Literature at a Glance
A guide to this month’s studies.
- Adverse events are common after stopping clopidogrel following acute coronary syndrome.
- Treatment intensification with insulin improves inpatient glucose control.
- Pressure for early antibiotic administration leads to inaccuracy of pneumonia diagnosis.
- Multifaceted ventilation strategy no better than low-tidal-volume protocol.
- Higher PEEP ventilation strategy reduces duration of ventilation but not mortality.
- N-acetylcysteine reduces contrast-induced nephropathy.
- Vasopressin is no better than norepinephrine in patients with septic shock.
- Hospital patients desire greater participation in decision-making.
- Outcomes of patients with upper- or lower-extremity DVT are similar.
- Oral and IV steroids may be equally effective in COPD exacerbation.
Background: Clopidogrel is recommended in treatment of acute coronary syndrome (ACS) with or without stent placement. A rebound hypercoagulable state may occur following clopidogrel cessation, but this has not been investigated previously.
Study design: Retrospective cohort.
Setting: 127 VA medical centers.
Synopsis: Data were collected as part of the Veterans Health Administration Cardiac Care Follow-up Clinical Study from October 2003 through March 2005 on all patients with acute myocardial infarction (MI) or unstable angina who were discharged with clopidogrel treatment (3,137 patients). The analysis assessed the incidence and timing of adverse events after stopping clopidogrel among medically treated patients and among those treated with percutaneous coronary intervention (PCI).
In adjusted analyses among medically treated patients, the risk of death or acute MI in the first 90 days after clopidogrel cessation was 1.98 times higher, compared with the interval from 91-180 days. Among patients who received PCI (usually with a bare-metal stent), the risk was 1.82 times higher in the first 90 days. The clustering of events shortly after clopidogrel cessation support the possibility of a rebound hypercoagulable state.
Bottom line: In patients with ACS who received medical management or PCI, there was a higher rate of adverse events in the first 90 days after clopidogrel cessation.
Citation: Ho PM, Peterson ED, Wang L, et al. Incidence of death and acute myocardial infarction associated with stopping clopidorel after acute coronary syndrome. JAMA 2008;299(5):532-539.
What is the Relationship Between Treatment Intensification, Blood Pressure Changes in Diabetes Patients?
Background: Hyperglycemia is common in hospitalized patients with diabetes and associated with poor outcomes. Prior research on treatment intensification has focused on the intensive care unit or outpatient setting. The effect of treatment intensification in the inpatient (non-ICU) setting is not known.
Study design: Retrospective cohort.
Setting: 734-bed teaching hospital in Boston.
Synopsis: Between January 2003 and August 2004, data on blood glucose and daily pharmacologic management were gathered from electronic sources on 3,613 inpatients with diabetes. Inpatient hyperglycemia (glucose more than 180 mg/dL) occurred at least once in 2,980 (82.5%) hospitalizations.
Intensification of antihyperglycemic therapy occurred after only 22% of hospital days with hyperglycemia. Intensification included scheduled insulin, sliding scale insulin, and oral antihyperglycemic medications. Intensification of sliding scale insulin, as well as scheduled insulin, but not oral medications, was associated with a significant (12.2 mg/dL and 11.1 mg/dL respectively) average daily reduction in bedside glucose. Hypoglycemia was documented in 2.2% of days after intensification of antihyperglycemic treatment.
Bottom line: Inpatient hyperglycemia is common, and treatment intensification should be considered more often among hospitalized patients with diabetes.
Citation: Matheny ME, Shubina M, Kimmel ZM, Pendergrass ML, Turchin A. Treatment intensification and blood glucose control among hospitalized diabetic patients. J Gen Intern Med. 2008;23(2):184-189.
Background: A period of less than our hour from emergency department presentation to first antibiotic dose is a core quality measure for community-acquired pneumonia (CAP). Time pressures might reduce the accuracy of pneumonia diagnosis and lead to unnecessary antibiotic administration.
Study design: Retrospective cohort.
Setting: 365-bed university-affiliated community hospital in Baltimore.
Synopsis: Patients admitted with an initial diagnosis of CAP were studied when the time to first antibiotic dose (TFAD) quality standard was eight hours (n=255) and later when the goal TFAD was four hours (n=293).
