratification. An effective way to do this might be to categorize surgeries as long, short, or average, the authors suggested. Current risk stratification scores (the Caprini and Rogers scores) put little weight on the duration of surgery, the authors noted.

The study's observational design prohibits any definitive conclusion that there is a causal relationship between surgery duration and VTE risk. However, even if the association is not cause-and-effect, surgery duration could serve as a marker for the increase in risk caused by whatever confounding factor, the authors concluded.

Poorest neighborhoods have increased 30-day readmission risk

Living in a very disadvantaged neighborhood is associated with an increased risk of 30-day readmission equivalent to having chronic obstructive pulmonary disease, a recent study found.

Researchers used a random 5% sample of Medicare patients (n=255,744) who had been discharged from a hospital with congestive heart failure, pneumonia, or myocardial infarction between 2004 and 2009. The patients' rate of readmission within 30 days of discharge was compared to their area deprivation index (ADI), a measure of neighborhood socioeconomic status based on the 2000 Census. Results were published in the Dec. 2, 2014, Annals of Internal Medicine.

In the 85% of neighborhoods that were less disadvantaged, the readmission rate was 21% on average, and it did not differ significantly by neighborhood. However, in the other 15% of neighborhoods, worsening ADI was associated with a significant increase in readmission rates, from 22% in the best to 27% in the worst. Researchers calculated that patients in the most disadvantaged neighborhoods would have a risk ratio of readmission of 1.09 (95% CI, 1.05 to 1.12), similar to that associated with chronic obstructive pulmonary disease.

The results show that living in a severely disadvantaged neighborhood predicts readmission risk and that patients living in these areas are at higher risk for readmission regardless of their treating hospital, the study authors concluded. This information and the ADI measure itself could be useful not only for research but for individual readmission risk prediction. A free online tool allows clinicians to look up a patient's ADI using only his or her ZIP+4 code.

The ADI could then be used to target efforts to prevent readmissions, including transitional care services, discussion of the socioeconomic environment and need, and connections to community resources. It could also potentially be used on a health system or policy level to identify neighborhoods in need of more services. The ADI could also be used as a method to adjust Medicare readmissions penalties based on socioeconomic status, the authors suggested.

In response to the study, 2 of the developers of the Medicare readmissions measures wrote an accompanying editorial. They noted that the exclusion of race and socioeconomic status (SES) was intentional. Adjusting based on SES could be misleading and provide benefits to hospitals providing inferior care to poor patients, the editorialists said. “Measures that obscure disparities can contribute to complacency in addressing differences in outcomes by SES and race. Nevertheless, payment policies should strive to improve, and certainly not worsen, the situation for patients,” the editorial said.

Early tube feeding didn't reduce infections, mortality in severe pancreatitis

Feeding patients with acute pancreatitis through a nasoenteric tube only if they failed to tolerate oral intake 72 hours after diagnosis resulted in similar outcomes as early tube feeding, a Dutch study found.

The study included 208 patients from 19 Dutch hospitals who had acute pancreatitis and were considered at high risk for complications, based on an Acute Physiology and Chronic Health Evaluation II score of 8 or higher, an Imrie or modified Glasgow score of 3 or higher, or a serum C-reactive protein of more than 150 mg/L. They were randomly assigned to nasoenteric tube feeding within 24 hours (early) or an oral diet initiated 72 hours after presentation with tube feeding only if the oral diet was not tolerated (on demand).

The primary end point of the study was a composite of major infection or death within 6 months. That occurred in similar numbers of patients in each group: 30% of the early group and 27% of the on-demand group (risk ratio, 1.07; 95% CI, 0.79 to 1.44; P=0.76). The groups also showed no significant difference in major infection (25% early vs. 26% on demand; P=0.87) or death (11% vs. 7%; P=0.33). Most patients in the on-demand group (69%) tolerated the oral diet and never required tube feeding. Results were published in the New England Journal of Medicine on Nov. 20, 2014.

Early nasoenteric tube feeding was not superior to on-demand feeding in this analysis, the study authors concluded. That finding differs from both clinical guidelines supporting early nasoenteric feeding and previous research. However, previous randomized trials compared early nasoenteric tube feeding with total parenteral nutrition, which carries complication risks of its own, and prior observational studies comparing early and later feeding may have been confounded by healthier patients being fed sooner.

