Recent Research

Statins and stroke, azithromycin and mortality, and more.


Statins not associated with more strokes in meta-analysis

Statin therapy was not associated with a significant increase in intracerebral hemorrhages (ICHs) and was associated with significant reductions in all strokes and death in a meta-analysis of 31 randomized, controlled trials.

Study authors searched the literature through January 2012 to identify randomized, controlled trials of statin therapy that reported ICH or hemorrhagic stroke. The primary outcome was ICH. Results were published in the August Stroke.

There were 91,588 subjects in the active (statin-taking) group and 91,215 in the control group, with a median length of follow-up of 46.8 months. ICH occurred in 358 subjects (0.39%) in the active group versus 318 (0.35%) in the control group. In the primary analysis, assessing ICH risk in 30 studies of statin treatment, active therapy was not associated with an increase in ICH (odds ratio [OR], 1.08; 95% CI, 0.88 to 1.32; P=0.47).

There were 6,262 strokes in this meta-analysis. The overall stroke rate was 3.13% in the active group versus 3.72% in the control group. Statin therapy was associated with a significant reduction in total stroke (OR, 0.84; 95% CI, 0.78 to 0.91; P<0.0001).

Overall mortality was 20,195 deaths. There was a significantly lower rate of all-cause mortality in the active group (10.67%) than in the control group (11.43%; OR, 0.92; 95% CI, 0.87 to 0.96; P=0.0007). The number needed to treat with active statin therapy to prevent 1 death was 167 (absolute risk reduction=0.6%, P<0.0001). The authors wrote, “These findings support the current recommendations to prescribe statins in otherwise appropriate patients.”

Study suggests not to lower blood pressure in acute phase of stroke

Blood pressure-lowering should probably be avoided in the acute phase of stroke, results of a secondary analysis suggest.

An initial analysis found that the angiotensin receptor blocker candesartan modestly reduced blood pressure in acute stroke, but didn't reduce vascular events or improve functional outcomes at six months. For the secondary analysis, researchers sought to investigate the effect of a decline in systolic blood pressure (SBP) over the first two days after stroke. The study comprised 2,029 patients who presented within 30 hours of acute ischemic or hemorrhagic stroke who had an SBP of at least 140 mm Hg. They were randomized to either candesartan or placebo. The main outcome (“adverse events”) was a combined end point of recurrent stroke, stroke progression and symptomatic hypotension during the first seven days of treatment. Secondary outcomes were neurological status at seven days, difference in neurological status from baseline to Day 7, and functional outcome at six months.

Seventy-one percent of patients (n=1421) had a reduction in SBP from baseline, and 29% had unchanged or increased SBP. The group with the largest decline in SBP had significantly higher baseline SBP and diastolic blood pressure, shorter duration of stroke symptoms before randomization, and less severe strokes. Compared to patients with a small decrease in SBP, those with a large decrease had a significantly higher risk of early adverse events (odds ratio [OR], 2.08). Patients with an increase or no change in SBP also had a higher risk of early adverse events (OR, 1.96) than those with a small decrease, as well as a higher risk of poor neurological outcome at 7 days compared to all other groups (P=0.001). No differences were seen in functional outcomes at six months. Results were published in the August Stroke.

The finding that patients with an increase in SBP had a higher risk of early adverse events could be because the increase was a marker for other disease, infection or pain, the authors said. Patients in this group also had lower stroke scale scores at the time of inclusion and were more likely to receive thrombolysis, which could mean they had a poorer prognosis at baseline, they added. Overall, the results suggest that “large reductions in blood pressure should probably be avoided, and blood pressure-lowering should not be given routinely in the acute phase of stroke,” they wrote.

Azithromycin associated with more cardiac, all-cause mortality

Taking azithromycin can increase one's risk of cardiovascular death, especially for patients who have a high baseline risk of cardiovascular disease, a recent study found.

The cohort study of Tennessee Medicaid patients was motivated by existing evidence that azithromycin may be proarrhythmic. In the study, about 350,000 patients who took azithromycin were propensity-score matched with people who took no antibiotics (about 1.4 million control periods), 1.3 million patients who took amoxicillin, 265,000 taking ciprofloxacin and 194,000 on levofloxacin. The results were published in the May 17 New England Journal of Medicine.

