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Generic, Brand-Name Drugs Used for Cardiovascular Disease Are Clinically Equivalent

Clinical question: Is there a clinical risk when substituting generic drugs for brand-name drugs in the treatment of cardiovascular disease?

Background: Spending on healthcare in the U.S. has reached critical levels. Increasing prescription drug costs make up a large portion of healthcare expenditures. The high cost of medicines directly affect adherence to treatment regimens and contribute to poor health outcomes. Cardiovascular drugs make up the largest portion of outpatient prescription drug spending.

Study design: Systematic review of relevant articles with a meta-analysis performed to determine an aggregate effect size.

Setting: Multiple locations and varied patient populations.

Synopsis: A total of 47 articles were included in the review, of which 38 were randomized controlled trials (RCTs). The studies measured both clinical efficacy and safety end points. More than half the articles were published prior to 2000. Clinical equivalence was noted in all seven beta-blocker RCTs; 10 of 11 diuretic RCTs; five of seven calcium-channel-blocker RCTs; all three antiplatelet-agent RCTs (clopidogrel, enteric-coated aspirin); two statin RCTs; one ACE-inhibitor RCT; and one alpha-blocker RCT. For drugs with a narrow therapeutic index, clinical equivalence was noted in all five warfarin RCTs and a single Class 1 anti-arrhythmic-agent RCT.

The aggregate effect size was -0.03 (95% CI, -0.15 to 0.08), which indicates nearly complete overlap of the generic and brand-name distributions. The data show no evidence of superiority of brand-name to generic drugs in clinical outcomes measured in the various studies.

In a separate review of editorials addressing generic substitution for cardiovascular drugs, 53% expressed a negative view of generic-drug substitution.

Bottom line: There is clinical equivalency between generic and brand-name drugs used in the treatment of cardiovascular disease. Despite this conclusion, a substantial number of editorials advise against generic substitution, which affects both patient and physician drug preferences.

Citation: Kesselheim A, Misono A, Lee J, et al. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and meta-analysis. JAMA. 2008; 300(21):2514-2526.

PEDIATRIC LITERATURE

Oral Prednisolone Does Not Shorten Hospitalization in Preschool-Age Children with Acute Virus-Induced Wheezing

Clinical question: Does oral prednisolone shorten duration of hospitalization in preschool-age children with acute virus-induced wheezing?

Background: Wheezing illnesses in young children are commonly associated with viral infections and may resolve with age without further stigmata of atopic asthma. Although systemic corticosteroids are commonly recommended for this population, evidence of their effectiveness is limited.

Study design: Randomized, double-blind, placebo-controlled trial.

Setting: Three hospitals in the United Kingdom.

Synopsis: Children between 10 and 60 months that presented to a hospital with a physician-diagnosed attack of wheezing preceded by a viral infection were randomized to receive oral prednisolone or a placebo. There was no significant difference between the groups in the time to hospital discharge. There also was no difference in the prespecified subgroup analysis of children at high risk for atopic asthma.

The median time between presentation and “fit for discharge” was relatively low in this sample—12 hours in the placebo group and 10.1 hours in the prednisolone group. Nearly half the patients were discharged within the first several hours after presentation, and not all patients were admitted to a pediatric ward. A short-stay observation ward within the ED was an option. Thus, the results may be most applicable to patients with mild to moderate disease, some of which may not be admitted to a traditional inpatient unit.

Bottom line: Systemic corticosteroids do not dramatically shorten hospital and ED stays in preschool-aged children with mild to moderate virus-induced wheezing.

Citation: Panickar J, Lakhanpaul M, Lambert P, et al. Oral prednisolone for preschool children with acute virus-induced wheezing. N Engl J Med. 2009;360(4):329-338.

Reviewed by pediatric editor Mark Shen, MD, medical director of hospital medicine at Dell Children’s Medical Center, Austin, Texas.

RRT Implement-ation Doesn’t Affect Hospitalwide Code Rates or Mortality

Clinical question: Does the use of a rapid-response team (RRT) affect hospitalwide code rates and mortality?

Background: In the 100,000 Lives campaign, the Institute for Healthcare Improvement recommended that hospitals implement RRTs to help reduce preventable, in-hospital deaths. Studies have demonstrated that rates of non-ICU codes decrease after RRT implementation. It is unclear if this translates to changes in mortality rates.