The study authors suggested several possible explanations for their findings, including that enteral feeding is not as effective as believed, that tube feeding should have been started even earlier, that the study was too small to detect a difference, and that patients were misclassified with severe pancreatitis. However, if tube feeding were restricted to severe pancreatitis patients who couldn't tolerate an oral diet, both patient discomfort and cost would be significantly reduced, the authors concluded.

Left atrial appendage closure fares better than warfarin for nonvalvular afib

Patients with nonvalvular atrial fibrillation and elevated stroke risk had better outcomes with mechanical left atrial appendage closure than with warfarin, a study found.

Researchers studied 707 patients from 59 hospitals who had nonvalvular atrial fibrillation (AF) and at least 1 additional stroke risk factor. Patients were enrolled between February 2005 and June 2008, and were followed for a mean of 3.8 years. They were randomized to receive percutaneous left atrial appendage (LAA) closure (n=463) using the WATCHMAN device, or warfarin (n=244) at a target international normalized ratio of 2-3. The main outcome was a composite including stroke, systemic embolism, and cardiovascular or unexplained death. Secondary endpoints included cardiovascular and all-cause mortality. Results were published Nov. 19, 2014, by the Journal of the American Medical Association, and the study was funded by Atritech, the WATCHMAN manufacturer.

Patients in the LAA group had 40% lower incidence of composite events (8.4%, 39 events) compared with the warfarin group (13.9%, 34 events; rate ratio, 0.60; 95% CI, 0.41 to 1.05), which met prespecified criteria for noninferiority and superiority. LAA patients had lower rates of all-cause death (12.3% LAA vs. 18% warfarin; hazard ratio [HR], 0.66; 95% CI, 0.45 to 0.98; P=0.04) and cardiovascular mortality (3.7% vs. 9.0%; HR, 0.40; 95% CI, 0.21 to 0.75; P=0.005). The latter appeared to have been influenced heavily by lower rates of hemorrhagic stroke (0.4% vs. 3.3%; P=0.004). Adherence to treatment in the warfarin group was high at 70% of time being in therapeutic range.

The authors cautioned that all-cause and cardiovascular death, which were apparently reduced with LAA, were secondary end points and “due to multiplicity of data analysis, there is some uncertainty in the confidence of [these] conclusion[s].” Also, LAA closure in this trial was randomized against warfarin, and the results shouldn't be generalized to the newer Factor II and Xa inhibitors, they said. Inclusion and exclusion criteria in the trials were similar to other large stroke prevention trials, except that patients with a left-ventricular ejection fraction less than 30% were excluded since LAA closure wouldn't prevent thromboembolism from the left ventricle, they also noted.

More bleeds and clots in afib patients who took NSAIDs

Patients with atrial fibrillation who were prescribed NSAIDs had more serious bleeding and thromboembolic events than those not on NSAIDs, a Danish study found.

The observational cohort study included more than 150,000 patients with atrial fibrillation who were hospitalized in Denmark between 1997 and 2011. During a median follow-up of 6.2 years, 35.6% of them were prescribed an NSAID. In the overall patient group, 11.4% had a serious bleed and 13% had a thromboembolism, which were the study's primary outcomes. Results were published in the Nov. 18, 2014, Annals of Internal Medicine.

Within 14 days of taking NSAIDs, the risk of a bleed or thromboembolism was 3.5 per 1,000 patients compared to 1.5 per 1,000 patients in those not taking NSAIDs (difference, 1.9 events per 1,000), according to the researchers' calculations at 3 months from study inclusion. In patients who were taking oral anticoagulant therapy, the increase in risk associated with NSAID use was even greater, with an additional 2.5 events per 1,000 patients. NSAIDs were associated with an increased risk for both adverse outcomes across all antithrombotic regimens and NSAID types. A dose-response effect was found, with NSAID doses above the recommended minimum being associated with a greater risk for bleeding.

Use of NSAIDs in atrial fibrillation patients was associated with an increased risk for serious bleeding even when the drugs were only used for a short time, the researchers concluded. Although this association had been assumed, the magnitude of the hazard—which the researchers calculated to be 1 serious bleeding event per 400 to 500 patients on NSAIDs—had not previously been defined. NSAIDs were also shown to be associated with thromboembolism risk, which is important because it suggests that prescribing an NSAID to a patient with atrial fibrillation could counteract the effects of oral anticoagulant therapy, the authors said.

Based on these results, physicians should use caution prescribing NSAIDs to atrial fibrillation patients, avoiding them unless other options, such as physical therapy and acetaminophen or other drugs, have failed, the study authors concluded. They acknowledged that the study was limited by its observational design, inclusion of only patients sick enough to be hospitalized, and unmeasured confounders.