At admission, under the eight-hour goal, 45.9% of patients met prespecified diagnostic criteria for CAP, compared with 33.8% of patients under the four-hour goal (odds ratio [OR]=0.61, p=0.004). At discharge, 74.5% of patients had a diagnosis of pneumonia with an eight-hour TFAD standard, vs. 66.9% with a four-hour standard (p=0.05). The most common alternate diagnoses were acute bronchitis, heart failure, and COPD exacerbation.
No significant difference in antibiotic-associated adverse drug events, morbidity, or mortality were detected. Importantly, the goal TFAD reduction did not significantly increase the percentage of patients who received antibiotics within four hours (81.6% when the goal was within eight hours, vs. 85.3% when the goal was within four hours, p=0.21). The study is limited by its retrospective nature and the absence of gold standards for the diagnosis of CAP.
Bottom line: Greater pressure to administer antibiotics early in suspected cases of CAP may decrease diagnostic accuracy, without substantially improving antibiotic administration time.
Citation: Welker JA, Huston M, McCue JD. Antibiotic timing and errors in diagnosing pneumonia. Arch Intern Med. 2008;168(4):351-356.
Do Recruitment Maneuvers and High PEEP Reduce All-cause Hospital Mortality in Acute Lung Injury, ARDS?
Background: Low-tidal-volume ventilation reduces mortality in acute lung injury and acute respiratory distress syndrome (ARDS). Adding methods to open collapsed lung, such as employing recruitment maneuvers or using higher positive end-expiratory pressures (PEEP), may further reduce mortality.
Study design: Randomized controlled trial with blinded analysis. Patients were randomized to ventilation using the ARDS Network protocol (tidal volume of 6 ml/kg predicted body weight, assist control ventilation, low PEEP) vs. a higher PEEP intervention algorithm (using pressure control ventilation but still using 6 ml/kg tidal volume).
Setting: 30 intensive-care units in Canada, Australia, and Saudi Arabia.
Synopsis: Despite higher PEEP in the experimental group (14.6 cm H2O, SD 3.4) vs. the control group (9.8 cm H2O, SD 2.7) during the first 72 hours (p<0.001), there was no difference in all-cause hospital mortality or barotrauma between the two groups. The experimental group did, however, have a lower frequency of refractory hypoxemia (4.6% vs. 10.2%, 95% confidence interval [CI] 0.34-0.86, p=0.01).
At the end of the trial, a difference in the number of patients allocated to each group was noted. Investigation uncovered a programming error that disrupted the specified randomization blocks. Sensitivity analyses, which were not described, indicated that this error did not undermine randomization.
Bottom line: The addition of recruitment maneuvers and high PEEP to low-tidal-volume ventilation in acute lung injury and acute respiratory distress syndrome improved oxygenation but did not lower mortality.
Citation: Meade MO, Cook DJ, Guyatt GH, et al. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome. A randomized controlled trial. JAMA 2008;299(6):637-645.
Does a Ventilation Strategy Setting PEEP to Increase Alveolar Recruitment, Limit Hyperinflation Improve 28-day Mortality in Acute Lung Injury, ARDS?
Background: The need for lung protection in patients with acute lung injury or acute respiratory distress syndrome (ARDS) is accepted. The optimal level of positive end-expiratory pressure (PEEP) to provide protection yet allow alveolar expansion is debated
Study design: Unblinded, randomized controlled trial. Patients were randomized to standard low tidal volume ventilation with low PEEP or low tidal volume ventilation with higher PEEP (intervention group). PEEP was increased in the intervention group to attain a plateau pressure of 28-30 cm H2O
Setting: 37 intensive care units in France.
Synopsis: Though PEEP, total PEEP, and plateau pressure were considerably higher in the experimental group, there was no difference in 28-day mortality compared with the control group, 27.8% vs. 31.2% (95% CI 0.90-1.40, p=0.31). There was, however, an increase in the number of ventilator-free days (seven vs. three, p=0.04) and organ-failure-free days (six vs. two, p=0.04) in the experimental group compared with the control group. Criteria were used to evaluate patients for readiness for extubation, but the differential application of PEEP between arms may have altered the timing of these evaluations in the two arms and may be at least partly responsible for the difference in ventilator-free days.