The risk of cardiovascular death during five days of azithromycin therapy was almost three times that of patients taking no antibiotics (hazard ratio, 2.88; P<0.001). Azithromycin patients also had an increased risk of death from any cause (hazard ratio, 1.85; P=0.002). The increased risk of both cardiovascular and all-cause death was also found when the azithromycin patients were compared to the amoxicillin patients, who had no increase in risk compared to non-antibiotic-taking controls. The risk associated with azithromycin also exceeded that associated with ciprofloxacin but was similar to the risk from levofloxacin.

The study authors calculated that use of azithromycin could result in 47 additional cardiovascular deaths per 1 million courses of antibiotics. The danger for patients with high baseline cardiovascular risk is even greater: 245 cases per 1 million courses. Although a specific causal mechanism cannot be established, the data from this study are consistent with an adverse cardiac effect of azithromycin, the authors concluded. They also noted that the increase in risk does not persist after azithromycin therapy ends.

In response to the study, the FDA announced that it is in the process of updating risk information on the labels of macrolide antibiotics and will review the data from this study. For now, clinicians should be aware of the potential for QT prolongation and arrhythmias in patients taking macrolides, it said.

Combination therapy for pulmonary fibrosis may increase risk of death

A combination of prednisone, azathioprine and N-acetylcysteine (NAC) for pulmonary fibrosis prompted a trial to stop early after it showed an increased risk of death and hospitalization compared with NAC alone and with placebo.

The randomized, double-blind, placebo-controlled trial examined patients ages 35 to 85 with idiopathic pulmonary fibrosis who had mild-to-moderate lung function impairment, defined as forced vital capacity ≥50% and a carbon dioxide diffusing capacity ≥30%. They were randomized equally into one of three groups: combination therapy, NAC alone or placebo.

Prednisone was started at 0.5 mg/kg of ideal body weight and was tapered to 0.15 mg/kg over 25 weeks. Azathioprine was given at a maximum of 150 mg/d, while NAC was given at 600 mg orally three times a day. The primary study outcome was the change in longitudinal measurements of forced vital capacity during a 60-week treatment period.

After about half the data had been collected (with 77 patients on combination therapy and 78 in the placebo group), a planned interim analysis revealed that combination therapy patients had an increased rate of death compared with placebo (8 vs. 1; P=0.01) and hospitalization (23 vs. 7; P<0.001). There was no evidence of physiological or clinical benefit for combination therapy. Forced vital capacity was −0.24 L in the combination-therapy group and −0.23 L in the placebo group (P=0.85).

The data and safety monitoring board recommended ending the combination therapy group. “Our data that show increased rates of death and hospitalization provide compelling evidence against the use of the combination of azathioprine, prednisone and NAC for patients with idiopathic pulmonary fibrosis who have mild-to-moderate impairment in pulmonary function,” they concluded. The trial was published in the May 24 New England Journal of Medicine.

Aspirin may reduce VTE recurrence after stopping anticoagulants

Aspirin reduced the risk of venous thromboembolism (VTE) recurrence with no apparent increase in major bleeding in patients who had an initial unprovoked VTE and had discontinued anticoagulant treatment, a study found.

Researchers conducted a multicenter, double-blind trial among patients with first-ever unprovoked proximal deep venous thrombosis, pulmonary embolism or both who had completed six to 18 months of oral anticoagulant treatment with a target international normalized ratio (INR) of 2.0 to 3.0. VTE was considered to be unprovoked when it occurred in the absence of any known risk factor. More than 400 patients were randomized to aspirin, 100 mg once daily, or placebo for two years. Randomization occurred within two weeks after vitamin K antagonists had been withdrawn. The primary efficacy outcome was recurrence of VTE, and the primary safety outcome was major bleeding.

An overt bleeding event was defined as major if it was fatal, if it occurred in a critical location (intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, pericardial, or intramuscular [leading to a compartment syndrome]), or if it was associated with a decrease in hemoglobin level of at least 2.0 g/dL or required a transfusion of two or more units of whole blood or red cells. Clinically relevant, nonmajor bleeding was defined as any overt bleeding that required a medical intervention and did not meet any of the criteria for major bleeding. Study results appeared in the May 24 New England Journal of Medicine.