Study design: Prospective cohort study of adult inpatients.

Setting: Saint Luke’s Hospital, a 404-bed tertiary-care academic hospital in Kansas City, Mo.

Synopsis: The hospital documented a total of 376 RRT activations. After RRT implementation, mean hospitalwide code rates decreased to 7.5 per 1,000 admissions from 11.2 per 1,000 admissions. This was not associated with a statistically significant reduction in hospitalwide code rates (adjusted odds ratio 0.76; 95% CI; 0.57-1.01; P=0.06). Secondary analyses noted lower rates of non-ICU codes (0.59; 95% CI, 0.40-0.89) compared with ICU codes (0.95; 95% CI; 0.64-1.43; P=0.03 for interaction). Finally, the RRT implementation was not associated with lower hospital-wide mortality (0.95; 95% CI; 0.81-1.11; P=0.52).

Secondary analyses also revealed few instances of RRT undertreatment or underutilization that may have affected the mortality numbers.

A limitation of this study is that it was slightly underpowered (78%) to detect a significant mortality difference. The findings also represent a single institution experience, and may not be generalized to other adult hospital settings or RRT programs.

Bottom line: Implementation of an RRT does not confer lower rates of hospital-wide code arrests or mortality.

Citation: Chan P, Khalid A, Longmore L, et al. Hospital-wide code rates and mortality before and after implementation of a rapid response team. JAMA. 2008;300(21):2506-2513.

Short Takes

ROSUVASTATIN REDUCES CARDIOVASCULAR EVENTS IN OLDER ADULTS WITH NORMAL LDL, ELEVATED CRP LEVELS

In this industry-sponsored, randomized, placebo-controlled study, rosuvastatin decreased cardiovascular events in healthy men older than 50 and healthy women older than 60 with LDL levels ≤ 130 mg/dL but elevated CRP levels 2.0 mg/dL.

Citation: Ridker P, Danielson E, Fonseca F, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-2207.

GINKGO BILOBA DOES NOT DECREASE INCIDENCE OF DEMENTIA IN ADULTS 75 AND OLDER

Randomized placebo-control study of 3,069 adults 75 and older with no cognitive impairment found that ginkgo biloba did not decrease overall incidence of dementia or Alzheimer’s disease.

Citation: DeKosky S, Williamson J, Fitzpatrick A, et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA. 2008;300(19):2253-2262.

INDIVIDUAL HAPPINESS PREDICTED BY HAPPINESS OF FAMILY MEMBERS

A prospective study from the Framingham Heart Study followed 4,793 participants from 1983 to 2003 and found participant happiness to be associated with the happiness of people in their social networks.

Citation: Fowler J, Christakis N. Dynamic spread of happiness in a large social network: longitudinal analysis over 20 years in the Framingham Heart Study. BMJ. 2008;337:a2338.

STATIN ADMINISTRATION PRIOR TO CARDIAC SURGERY DECREASES INCIDENCE OF POSTOPERATIVE DELIRIUM

Analysis of prospectively collected data of 1,059 patients undergoing cardiac surgery with cardiopulmonary bypass at an academic hospital found that preoperative statin use reduced the odds of delirium by 46%.

Citation: Katznelson R, Djaiani G, Borger M, et al. Preoperative use of statins is associated with reduced early delirium rates after cardiac surgery. Anesthesiology. 2009;110(1):67-73.

CERTAIN NSAIDS ASSOCIATED WITH A HIGHER RISK OF ACUTE KIDNEY INJURY

This prospective cohort study of Medicare beneficiaries compared acute renal injury among users of COX-2 inhibitors and other NSAIDS, demonstrating that use of indomethacin, ibuprofen, and rofecoxib resulted in the highest rates of renal injury.

Citation: Winkelmayer W, Waikar S, Mogun H, Solomon D. Nonselective and cyclooxygenase-2-selective NSAIDs and acute kidney injury. Am J Med. 2008;121:1092-1098.

LESS SLEEP INCREASES CORONARY CALCIFICATIONS

This prospective, cohort study found an inverse association between coronary artery calcifications on CT scan and sleep duration as measured by actigraphy; this association was independent of common confounders.

Citation: King C, Knutson K, Rathouz P, et al. Short sleep duration and incident coronary artery calcification. JAMA. 2008;300(24):2859-2866.