Throughout patient recruitment, the primary end point was monitored, resulting in 18 interim analyses of the data. No statistical adjustments were made for these frequent examinations of the data.
Bottom line: The use of higher PEEP and maximum plateau pressure to increase alveolar recruitment while limiting hyperinflation results in more ventilator-free and organ failure-free days in patients with acute lung injury and ARDS. These maneuvers do not, however, alter mortality.
Citation: Mercat A, Richard JCM, Vielle B, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome. A randomized controlled trial. JAMA 2008;299(6):646-655.
What are the Effects of N-acetylcysteine, Theophylline, Other Agents on Preventing Contrast-induced Nephropathy
Background: Contrast-induced nephropathy is the third-most common cause of new acute renal failure in hospitalized patients, occurring in up to 25% of patients with renal impairment, diabetes, heart failure, advanced age, or concurrent use of nephrotoxic drugs. Clinicians use different agents to reduce the risk, including intravenous hydration, N-acetylcysteine, theophylline, fenoldopam, dopamine, furosemide, mannitol, and bicarbonate.
Study design: Meta-analysis of randomized controlled trials.
Setting: 41 studies involving 6,379 patients, published internationally between 1994 and 2006.
Synopsis: All but one study evaluated patients undergoing cardiac catheterization, and 34 trials evaluated patients with impaired renal function. N-acetylcysteine significantly reduced the risk of contrast-induced nephropathy more than saline hydration alone (risk ratio [RR]=0.62, 95% CI 0.44 to 0.88). Theophylline may have renoprotective effects but the findings were not statistically significant (RR=0.49, 95% CI 0.23 to 1.06). Ascorbic acid and bicarbonate significantly reduced nephropathy, though only one study was found for each. The other agents evaluated did not significantly reduce risk. Furosemide increased the risk (RR=3.27, 95% CI 1.48 to 7.26).
Bottom line: N-acetylcycteine is an effective agent for prevention of contrast-induced nephropathy, and it has the added benefits of low cost, few side effects, and rare drug interactions.
Citation: Kelly AM, Dwamena B, Cronin P, Bernstein SJ, Carlos RC. Meta-analysis: effectiveness of drugs for preventing contrast-induced nephropathy. Ann Intern Med. 2008;148(4):284-294.
Background: Vasopressin is commonly used to support blood pressure in patients with septic shock. It has been shown to restore vascular tone, maintain blood pressure, and decrease catecholamine requirements, but its effect on mortality is uncertain.
Study design: Randomized, double-blind trial.
Setting: 27 centers in Canada, Australia, and the United States.
Synopsis: Patients with septic shock who required at least 5 mcg/min of norepinephrine were randomized to receive either low-dose vasopressin infusion (0.01 to 0.03 U/min) or norepinephrine (5 to 15 mcg/min). There was no significant difference in mortality at 28 days (35.4% for vasopressin vs. 39.3% for norepinephrine, p=0.26) or at 90 days (43.9% vs. 49.6%, p=0.11). The vasopressin group had lower heart rate and norepinephrine requirements. There were no significant differences in the frequency of adverse events.
However, since mean blood pressure at baseline was 72-73 mmHg, study patients did not necessarily have catecholamine unresponsive shock. Also, the mean time from meeting criteria for study entry to infusion of the drug was 12 hours, longer than the six-hour time period identified as important in studies of early goal-directed therapy. This may have limited the effectiveness of vasopressin infusion.
Bottom line: Low-dose vasopressin as compared with norepinephrine did not improve mortality in patients with septic shock.
Citation: Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877-887.
How Much do Hospitalized Patients Want to Participate in Decisions on Therapies of Varying Risk, Benefit?
Background: Obtaining informed consent is required for invasive procedures, but most non-invasive medical treatments are performed without discussing the risks, benefits, and alternatives with patients.
Study design: Questionnaire with four scenarios.
Setting: Medical wards in a Connecticut hospital.
Synopsis: Among the 210 patients studied, about one-fourth wanted physicians to obtain their permission “no matter what” even for mundane therapies like potassium supplementation (24%) or diuretic administration (28%). When presented with a higher risk scenario, such as thrombolysis with a greater than 20% chance of hemorrhage, 40.8% of patients definitely wanted to participate in decision-making.