ARBs appear beneficial in STEMI with preserved left ventricular systolic function

Angiotensin-receptor blockers (ARBs) may provide benefits similar to angiotensin-converting enzyme (ACE) inhibitors in patients with ST-segment elevation myocardial infarction (STEMI) and preserved left ventricular systolic function, according to a recent study.

Researchers in Korea performed a prospective cohort study using data from a nationwide registry to examine the effect of ARB treatment on clinical outcomes in patients with STEMI who had primary percutaneous coronary intervention and a left ventricular ejection fraction of 40% or greater. Patients were categorized as receiving ARBs, ACE inhibitors, or no renin angiotensin system blockers. The study's main outcome measures were cardiac death or MI. Results were published online Nov. 14, 2014, by The BMJ.

A total of 6,698 patients seen between November 2005 and September 2010 were included in the study. Of these, 1,185 received ARBs (17.7%), 4,564 received ACE inhibitors (68.1%), and 949 received no renin angiotensin system blockers (14.2%). In these groups, respectively, 21 patients (1.8%), 77 patients (1.7%), and 33 patients (3.5%) experienced cardiac death or MI over a median follow-up of 371 days (interquartile range, 167 to 450 days). With propensity score matching done for 1,175 pairs, no significant difference was seen in cardiac death or MI rates between the ARB group and the ACE inhibitor group (1.8% vs. 2.0%; adjusted hazard ratio, 0.65; 95% CI, 0.30 to 1.38; P=0.65). In matched populations (803 pairs), the ARB group had a lower rate of cardiac death or MI than the no renin angiotensin system blocker group (1.7% vs. 3.1%; adjusted hazard ratio, 0.35; 95% CI, 0.14 to 0.90; P=0.03).

The authors noted that they did not have information on doses or duration of ACE inhibitors or ARBs, that the registry data they used were not randomized, and that the study was underpowered, among other limitations. However, they concluded that use of ARBs at discharge after STEMI in patients with preserved or slightly reduced systolic function yielded similar results to use of ACE inhibitors. They pointed out that although guidelines recommend consideration of ACE inhibitors for all patients without contraindications after STEMI, many patients cannot tolerate the drugs. “As the number of patients with preserved left ventricular systolic function is much greater than the number with depressed left ventricular systolic function after STEMI, the establishment of the role of angiotensin receptor blocker in patients with preserved left ventricular systolic function after STEMI is important,” the authors wrote.

COX-2 inhibitors associated with greater risk for death after ischemic stroke

Cyclooxygenase (COX)-2 inhibitor use before hospital admission for ischemic stroke was associated with a higher 30-day mortality rate, according to a recent study.

Researchers performed a nationwide population-based cohort study in Denmark to investigate whether nonselective NSAID use or COX-2 inhibitor use before hospital admission for stroke was associated with 30-day mortality. Medical databases were used to identify all hospitalizations for first-time stroke between 2004 and 2012, as well as subsequent death. NSAID use was defined as current use (i.e., redeeming a prescription within 60 days pre-hospital admission), former use, and nonuse. Current use was then classified as new or long-term, and hazard ratios for death within 30 days were calculated. Study results were published online Nov. 5, 2014, by Neurology.

A total of 100,043 patients with first-time stroke were identified. Of these, 51,224 (51%) had ischemic stroke, 11,779 (12%) had intracranial hemorrhage, 4,528 (5%) had subarachnoid hemorrhage, and 32,512 (32%) had unspecified stroke. Median patient age in these groups was 74 years, 72 years, 58 years, and 76 years, respectively. Overall, 10,835 patients (10.8%) reported currently using NSAIDs (54.2% ibuprofen, 3.2% naproxen, 27.0% diclofenac, 10.7% etodolac, 1.0% celecoxib, and 0.5% rofecoxib). In addition, 8,402 (8.4%) reported former NSAID use and 80,806 (80.8%) reported no use. A total of 15.5% of patients used NSAIDs after discharge for ischemic stroke, 6.1% used them after intracranial hemorrhage, and 4.9% used them after subarachnoid hemorrhage.