From May 2004 through August 2010, VTE recurred in 71 patients (8.6% patients per year). Recurrent VTE was due to deep venous thrombosis in 44 patients (ipsilateral in 51% of cases) and to pulmonary embolism in 27 patients (fatal in 2 patients). In 77% of cases, recurrence took place in the absence of any known risk factor for VTE. A recurrence in the form of pulmonary embolism was more common among patients who entered the study because of prior pulmonary embolism than among those who entered because of deep venous thrombosis (12.7% vs. 3.2%; hazard ratio [HR, 5.52; P<0.001). Overall, VTE recurred in 28 of the 205 patients who received aspirin, as compared with 43 of the 197 patients who received placebo (6.6% vs. 11.2% per year; HR, 0.58; P=0.02)

Over a median treatment period of 23.9 months, while taking the study drug, 23 patients in the aspirin group had a recurrence, as compared with 39 patients in the placebo group (5.9% vs. 11.0% per year; HR, 0.55; P=0.02). Eleven of 83 patients in the aspirin group who entered the study because of pulmonary embolism had a recurrent event, as compared with 16 of 67 patients in the placebo group (6.7% vs. 13.5% per year; HR, 0.38; P=0.02). Among the patients who entered the study because of deep venous thrombosis, 17 of 122 in the aspirin group and 27 of 130 in the placebo group had a recurrent event (6.5% and 10.2% per year, respectively; HR, 0.65; P=0.17).

Two episodes of nonfatal major bleeding occurred in the study, one in the placebo group (gastric ulcer) and one in the aspirin group (bowel angiodysplasia). Three patients in the aspirin group and three patients in the placebo group developed clinically relevant nonmajor bleeding (gingival bleeding and two cases of cutaneous hematomas in the aspirin group, hemorrhagic gastritis and two cases of musculoskeletal bleeding post-trauma in the placebo group). Five patients developed an adverse event that was attributed to the study drug and led to treatment withdrawal: gastric pain in three patients (two in the placebo group, one in the aspirin group), a cutaneous reaction in one patient (aspirin group), and renal failure in one patient (aspirin group).

In patients with unprovoked VTE, aspirin therapy begun after six to 18 months of oral anticoagulant treatment reduced the rate of recurrence by about 40%, vs. placebo, the authors wrote, and with no apparent increase in major bleeding risk.

Higher glucose levels at admission may predict mortality in CAP

Patients hospitalized for community-acquired pneumonia (CAP) who have higher glucose levels at admission may be at increased risk for death, a recent study indicated.

European researchers performed a multicenter prospective cohort study using data from a German collaborative CAP network to examine whether acute dysglycemia was associated with death in patients admitted for CAP. Primary outcome measures were univariable and multivariable hazard ratios, according to glucose levels at admission, for death at 28, 90 and 180 days, adjusted for age, sex, smoking status, CAP severity by the CRB-65 score (which measures confusion, respiratory rate >30/min, age ≥65 years, systolic blood pressure ≤90 mm Hg or diastolic blood pressure ≤60 mm Hg) and comorbid conditions. The study results were published online by BMJ on May 29.

The study included data from 6,891 patients with CAP who were hospitalized between 2003 and 2009. Three hundred twenty-four (4.7%) died within 28 days, 514 (7.5%) died within 90 days, and 648 (9.4%) died within 180 days. Increased glucose levels at admission were a predictor of death at 28 and 90 days in patients without preexisting diabetes. Risk for death at 90 days was significantly increased in patients with mild acute hyperglycemia at admission (serum glucose level, 6 mmol/L to 10.99 mmol/L [108 mg/dL to 198 mg/dL]) compared with those whose glucose levels were normal (hazard ratio [HR], 1.56; P<0.001); the risk was greater in patients with glucose levels of 14 mmol/L or higher (HR, 2.37; P<0.001). Patients who had preexisting diabetes at admission had a higher risk for death than those who did not, but this risk did not appear to be affected by admission glucose levels (P=0.18 for the interaction). CRB-65 score was also associated with increased mortality (P<0.001), while male sex and comorbidities were associated with increased mortality at 90 days (P<0.001).