Younger patients (age 65 or younger) were more likely to want to participate in decision-making. For each scenario, at least 85% of patients noted they would like to be consulted about the decision “no matter what” or if time allowed. Importantly, patients expressed these preferences in response to written scenarios that did not provide detailed information about the risks and benefits. Further, patients did not receive explanations of the logistical hurdles of trying to obtain patient input for each decision.
Bottom line: The great majority of patients in this study wished to participate in decision making for hypothetical medical treatments, especially if time allowed. At least 24% always wanted to be consulted, even about mundane therapies like potassium supplementation.
Citation: Upadhyay S, Beck A, Rishi A, Amoateng-Adjepong Y, Manthous CA. Patients’ predilections regarding informed consent for hospital treatments. J Hosp Med. 2008; 3(1):6-11.
What are the Clinical Characteristics, Treatments, and Three-month Outcomes of Patients With Upper-extremity DVT
Background: Anticoagulation is the treatment of choice for upper-extremity deep venous thrombosis (DVT). However, no large studies have characterized the nature, management, and prognosis of upper-extremity DVT.
Study design: Prospective registry of consecutive patients (RIETE registry).
Setting: International multicenter study (124 centers in Spain, France, Italy, Israel, and Argentina).
Synopsis: Among the 11,564 registry patients with acute DVT, 512 (4.4%) were noted to have upper-extremity DVT. Cancer was more common and immobility was less common with upper-extremity DVT. Initially, most patients (91%) were treated with low-molecular-weight heparin (LMWH). For long-term therapy, 75% of patients with cancer received LMWH, and 76% of patients without cancer were given oral vitamin K antagonists. At diagnosis, only 9% of patients with upper-extremity DVT had clinically apparent pulmonary embolism (PE) versus 29% of those with lower-extremity DVT. During the three-month follow-up, the incidence of PE, fatal PE, recurrent DVT, and bleeding was similar for upper- and lower-extremity DVT. Mortality was higher in patients with upper-extremity DVT, which in multivariable analyses, was explained by the higher prevalence of cancer in that group.
Bottom line: Because the incidence of recurrent DVT/PE, fatal PE, or major bleeding is similar between upper and lower extremity DVT, therapy should not differ.
Citation: Muñoz FJ, Mismetti P, Poggio R, et al. Clinical outcome of patients with upper-extremity deep vein thrombosis. Chest 2008;133(1):143-148.
Background: Oral prednisolone has near 100% bioavailability following oral administration. Although current guidelines suggest using oral steroids in the treatment of COPD exacerbation, the optimal route of administration has not been studied rigorously.
Study design: Non-inferiority, double-blinded, randomized controlled trial.
Setting: Single hospital in the Netherlands.
Synopsis: Patients were randomized to receive either a five-day course of IV or oral prednisolone 60 mg, followed by an oral prednisolone taper. All received nebulized ipratropium and albuterol four times daily, as well as oral amoxicillin/clavulanate (or doxycycline if allergic). The primary outcome was treatment failure, which included death, ICU admission, hospital readmission for COPD, or treatment intensification during 90-day follow-up.
Non-inferiority was defined as a treatment failure rate for oral steroids not more than 15% worse than the treatment failure rate for IV steroids. The study design called for 256 patients to provide adequate (80%) power for the primary analysis. However, only 210 were enrolled due to slow recruitment, and 17 withdrew consent or did not meet study entry criteria.
The intention-to-treat analysis showed no significant difference between oral and IV steroids in the treatment failure rate (56.3% vs. 61.7%, respectively). Results of the per-protocol analysis were similar. However, insufficient power and poor patient accounting raise questions about the validity of the results.
Bottom line: Oral steroids appeared no worse than IV steroids in the treatment of COPD exacerbation, but the study was underpowered, which prevents definitive conclusions.
Citation: De Jong YP, Uil SM, Grotjohan HP, et al. Oral or IV prednisolone in the treatment of COPD exacerbations. A randomized, controlled, double-blind study. Chest 2007;132(6):1741-1747. TH