Thirty-day mortality rates among NSAID users were 8.7% for ischemic stroke, 35.1% for intracranial hemorrhage, 24.5% for subarachnoid hemorrhage, and 14.3% for unspecified stroke. At 30 days, the adjusted hazard ratios for death were 1.19 (95% CI, 1.02 to 1.38) in patients who had ischemic stroke and were current users of selective COX-2 inhibitors compared with nonusers. The mortality hazard ratio for new users in this group was 1.42 (95% CI, 1.14 to 1.77). When different COX-2 inhibitors were compared, the hazard ratio was 1.42 (95% CI, 1.14 to 1.78) for new users of older, traditional COX-2 inhibitors; separately, etodolac use had a hazard ratio of 1.53 (95% CI, 1.02 to 2.28) and diclofenac use had a hazard ratio of 1.28 (95% CI, 0.98 to 1.68). No association was seen between use of nonselective NSAIDs or COX-2 inhibitors and death from intracerebral hemorrhage.

The researchers noted that patients were not randomly assigned and that detailed data were not available on such characteristics as smoking, body weight, or indications for NSAIDs, among other limitations. However, they concluded that use of COX-2 inhibitors before hospital admission for ischemic stroke was associated with an increased risk for 30-day mortality. This association was not seen for hemorrhagic stroke or with nonselective NSAIDs. They also pointed out that the increased mortality rate for ischemic stroke was noted only in current users of COX-2 inhibitors, increasing the likelihood that the finding was a true drug effect.

“Our study adds to the increasing body of evidence concerning the vascular risk and prognostic impact associated with use of COX-2 inhibitors,” the researchers wrote. “The prognostic impact also needs to be considered when prescribing older or newer COX-2 inhibitors to patients at increased risk of thromboembolic events.” A true causal association would strongly support efforts to ensure that COX-2 inhibitors aren't prescribed to patients at high risk for stroke if other treatments are available, they noted.

Random or fasting glucose tests can target diabetes screening after MI

Random or fasting glucose measurements can be used to screen for diabetes in patients admitted for acute myocardial infarction, a study found.

The prospective study included 1,574 patients at 24 hospitals who were not taking any glucose-lowering medications when they were admitted for acute myocardial infarction (MI). All of the patients had a random plasma glucose (RPG) taken at admission and at least 2 fasting plasma glucose (FPG) levels measured during hospitalization. All also received an HbA1c test (with a result ≥6.5% considered a diabetes diagnosis) to evaluate the accuracy of RPG and FPG as screening tools. Results were published online Nov. 4, 2014, by BMJ Open Diabetes Research & Care.

The study found that a RPG >140 mg/dL or an FPG ≥126 mg/dL was highly sensitive for diabetes diagnosis. Using those glucose levels as cutoffs for HbA1c testing would have identified 86% of the patients with diabetes and necessitated only half of the overall MI group getting their HbA1c tested. With those cutoffs, the number needed to screen (NNS) would be 3.3 to identify 1 case of diabetes versus 5.6 with universal HbA1c testing of MI patients. Raising the cutoff to RPG >180 identified 82% of diabetics, required 40% of MI patients to get an HbA1c, and had an NNS of 2.7.

These selective screening methods could identify the vast majority of incident diabetes in MI patients with less-than-universal HbA1c testing, the study authors concluded. Targeting screening would be more cost-effective in practice, and these cutoffs could also be useful for research in which HbA1c results are unavailable, they noted. The patients whose diabetes would be missed by this screening method were the ones with relatively mild elevations in HbA1c, perhaps lessening the consequences of the missed diagnoses, the researchers noted, although they also acknowledged that this screening system would not identify patients with pre-diabetes for intervention.

Screening for diabetes with RPG or FPG could be particularly useful in resource-limited settings, to accomplish the important goal of identifying diabetes during hospitalization for acute MI, and targeting diabetic patients for educational, lifestyle and medical interventions, the study authors concluded.

Trials show no benefit of progesterone in traumatic brain injury

Two phase III trials published in the Dec. 25, 2014, New England Journal of Medicine found no benefit to progesterone therapy in traumatic brain injury (TBI).

In a multinational, industry-funded, placebo-controlled trial, 1,195 patients aged 16 to 70 years who had severe TBI were randomly assigned to receive IV progesterone or placebo, starting 8 hours after injury and continuing for 120 hours. The median progesterone level after treatment was 333.5 ng/mL. The Glasgow Outcome Scale score at 6 months after the injury was the primary efficacy end point.

After proportional-odds analysis with covariate adjustment, no treatment effect was seen with progesterone compared with placebo (odds ratio, 0.96; 95% CI, 0.77 to 1.18). Overall, 50.4% of the progesterone group had a favorable outcome, defined as good recovery or moderate disability, on the Glasgow Outcome Scale, versus 50.4% in the placebo group. Both groups had similar mortality rates and no relevant differences in safety.