CIGARETTE SMOKING IMPARTS HIGHER RISK OF COLORECTAL CANCER

This meta-analysis showed a direct association between cigarette smoking and colorectal cancer incidence and mortality, suggesting that smoking should be used in patient-risk stratification in colorectal cancer screening.

Citation: Botteri E, Iodice S, Bagnardi V, et al. Smoking and colorectal cancer: a meta-analysis. JAMA. 2008;300(23):2765-2778.

INACTIVITY AND DEPRESSION INCREASES RISK FOR CARDIOVASCULAR EVENTS

In this prospective study of outpatients with coronary heart disease, the association between depressive symptoms and future cardiovascular events was primarily explained by health behaviors, including physical inactivity.

Citation: Whooley M, de Jonge P, Vittinghoff E, et al. Depressive symptoms, health behaviors, and risk of cardiovascular events in patients with coronary heart disease. JAMA. 2008;300(20):2379-2388.

Simple Scoring System Provides Timely Prediction of Mortality in Acute Pancreatitis

Clinical question: How can physicians predict mortality in acute pancreatitis?

Background: Historical predictors of mortality in acute pancreatitis require up to 48 hours of data, such as with the Ranson Criteria, or extensive amounts of data, such as with the APACHE II score. An easier tool is needed to predict which patients are at higher risk of mortality.

Study design: Retrospective cohort.

Setting: Patients in the Cardinal Health clinical outcomes research database, which supports public reporting of hospital performance.

Synopsis: The authors identified patients with the principal diagnosis of pancreatitis from 2000-2001 and explored numerous diagnostic findings available within the first 24 hours. Ultimately, BUN >25, impaired mental status, presence of SIRS (systemic inflammatory response syndrome), age >60, and presence of a pleural effusion were found to be predictive of mortality. These diagnostic findings correspond to the mnemonic BISAP. The BISAP score was then validated in a second cohort that included patients from 2004-2005.

Each finding in the BISAP score was given one point. A score of less than 2 was present in approximately 60% of patients admitted with acute pancreatitis, and corresponded to a mortality of less than 1%. A score of 2 corresponded to a mortality of 2%. Higher scores were associated with steeply increasing mortality, with a score of 5 corresponding with greater than 20% mortality.

The BISAP score performed similarly to the APACHE II score, but the former is easier to calculate on the day of admission and has fewer parameters. A more challenging research step will be to demonstrate that using the BISAP score to determine treatment strategies can affect patient outcomes.

Bottom line: The easy-to-calculate BISAP score is a new method for predicting mortality in patients with acute pancreatitis. This tool should help hospitalists determine, on the day of admission, to what extent patients with acute pancreatitis need aggressive management, such as ICU admission and early involvement of specialists.

Citation: Wu B, Johannes R, Sun X, Tabak Y, Conwell D, Banks P. The early prediction of mortality in acute pancreatitis: a large population-based study. Gut. 2008;57(12): 1698-1703.

Nasal Swabs Identify Viral Causes in CAP Patients

Clinical question: How often is viral infection associated with community-acquired pneumonia (CAP) in adults?

Background: CAP is a clinically important disease that is associated with significant hospitalization and mortality. CAP treatment guidelines acknowledge respiratory viruses as an etiology for pneumonia, but few recommendations are made regarding management of these viral infections.

Study design: Prospective study.

Setting: Five hospitals in Edmonton, Alberta, from 2004-2006.

Synopsis: The authors enrolled 193 hospitalized adults, median age 71. Nucleic amplification tests (NATs) from nasopharyngeal swab specimens were tested for human metapneumovirus, respiratory syncytial virus, rhinovirus, parainfluenza virus 1-4, coronaviruses, and adenovirus.

Fifteen percent of these patients had a nasal swab positive for a viral infection. Interestingly, 4% of patients had both a positive viral nasal swab and positive bacterial cultures. Compared with bacterial infection, patients with viral infection tended to be older (76 vs. 64 years, P=0.01), have limited ambulation (66% vs. 32%, P=0.006), and have a history of cardiac disease (66% vs. 32%, P=0.02). Patients with bacterial pneumonia showed a statistically significant trend toward having chest pain, an abnormal white blood count, and a lobar infiltrate on chest X-ray.

