Recent Research

Neurological deficit and outcomes in mild stroke, cangrelor as potential bridging therapy in CABG, and more.


Type of neurological deficit not associated with outcomes in mild stroke

In patients with mild stroke, the type of neurological deficit doesn't independently predict long-term prognosis and shouldn't be a factor in decisions about reperfusion therapy, a study has suggested.

Researchers retrospectively analyzed data from a large stroke trial that enrolled patients with a wide range of stroke syndromes, including those with relatively mild neurological impairment. They identified 194 patients with a baseline National Institutes of Health Stroke Scale (NIHSS) score of ≤6 who presented to the ED within 4.5 hours of symptom onset. They performed multivariate logistic regression analyses with predictors comprising each individual item of the NIHSS exam, as well as syndromic combinations of NIHSS scores. A “very favorable outcome” (VFO) at three months was defined as having a Glasgow Outcome Scale score of 1 and a Barthel Index score of 19 to 20. Results were published in the March Stroke.

The mean and median baseline NIHSS scores were 4.22 and 4, respectively. Facial weakness was the most common neurological deficit (63%), followed by dysarthria (42.3%) and limb ataxia (38.1%). Prevalence of “classic” stroke syndromes was low (for example, 4.1% and 0.5%, respectively, for pure motor and pure sensory stroke). A VFO was seen at three months by 68% of the patients studied, with higher total scores associated with a lower chance of a VFO. No single NIHSS item or syndromic combination of NIHSS scores was independently associated with a VFO at three months.

Physicians are sometimes hesitant to treat patients with low NIHSS scores with recombinant tissue plasminogen activator (rtPA) due to the treatment's hemorrhagic risks; further, they may favor treating patients with visual or language deficits over those whose symptoms they perceive as not disabling, the authors noted. However, the current study argues against using specific types of deficits as a basis for deciding on use of rtPA in mild stroke patients, they said. Also, current guidelines for using rtPA “might be unnecessarily restrictive for treating patients with mild strokes,” they concluded.

An editorialist agreed, saying it “appears current thrombolysis guidelines need revision” and that it “seems reasonable to at least strongly consider patients with mild stroke for IV thrombolytic therapy.”

A second study, published in the May Stroke, found that an existing stroke outcome prediction tool (the iScore) can be used to estimate response to, and complications from, rtPA. For acute ischemic stroke patients whose iScores indicated low and medium risks, rtPA was associated with a benefit in the primary outcome (death or disability), while those with high iScores saw no primary benefit with rtPA use. Similar results were seen for disability at discharge and length of stay. The incident risk of hemorrhagic transformation or neurological deterioration with rtPA also increased with iScore.

CT angiography as good as MRI to predict recurrent stroke

CT angiography (CTA) can predict recurrent stroke as accurately as MRI in patients with transient ischemic attack (TIA) or minor stroke, a study found.

Researchers studied 510 consecutive patients who presented with TIA or minor stroke at a single center in Calgary, Canada over 29 months. They were examined by a stroke neurologist and had a CT brain scan and CTA of the circle of Willis and neck within 24 hours of symptom onset; 420 (82%) of the patients also had an MRI. Patients were excluded if they had a premodified Rankin scale score of at least two, acute treatment with thrombolytics, or a serious comorbid illness that would likely lead to death within three months. The researchers assessed risk of recurrent stroke within 90 days using standard clinical variables and predefined abnormalities on the CT/CTA and MRI. The abnormalities were acute ischemia on CT and/or ipsilateral intracranial or extracranial occlusion or stenosis of 50% or greater, and diffusion-weighted imaging-positive MRI results.

There were 36 recurrent strokes (7.1%), with the median time to recurrent stroke being one day from initial assessment. Of these, 19 (53%) were considered progression of the presenting event and 17 were distinct recurrent strokes. Median time from symptom onset to CTA was 5.5 hours compared to 17.5 hours for MRI. Predictors of recurrent stroke were ongoing symptoms at first assessment (hazard ratio [HR], 2.2), CT/CTA abnormalities (HR, 4.0), and diffusion-weighted imaging positivity (HR, 2.2). In multivariable analysis, only CT/CTA abnormalities predicted recurrent stroke. In secondary analysis using receiver-operating characteristic analysis, CT/CTA and MRI did not differ significantly in their discriminative value in predicting recurrent stroke (0.67 vs. 0.59; P=0.09). Results were published in the April Stroke.

Past studies have shown that the greatest risk of recurrent stroke after TIA/minor stroke is within 48 hours of symptom onset, consistent with this study's median time to event of one day, the researchers wrote. CT/CTA imaging is generally more readily available in emergency departments than MRI imaging, they noted, and therefore the finding that CT/CTA predicts recurrent stroke as well as MRI is useful in ensuring patients are assessed for potential recurrent stroke as quickly as possible.