The authors noted that TBI trials often fail, probably because the condition is complex and variable and because the available outcome measures lack sensitivity. In addition, they said, current methods of categorizing TBI are “mainly unidimensional” and don't allow the use of appropriately targeted therapy. The authors concluded that the progesterone regimen tested in their trial did not benefit patients with severe TBI and called for “a rethinking of procedures for drug development and testing in TBI.”

The second study was a double-blind, multicenter clinical trial funded primarily by the National Institute of Neurological Disorders and Stroke that examined very early administration of progesterone for acute TBI. Patients with severe, moderate-to-severe, or moderate acute Glasgow Coma Scale scores were randomly assigned to receive IV progesterone or placebo. Treatment was begun within 4 hours of an injury and continued for 96 hours (1-hour loading dose, 71 hours of maintenance infusion, and a 24-hour taper). The primary efficacy outcome was an increase of 10 percentage points in patients with a favorable outcome at 6 months according to the stratified dichotomy of the Extended Glasgow Outcome Scale score.

A sample of 1,140 adult patients was planned, but the trial was stopped for futility regarding the primary outcome after 882 patients had undergone randomization. No significant difference was seen in proportion of patients with a favorable outcome (51.0% in the progesterone group vs. 55.5% of the placebo group); the relative benefit of progesterone was 0.95 (95% CI, 0.85 to 1.06; P=0.35). Although phlebitis or thrombophlebitis was more common in the progesterone group (relative risk, 3.03; 95% CI, 1.96 to 4.66), no other significant differences were seen in safety outcomes.

The authors noted that the heterogeneity of TBI poses many challenges in clinical trials and that approaches to reduce heterogeneity result in less generalizability. They called for new paradigms in early-phase clinical trials that allow the identification of effective drug doses and timing, targeted outcomes based on the mechanism of injury, and trials in animals that are better at simulating trials in humans.

The author of an accompanying editorial also said that changes in research are necessary, since failed trials share many of the same features, including “slower-than-expected enrollment, overly optimistic effect sizes, better-than-expected performance in the placebo groups, and sample-size estimates that were based on one of multiple efficacy outcomes in small safety trials.” He called for “radical change in the culture of investigation and its funding,” including collaborative research networks; better reporting and pooling of preclinical data; coordinated, sequential exploratory phase 2 trials with standardized outcomes; and phase 3 trials that test “well-vetted hypotheses.” If such changes are made, the editorialist wrote, “Negative trial results, when they do occur, will contribute more to medical progress because they will have definitively answered a question that was worth asking in the first place.”

Emphysema on CT may be an important independent risk factor for death

Emphysema found on computed tomography (CT) was associated with an increased risk for mortality among people without airflow obstruction or chronic obstructive pulmonary disorder (COPD), a study found.

To determine the prognostic significance of emphysema-like lung among patients without COPD, researchers conducted a prospective cohort study among 2,965 patients aged 45 to 84 years who had no COPD on spirometry for 6 years. The study population was adapted from MESA (Multi-Ethnic Study of Atherosclerosis), which enrolled patients from 2000 to 2002 from 6 study sites across the U.S. Each patient had cardiac CT at baseline as part of that study.

Results appeared in the Dec. 16, 2014, Annals of Internal Medicine.

There were 186 deaths over a median of 6.2 years, for a mortality rate of 10.0 per 1,000 person-years. Greater emphysema-like lung was associated with higher mortality (adjusted hazard ratio [HR] per one-half interquartile range [IQR], 1.14; 95% CI, 1.04 to 1.24; P=0.004) after adjustment for potential confounders, including cardiovascular risk factors and FEV1. Potential mediators minimally attenuated the results (HR per half-IQR of emphysematous voxels, 1.13; 95% CI, 1.04 to 1.24]; P=0.006).

Associations with mortality were strengthened after excluding patients below the fifth percentile and above the 95th percentile for emphysematous voxels (HR per half-IQR, 1.27; 95% CI, 1.09 to 1.48; P=0.002). An additive model showed little evidence for a nonlinear relationship (P for linear term=0.006; P for nonlinearity=0.22)

The authors wrote, “These findings suggest that emphysema confers excess risk independent of spirometrically defined COPD. Clinical appreciation of the prognostic implications of emphysema on CT and investigation of therapies specifically targeting emphysema, of which there are none, are warranted.”

Thrombectomy up to 6 hours after ischemic stroke symptoms shows benefit

Patients with severe ischemic stroke may benefit from thrombectomy within 6 hours of symptom onset, a recent study found.