The authors acknowledged that their study did not establish a causal relationship between glucose levels at admission and death and that it was difficult to distinguish between patients with undiagnosed diabetes and those with stress-related hyperglycemia, among other limitations. However, they concluded that even slightly increased serum glucose levels at hospital admission for CAP increase mortality risk. “Large scale trials are needed to define optimal serum glucose levels and to determine if a drug intervention is suitable to reduce mortality in patients with community acquired pneumonia,” they wrote.

Elevated troponin T may help predict 30-day mortality

Troponin T levels independently predict 30-day mortality after noncardiac surgery, a recent study found.

The prospective, international cohort study involved more than 15,000 patients age 45 and older who had noncardiac surgery requiring at least overnight hospital admission. Fourth-generation troponin T (TnT) measurements were taken six to 12 hours after surgery and on postsurgery days 1, 2 and 3. The patients' peak troponin T measurements were collected and compared with 30-day mortality rates.

Overall, 30-day mortality among the patients was 1.9%. In multivariable analysis, the study authors found that troponin T levels of 0.02 ng/mL or higher predicted increased risk of 30-day mortality. Compared to patients whose TnT never went above 0.01 ng/mL, those with a peak of 0.02 ng/mL had an adjusted hazard ratio of death of 2.41. The risk was even higher for patients with peaks of 0.03 to 0.29 ng/mL (hazard ratio, 5.00) and 0.30 ng/mL or above (hazard ratio, 10.48). Within the 30 days after surgery, mortality rates were 1.0%, 4.0%, 9.3% and 16.9% for patients with TnT peaks of 0.01 or greater, 0.02, 0.03 to 0.29, and 0.30 or greater, respectively.

Based on these findings, elevated TnT levels may have predicted 41.8% of the deaths in the study population, researchers calculated. They noted that this multicenter study had consistent results across sites, indicating that the observed TnT thresholds could be relevant worldwide. The study differed from many laboratories' current practice in that specific thresholds were used instead of cutoffs at the 99th percentile or coefficients of variation less than 10%, which often work out to 0.04 ng/mL or higher. These results show that TnT values below 0.04 ng/mL are strongly associated with mortality, the authors said.

The next step in this research would be to determine whether interventions in the immediate post-surgical period (74.2% of patients with elevated TnT had it in the first 24 hours after surgery) could reduce the risk of mortality, the authors said. The study was published in the June 6 Journal of the American Medical Association.

Low-dose aspirin associated with bleeding events

Daily use of low-dose aspirin was associated with an increased risk of major gastrointestinal or cerebral bleeding, a study found.

Researchers used administrative data from 4.1 million citizens in 12 local health authorities in Italy to identify a cohort of 186,425 individuals taking aspirin (daily doses of 300 mg or less) from January 2003 to December 2008 and 186,425 matched controls who didn't take aspirin.

Results appeared in the June 6 Journal of the American Medical Association. During a median follow-up of 5.7 years, there were 6,907 first episodes of major bleeding requiring hospitalization. There were 4,487 episodes of gastrointestinal bleeding and 2,464 episodes of intracranial hemorrhage.

The incidence rates of total hemorrhagic events were 5.58 (95% CI, 5.39 to 5.77) per 1,000 person-years for those on aspirin and 3.60 (95% CI, 3.48 to 3.72) per 1,000 person-years for those without aspirin use (incidence rate ratio [IRR], 1.55; 95% CI, 1.48 to 1.63). Aspirin was associated with an excess risk of gastrointestinal bleeding (IRR, 1.55; 95% CI, 1.46 to 1.65) and intracranial bleeding (IRR, 1.54; 95% CI, 1.43 to 1.67). Regardless of aspirin use, diabetes was independently associated with an increased risk of major bleeding episodes (IRR, 1.36; 95% CI, 1.28 to 1.44).

The authors noted, “[W]eighing the benefits of aspirin therapy against the potential harms is of particular relevance in the primary prevention setting, in which benefits seem to be lower than expected based on results in high-risk populations. In this population-based cohort, aspirin use was significantly associated with an increased risk of major bleeding, but this association was not observed for patients with diabetes. In this respect, diabetes might represent a different population in terms of both expected benefits and risks associated with antiplatelet therapy.”