Cangrelor shows promise as bridging antiplatelet therapy in CABG patients

Among patients who discontinued thienopyridine therapy before cardiac surgery, those who used the investigational drug cangrelor had better maintenance of platelet inhibition than those who used placebo, a study found.

The researchers conducted a prospective, randomized, double-blind, placebo-controlled, multicenter trial with 210 patients who were randomized to cangrelor or placebo. All patients had an acute coronary syndrome or were treated with a coronary stent, and were receiving a thienopyridine prior to coronary artery bypass grafting surgery (CABG). Thienopyridines were stopped five to seven days before surgery, and patients were given placebo or 0.75 µg/kg of cangrelor per minute for at least 48 hours, which was stopped one to six hours before surgery. Infusion time for cangrelor was 2.8 days on average (median) and 3.4 days (median) for placebo. The main efficacy end point was platelet reactivity of less than 240 P2Y12 Reaction Units (PRUs), assessed daily, and the main safety end point was excessive CABG-surgery-related bleeding.

The percentage of patients with platelet reactivity less than 240 PRUs throughout the infusion of the study drug was significantly higher than in the placebo group (98.8% vs. 19%; P<0.001). Excessive surgery-related bleeding was similar in both groups (11.8% in the cangrelor group vs. 10.4% in the placebo group; P=0.763). There were no significant differences in major bleeding before CABG surgery, although there were more episodes of minor bleeding with cangrelor. Results were published in the Jan. 19 Journal of the American Medical Association.

Cangrelor infusion “consistently achieved and maintained platelet inhibition at levels known to be associated with a low risk of thrombotic events compared with placebo,” while not increasing major bleeding before surgery, the authors noted. It's a feasible management strategy to inhibit platelets in cardiac patients who are awaiting surgery and have discontinued use of thienopyridine, they concluded. The study was sponsored by The Medicines Company, and the authors disclosed ties to numerous industry sources.

Different blood pressure in each arm may indicate vascular disease

Patients who have significant differences in systolic blood pressure between their right and left arms may be at increased risk of vascular disease, a recent study found.

The meta-analysis included 20 studies that compared blood pressure (BP) between patients' arms. Five studies used angiography and found that among patients with subclavian stenosis, the mean difference in systolic BP between arms was 36.9 mm Hg. In these invasively tested patients, a difference of 10 mm Hg or more was strongly associated with subclavian stenosis (risk ratio, 8.8). In the other, noninvasive studies included in the analysis, a difference of 10 mm Hg or more was associated with increased risk of peripheral vascular disease (risk ratio, 2.4; sensitivity, 32%; specificity, 91%).

When the cutoff for difference in systolic BP between arms was increased to 15 mm Hg, the analysis found patients who met that cutoff were more likely to have preexisting cerebrovascular disease (risk ratio, 1.6; sensitivity, 8%; specificity, 93%), cardiovascular mortality (hazard ratio [HR], 1.7) and all-cause mortality (HR, 1.6). The findings were published in the March 10 The Lancet.

The study authors concluded that a difference in systolic BP of 10 mm Hg or higher or 15 mm Hg or higher is associated with peripheral vascular disease, although with low sensitivity but high specificity, in both community- and hospital-recruited patient cohorts. This finding might be useful for identifying patients in need of further vascular assessment, they said, noting a cutoff of a 15 mm Hg difference would lead to further assessment for fewer than 5% of overall patients.

Although the study concluded that a 15 mm Hg difference could be a useful indicator of mortality risk, this finding was gathered from populations with a high baseline cardiovascular risk and so is not necessarily generalizable to lower-risk patients, the authors said. They recommended that these findings be incorporated into future guidelines but also be clarified by further research into normal versus excessive BP differences between arms.

A comment accompanying the study noted that national and international hypertension guidelines have already recommended measurement of BP in both arms. One obstacle to effective implementation is that patients are twice as likely to show differences between arms if their BP is measured sequentially rather than simultaneously (due to the white-coat effect). The commentary authors recommended measurement of BP in both arms, ideally simultaneously, to accurately diagnose hypertension, but they noted that the low sensitivity found in this study means that the practice has little value as a screening tool for peripheral vascular disease.

Propofol shortage did not affect mechanical ventilation duration

A nationwide propofol shortage did not affect duration of mechanical ventilation at a single U.S. academic medical center, a recent study showed.

Researchers at Tufts Medical Center in Boston performed a before-after study in three noncardiac-surgery adult ICUs to determine whether patients spent less time on mechanical ventilation before the propofol shortage (Dec. 1, 2008 to May 31, 2009) than after (Dec. 1, 2009 to May 31, 2010). The study examined 281 consecutive patients who received mechanical ventilation for at least 48 hours, were given a continuous sedative infusion for at least 24 hours, and were then successfully extubated and discharged from the ICU. Results were published in the February Critical Care Medicine.