The current study aimed to correct the problems of previous studies in this population by enrolling patients with severe stroke who had proof of proximal vessel occlusion, initiating treatment as early as possible, and using modern devices, an editorialist wrote. Previous trial results were negative or ambiguous but had several methodological problems, including the use of older thrombectomy devices and a long interval between stroke onset and intervention, he noted.

The researchers enrolled 500 patients at 16 medical centers in The Netherlands, with 233 randomly assigned to intra-arterial treatment plus usual care (often thrombolysis) and 267 randomly assigned to usual care alone. Patients must have had a proximal arterial occlusion in the anterior cerebral circulation that was confirmed on vessel imaging and that could be treated intra-arterially within 6 hours after onset of stroke symptoms. The main outcome was functional outcomes at 90 days as measured by the modified Rankin score; scores ranged from 0 (no symptoms) to 6 (death). A score of 2 or less indicated functional independence. Results were published Dec. 17, 2014, by the New England Journal of Medicine.

Eighty-nine percent of all patients were treated with intravenous alteplase before randomization, and of those assigned to thrombectomy, 81.5% received retrievable stents. Intervention patients had significantly better functional outcomes than usual-treatment patients (adjusted common odds ratio, 1.67; 95% CI, 1.21 to 2.30). Specifically, there was a 13.5-percentage point difference between groups in the proportion of patients who were functionally independent on the Rankin score, in favor of the intervention (32.6% vs. 19.1%). The groups didn't differ significantly in mortality or the occurrence of symptomatic intracerebral hemorrhage.

The authors noted that, unlike previous trials of intra-arterial treatment that occurred when availability of computed tomographic angiography was limited, the current trial required a radiologically proven intracranial occlusion for patients to be eligible. “It is likely that intraarterial treatment will not alter the natural history of acute ischemic stroke in the absence of a proximal arterial occlusion,” they noted. The study also benefited from the widespread availability of retrievable stents, they wrote.

The editorialist said the trial was “the first step in the right direction” in determining if thrombectomy should become the new standard treatment for severe stroke with proximal large-vessel occlusion up to 6 hours after stroke onset. Because several similar trials are currently underway, “it is premature to conclude that there is no longer equipoise regarding thrombectomy. We need and will get results from other well-designed trials, not only to confirm or refute the [current] results but also to look at effects in subgroups…,” he wrote.

Benzodiazepines overused, especially in elderly women

Benzodiazepines are frequently prescribed long-term and to elderly patients, despite guidelines to the contrary, a recent study found.

Researchers used a prescription database that includes about 60% of U.S. retail pharmacies to identify prescriptions for benzodiazepines in 2008 and then extrapolated the results to the U.S. population. Overall, about 5.2% of adults age 18 to 80 filled a prescription for a benzodiazepine in 2008, the study found. Study results were published by JAMA Psychiatry on Dec. 17, 2014.

Benzodiazepine use increased with age, from 2.6% in 18- to 35-year-olds to 5.4% in 36- to 50-year-olds to 8.7% in 65- to 80-year-olds. Long-term use also increased with each age group, from 14.7% in the youngest to 31.4% in the oldest. Use was nearly twice as prevalent in women as in men, and older patients were much less likely to get their prescription from a psychiatrist than younger ones. In all age groups, about a quarter of prescriptions were for a long-acting benzodiazepine.

The study shows that benzodiazepine use remains common, especially in older patients, despite evidence of risks including falls, fractures, and motor vehicle crashes, the study authors said. The data don't show why the prescriptions were written, but it's likely that many were intended to treat insomnia, despite guidelines indicating that benzodiazepines should only be used for severe and impairing insomnia on a short-term basis. Physicians' failure to follow the guidelines might be attributable to deficits in clinicians' knowledge, time, or access to alternatives or to patient unwillingness to consider alternatives.

It appears that guidelines are insufficient to dissuade physicians from prescribing benzodiazepines to older patients, so other strategies should be tried, the study authors said. For patients on the drugs, the authors recommended gradual withdrawal with psychotherapy, if possible, or at least sending a letter or e-mail encouraging patients to stop or reduce use. Inappropriate prescriptions could put prescribers at liability risk, the authors said.

Benzodiazepines “fare little better than placebos” for effectiveness and are “far from safe,” an accompanying editorial said. To reduce inappropriate use, it may be necessary to restrict prescriptions of the drugs to psychiatrists or to categorize them as controlled substances, with limited-duration prescriptions with no refills, the editorialists concluded.