Recent Research

Reducing pain of propofol injections, high-dose clopidogrel after PCI, and more.

Pain of propofol injection reduced by using antecubital vein

Using the antecubital vein instead of the hand vein is the most effective single intervention to reduce the pain of propofol injection, a meta-analysis found.

Researchers analyzed results from 177 clinical and randomized controlled trials involving 25,260 adults. Studies compared drug and non-drug interventions with placebo or another intervention to alleviate the pain of propofol injection. Non-drug interventions included different infusion rates, venous occlusion, needle sizes, injection sites, microfiltration, temperature, and bacteriostatic saline. The drug interventions included use and combination of antiemetics, local anesthetics, benzodiazepines and barbiturates, among others. All studies reported the response rate and severity of pain of those receiving intravenous propofol. The meta-analysis was published online March 15 by BMJ.

The overall risk of pain from propofol injection without preventive measures was about 60%, the authors reported. Among the preventive measures, selecting an antecubital vein instead of a hand vein was the most efficacious single intervention (relative risk [RR], 0.14; 95% CI, 0.07 to 0.30), followed by pretreatment with lidocaine combined with venous occlusion (RR, 0.29; 95% CI, 0.22 to 0.38). Others that showed benefit included lidocaine-propofol admixture (RR, 0.40; 95% CI, 0.33 to 0.48); pretreatment with lidocaine (RR, 0.47; 95% CI, 0.40 to 0.56), opioids (RR, 0.49; 95% CI, 0.41 to 0.59), ketamine (RR, 0.52; 95% CI, 0.46 to 0.57), or nonsteroidal anti-inflammatory drugs (NSAIDs) (RR, 0.67; 95% CI, 0.49 to 0.91); and propofol emulsions containing medium and long-chain triglycerides (RR, 0.75; 95% CI, 0.67 to 0.84).

Based on these results, the authors recommended using an antecubital vein instead of a hand vein for the injection. They did note, however, that an intravenous line in the antecubital fossa may be occluded when the elbow is flexed, so extravasation may not be detected as quickly as when the dorsum of the hand is used. If the hand vein must be the site of injection, they recommended pretreatment with lidocaine in conjunction with venous occlusion, or a combined intervention “such as pretreatment with ketamine or lidocaine before injections of a propofol emulsion containing medium and long chain triglycerides.” The authors also recommended giving opioids, since they are commonly used as part of a balanced anesthesia protocol and they halve the risk of pain from propofol induction. It seems reasonable to routinely use a small dose of opioids on all patients before induction of anesthesia, unless contraindicated, they said. The authors recommended against using NSAIDs, however, as the results for these agents were heterogeneous and some NSAIDs can actually cause pain at injection.

High-dose clopidogrel after PCI doesn't reduce death rates

High-dose clopidogrel did not reduce death rates compared with standard-dose clopidogrel after percutaneous coronary intervention (PCI) with drug-eluting stents, a study found.

To evaluate the effect of the two regimens in patients with high on-treatment platelet reactivity (defined as 230 PRU [P2Y12 reaction units] or higher) after PCI, researchers conducted a randomized, double-blind, active-control trial. Study regimens were high-dose clopidogrel (600-mg initial dose, 150 mg daily thereafter) or standard-dose clopidogrel (no additional loading dose, 75 mg daily) for six months.

The study population included 2,214 patients with high on-treatment reactivity 12 to 24 hours after PCI at 83 North American centers from July 2008 to April 2010. Patients were eligible if they had undergone PCI for stable coronary artery disease or non-ST-elevation acute coronary syndromes. Major exclusion criteria included the use of periprocedural glycoprotein IIb/IIIa inhibitors, planned future use of oral anticoagulants, bleeding prior to platelet function measurement, or no use of a clopidogrel regimen around the time of PCI.

The primary end point of the study, Gauging Responsiveness with A VerifyNow assay-Impact on Thrombosis And Safety (GRAVITAS), was the six-month incidence of death from cardiovascular causes (including hemorrhagic deaths), nonfatal myocardial infarction or stent thrombosis. The key safety end point was severe or moderate bleeding, as defined by the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO). A key pharmacodynamic end point was persistently high on-treatment reactivity at 30 days. Results appeared in the March 16 Journal of the American Medical Association.

At six months, 25 of 1,109 patients (2.3%) receiving high-dose clopidogrel died, compared with 25 of 1,105 patients (2.3%) receiving standard-dose clopidogrel (hazard ratio [HR], 1.01; 95% CI, 0.58 to 1.76; P=0.97). Severe or moderate bleeding did not increase with the high-dose regimen (15 patients [1.4%] vs. 25 patients [2.3%]; HR, 0.59; 95% CI, 0.31 to 1.11; P=0.10). High-dose clopidogrel provided a modest pharmacodynamic effect compared with standard-dose clopidogrel and did not appear to cause an excess of severe or moderate bleeding events or intracranial hemorrhage.

Although GRAVITAS was the largest randomized trial done to date on the subject, few patients in the trial had high-risk acute coronary syndromes and the results may not apply to such patients, the study authors said. Researchers also could not assess the effectiveness of high-dose clopidogrel in reducing the incidence of periprocedural myocardial infarction. Because the therapeutic intervention was a fixed dose, the effect of iterative-dose adjustment to “normalize” platelet reactivity to a specific target was also not determined.