One hundred twenty-eight patients were ventilated after the propofol shortage, and 153 were ventilated before. Patients in the after group were younger, had a higher Acute Physiology and Chronic Health Evaluation II score at admission, and were more likely to have acute alcohol withdrawal and primarily receive pressure-controlled ventilation. Continuous infusion of propofol for at least 24 hours was much more common before the shortage than after (94% vs. 15%; P<0.0001), and patients who were mechanically ventilated after the shortage were more likely to receive continuous infusions of lorazepam (15% vs. 7%; P=0.037) and midazolam (81% vs. 30%; P<0.0001). In unadjusted analyses, the median duration of ventilation was 6.7 days before the shortage and 9.6 days after the shortage (P=0.02). However, in a regression model, duration of mechanical ventilation was affected by Acute Physiology and Chronic Health Evaluation II score (P<0.0001), medical service admission (P=0.009), and pressure-controlled ventilation (P=0.02), but not by propofol use (P=0.35).

The authors could not conclude definitively that the propofol shortage had no effect on mechanical ventilation duration, although they noted that such an effect, if present, was probably very small. Data on weaning efforts and the proportion of patients with delirium were not available, and the study did not include safety-related outcomes, among other limitations. However, the authors concluded that although propofol use at Tufts Medical Center's ICUs decreased dramatically during the nationwide shortage, lack of the drug did not appear to affect duration of mechanical ventilation. Additional research is needed, they said, on the reasons behind ICU drug shortages, legislation to address the issue, and the impact of such shortages on patient outcomes.

Meanwhile, an article published in the March 1 Clinical Infectious Diseases examined shortages of anti-infective drugs in the U.S. The authors found that such shortages are common and can have a substantial impact on patient care because anti-infectives are often the only treatments available for particular conditions. In addition, multidrug resistance has increased and fewer new anti-infective agents have been approved by the FDA in recent years. “These factors have converged to create a public health emergency,” the authors wrote.

Shortages can be due to manufacturing problems, business decisions to halt drug production, stockpiling, inferior inventory practices, or changed indications for drugs, among other factors. The authors pointed out that manufacturers are not required to explain why a drug is in short supply, which limits the information available on causes. They called for increased federal authority to manage such shortages, beginning with proposed amendments to the Food, Drug and Cosmetic Act. “Enhanced oversight by governmental agencies may be necessary to identify and correct shortages of these life-saving anti-infectives,” they concluded.

Antidepressants work for patients with comorbidities

Patients with comorbidities can be safely and effectively treated for major depressive disorder (MDD) with antidepressants, even combination therapy, with no more adverse effects than their healthier counterparts, researchers concluded.

The Combining Medications to Enhance Depression Outcomes (CO-MED) trial consisted of 12 weeks of acute care and 16 weeks of follow-up treatment. It was a multisite, single-blind, randomized trial that compared the efficacy of traditional selective serotonin reuptake inhibitor (SSRI) monotherapy (escitalopram plus placebo) versus that of two antidepressant medication combinations (escitalopram plus bupropion-SR and venlafaxine-XR plus mirtazapine) in patients with chronic and/or recurrent, nonpsychotic MDD. Clinicians were not blinded to maximize safety and to allow them to make informed flexible dosing decisions.

Patients underwent the Self-Administered Comorbidity Questionnaire, a self-report that assesses the presence of medical problems, their severity, and whether the condition limits functioning. Conditions on the questionnaire included heart disease, high blood pressure, lung disease, diabetes, gastrointestinal tract disorders, kidney disease, liver disease, anemia or other blood disease, cancer, arthritis, thyroid disease, and chronic back pain. Also, respondents could add three more conditions.

At 12 and 28 weeks, researchers compared unadjusted and adjusted outcomes (symptom severity, tolerability and functioning) among patients with none, one, two, and three or more general medical conditions. Results appeared in the January/February Annals of Family Medicine.

Of the 665 evaluable patients, 328 (49.5%) reported having no general medical conditions, 158 (23.8%) reported having one condition, 98 (14.8%) reported having two conditions and 79 (11.9%) reported having at least three conditions. (Two participants did not complete the questionnaire.)

There were no differences in outcomes associated with antidepressant monotherapy and either of the antidepressant combination therapies, regardless of the number of general medical conditions a patient had. Specifically, within each group having a given number of conditions, the three treatments did not differ significantly by efficacy or tolerability at weeks 12 and 28.

The authors concluded that the almost complete lack of difference among patients with differing numbers of conditions shows that all patients can receive equally safe and effective treatment for MDD with antidepressants without risk of additional adverse effects or intolerability. Combination antidepressant therapy had no additional benefit over SSRI monotherapy for patients with general medical conditions and comorbid, chronic or recurrent MDD.

“Participants with general medical conditions and comorbid MDD were more likely to be treated for depression by their primary care physician than a psychiatric care professional,” the authors wrote. “This greater likelihood of treatment in primary care could occur for a variety of reasons, the most obvious being that patients with general medical conditions and comorbid MDD may prefer to be treated by a single physician rather than use a separate mental health professional.”