An accompanying editorial noted that guidelines advocating the routine use of aspirin for primary prevention for individuals above a moderate level of risk of coronary heart disease should be carefully considered as this approach may not be advisable for all patients.

CAP patients with hypo- or hypercapnia have greater mortality

Hypocapnia and hypercapnia are associated with a greater need for ICU admission and higher 30-day mortality in patients hospitalized with community-acquired pneumonia (CAP), a study found.

Researchers conducted a retrospective cohort study of 453 hospitalized patients with an admission diagnosis of CAP at two tertiary teaching hospitals in San Antonio, Texas. All patients had a confirmed infiltrate or other finding consistent with CAP on chest X-ray or computed tomography of the chest within 24 hours of admission, and an arterial blood gas drawn within 24 hours of admission. Patients were stratified into three groups: normal (Paco2 35 to 45 mm Hg), hypocapnic (Paco2 <35 mm Hg) and hypercapnic (Paco2 >45 mm Hg). Researchers performed multivariate analysis with 30-day mortality as the primary outcome measure and ICU admission, length of stay and need for invasive mechanical ventilation as secondary outcome measures. Results were published in the June CHEST.

Forty-one percent of patients (n=189) had normal Paco2, 42% (n=194) were hypocapnic and 15% (n=70) were hypercapnic. After adjustment for illness severity, hypocapnic patients had greater 30-day mortality (odds ratio [OR], 2.84) and a greater need for ICU admission (OR, 2.88) compared to patients with normal blood gas measurements. Hypercapnic patients also had a higher 30-day mortality (OR, 3.38) and greater need for ICU admission (OR, 5.35). These differences between groups remained when chronic obstructive pulmonary disease (COPD) patients were excluded from the analysis. There was no statistically significant difference among groups in length of stay or need for invasive mechanical ventilation, though there was a higher need for invasive mechanical ventilation in hypercapnic patients without COPD.

Existing tools to predict 30-day mortality, which also have been recommended to identify patients for ICU admission, have been shown in recent research to not accurately predict ICU admission, the authors noted. These scores don't consider Paco2 levels as a predictive variable, but “our results suggest that abnormal Paco2 levels should be considered in severity of illness scores and requires further validation,” they wrote. In addition, the existing study found hypo- and hypercapnia were independently associated with 30-day mortality, “with no relationship to respiratory rate or pH level, suggesting they are likely to be intrinsically involved in the poor prognosis of these patients,” they wrote.

Disruption of catheter dressings poses major risk for infections

Disruption of catheter dressings is a common risk factor for catheter-related infections and can be partially avoided by using the subclavian insertion site, a recent analysis found.

Researchers performed a secondary analysis of a multicenter randomized trial conducted at seven ICUs in France. The original trial compared the effects of two dressing change intervals and two types of dressings on catheter-related infection in intensive care. In that study, patients were randomly assigned to one of four treatment groups: standard dressing changed every three days or every seven days, or chlorhexidine gluconate-impregnated sponge changed every three or seven days. Of the 1,636 patients in the original study, 1,419 with at least one dressing change were included in the secondary analysis.

Researchers identified 296 colonized catheters, 29 major catheter-related infections, and 23 catheter-related bloodstream infections. Sixty-seven percent of the 11,036 dressing changes were done before the planned date due to soiling or undressing. Patients with higher Sequential Organ Failure Assessment scores and those receiving renal replacement therapies experienced more dressing disruption, while males and comatose patients had less. At the catheter level, the use of the subclavian insertion site was protective against dressing disruption, the study found.

The number of disruptions was related to a higher risk for colonization of the skin around the catheter at removal (P<0.0001). After the second dressing disruption, the risk of major catheter-related infection and catheter-related bloodstream infection increased more than threefold; it increased more than 12-fold if the final dressing was disrupted. The results appeared in the June Critical Care Medicine.

This analysis “adds major arguments to include dressing integrity in catheter bundles” and “reinforces the need for a postinsertion bundle of care,” the authors said. Also, the data found that subclavian vein access led to a marked decline in dressing disruption, which may explain the significantly lower risk of catheter colonization and catheter-related bloodstream infection compared with jugular or femoral sites, they wrote.