Authors of an accompanying editorial wrote, “Because the intervention used in GRAVITAS was unable to alter patient outcomes, more work is needed before personalized anti-platelet therapy can be recommended. …Even though GRAVITAS demonstrated that platelet function testing after drug-eluting stent placement does not improve outcomes if high-dose clopidogrel is used as the remedy, it is hoped that future studies evaluating different platelet function cutpoints and more potent P2Y12 inhibitors will be effective.”

Tiotropium reduces risk of COPD exacerbations

The anticholinergic drug tiotropium (brand name: Spiriva) is superior to the β2-agonist salmeterol (brand name: Serevent) as first-line maintenance therapy to prevent exacerbations of chronic obstructive pulmonary disease (COPD) in patients with moderate to very severe stages, a study found.

The Prevention of Exacerbations with Tiotropium in COPD (POET-COPD) trial was a one-year, randomized, double-blind, double-dummy, parallel-group trial at 725 centers in 25 countries. Researchers compared tiotropium to salmeterol to assess the incidence of moderate or severe exacerbations in patients with moderate to very severe COPD and a history of exacerbations in the previous year. A total of 7,376 patients were randomly assigned to and treated with 18 µg of tiotropium once daily or 50 µg of salmeterol twice daily between January 2008 and April 2009. The primary end point was the time to the first exacerbation, defined as an increase in or new onset of more than one symptom (such as cough, sputum, wheezing, dyspnea or chest tightness) with at least one symptom lasting three days or more and leading to treatment with systemic glucocorticoids, antibiotics, or both (moderate exacerbation) or to hospitalization (severe exacerbation). Results appeared in the March 24 New England Journal of Medicine.

Tiotropium increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio [HR], 0.83; 95% CI, 0.77 to 0.90; P<0.001). Because 36.5% (n=2,691) of patients had an exacerbation, time to the first exacerbation in the first quartile of patients was calculated instead of the median.

Tiotropium significantly reduced the annual rate of exacerbations by 11% (rate ratio, 0.89; 95% CI, 0.83 to 0.96; P=0.002). It also reduced the risk of moderate exacerbations by 14% (HR, 0.86; 95% CI, 0.79 to 0.93; P<0.001) and of severe exacerbations by 28% (HR, 0.72; 95% CI, 0.61 to 0.85; P<0.001). In addition, tiotropium reduced the risk of exacerbations leading to treatment with systemic glucocorticoids by 23% (HR, 0.77; 95% CI, 0.69 to 0.85; P<0.001), treatment with antibiotics by 15% (HR, 0.85; 95% CI, 0.78 to 0.92; P<0.001), and treatment with both by 24% (HR, 0.76; 95% CI, 0.68 to 0.86; P<0.001). Benefits appeared as early as one month and lasted the duration of the one-year study. Serious adverse events, adverse events that stopped therapy, and deaths were similar between the two groups.

An editorialist wrote, “The main implications of this trial are for the initial care of symptomatic patients with moderate disease and a history of recent exacerbations....There is no evidence for the superiority of tiotropium in patients with mild COPD (those in whom the FEV1 is >70% of the predicted value) or symptomatic patients with moderate COPD but without a history of exacerbations.”

COPD inpatients with pneumonia less likely to die after use of inhaled corticosteroids vs. nonuse

Chronic obstructive pulmonary disease (COPD) inpatients with pneumonia who were treated with inhaled corticosteroids (ICS) had lower short-term mortality than those not treated with ICS, a recent analysis found.

In a retrospective analysis, researchers examined the medical records of 15,768 COPD patients over the age of 65 who had been admitted to Veterans Affairs hospitals for pneumonia between 2002 and 2007. Eligible patients had a pre-existing diagnosis of COPD and had received treatment with one or more pulmonary medications before being hospitalized; had at least one year of outpatient VA care prior to admission; and had received at least one dose of antibiotics within 48 hours of admission. Fifty-two-and-a-half percent of patients (n=8,271) were treated with ICS in the hospital, while 47.5% (n=7,497) were not. The primary outcomes were mortality at 30 and 90 days. Secondary outcomes were use of invasive mechanical ventilation and vasopressors during hospitalization.

ICS users had significantly lower mortality at 30 days compared to non-ICS users (10.2% vs. 13.6%, P<0.001) as well as at 90 days (17.3% vs. 22.8%, P<0.001). Patients who received ICS also were significantly less likely to need mechanical ventilation (5.9% vs. 7.3% for non-ICS users, P=0.001). There was no significant difference in the need for vasopressors. Overall, those who were not treated with ICS had about a 25% greater mortality risk than those who were treated with ICS. Results were published online April 21 by the American Journal of Respiratory and Critical Care Medicine.

Previous research has found that use of ICS in COPD patients reduced exacerbations but increased pneumonia, which made physicians hesitant to use them because they believed ICS must also increase mortality, noted Eric Mortensen, MD, the study's principal investigator, in a press release. “This [current analysis'] result is the opposite of what many experts have believed. We do, however, believe that this represents the reality because ours is one of the largest studies, and employed a rigorous definition of pneumonia that previous studies did not,” Dr. Mortensen said. “The results should reassure clinicians that they can give their COPD patients ICS without fearing that the increased risk of pneumonia will translate into higher risk of mortality.”