Further investigations might look at how nasal swab data could be used to improve infection control within the hospital for patients found to have easily transmissible viruses. Further research could explore the feasibility of avoiding antibiotic use in patients found to have viral pneumonia, assuming bacterial co-infection is reliably excluded.

Bottom line: Nasal swabs using NAT technology could play a significant role in identifying pathogens in CAP patients. How this technology should affect clinical decision-making and how it might improve outcomes remains unknown.

Citation: Johnstone J, Majumdar S, Fox J, Marrie T. Viral infection in adults hospitalized with community-acquired pneumonia: prevalence, pathogens, and presentation. Chest. 2008;134(6):1141-1148.

Intensive Insulin Therapy Doesn’t Reduce ICU Mortality

Clinical question: Does the use of intensive insulin therapy decrease mortality in the intensive-care unit (ICU)?

Background: In 2001, Van den Berghe et al (N Engl J Med. 2001;345(19):1359-67) reported a reduction in morbidity and mortality with intensive insulin therapy (IIT) in surgical ICU patients. This study led to the adoption of IIT protocols in many hospitals. Since 2001, further studies have failed to reproduce the same dramatic benefit of IIT.

Study design: Randomized, controlled trial.

Setting: National Guard King Abdulaziz Medical City, a tertiary-care teaching hospital in Saudi Arabia.

Synopsis: Patients were included in this study if they were 18 years or older with serum glucose levels greater than 110 mg/dL during the first 24 hours of ICU admission. There were multiple exclusion criteria, including patients with Type I diabetes, documented hypoglycemia on ICU admission (glucose <40), or diabetic ketoacidosis.

Enrolled patients were randomized to IIT or conventional insulin therapy (CIT). A multidisciplinary team designed the protocols to maintain glucose levels of 80 to 110 mg/dL and 180 to 200 mg/dL in the IIT and the CIT groups, respectively. The primary endpoint measured was ICU mortality.

The study did not produce a statistically significant difference in ICU mortality (13.5% for IIT vs. 17.1% for CIT; P=0.30). The adjusted hypoglycemia rate was 6.8 per 100 treatment days with IIT and 0.4 per 100 treatment days with CIT (P<0.0001). Patients with hypoglycemia had higher ICU mortality (23.8% vs. 13.7%, P=0.02).

In the measurement of secondary endpoints, there was a trend toward lower episodes of severe sepsis and septic shock in the IIT group (20.7% in IIT vs. 27.2% in CIT, P=0.08). However, this result was not statistically significant.

Bottom line: This well-designed study failed to show a survival benefit with IIT use in the critical-care setting. Given the findings of this and several other recent studies, one should question whether IIT should be prescribed as the standard of care in all critically-ill patients.

Citation: Arabi Y, Dabbagh O, Tamim H, et al. Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients. Crit Care Med. 2008;36(12):3190-3197.

Preoperative and Intraoperative Predictors of Cardiac Adverse Events

Clinical question: What are the incidence and risk factors for perioperative cardiac adverse events after noncardiac surgery?

Background: In the past few decades, the incidence of cardiac adverse events (CAEs) for a general surgery population has remained largely unchanged (approximately 1%). This is in spite of multiple studies evaluating predictive models and attempts at preventive treatment, including preoperative coronary revascularization and perioperative beta blockers.

Study design: Prospective observational study.

Setting: Single, large, tertiary-care university hospital.

Synopsis: A total of 7,740 cases were reviewed in this study, which consisted of general surgery (4,937), vascular surgery (1,846), and urological surgery (957). A trained nurse followed up for perioperative CAEs as many as 30 days after the operation via medical chart review, phone calls, and letters. CAEs were defined as: Q-wave myocardial infarction (MI), non-ST elevation MI, cardiac arrest, or new cardiac dysrhythmia. A total of 83 CAEs (1.1% of patients) had cardiac arrest, with cardiac dysrhythmia being most common.

A total of seven preoperative risk factors were identified as independent predictors for CAEs: age 68, BMI 30, emergent surgery, prior coronary intervention or cardiac surgery, active congestive heart failure, cerebrovascular disease, and hypertension. In addition, two intraoperative risk factors were identified: intraoperative transfusion of packed red blood cells and operative duration of 3.8 hours. (The P value was 0.05 for all independent predictors.)

A further evaluation of intraoperative parameters of high-risk patients experiencing a CAE showed that these patients were more likely to have an episode of mean arterial pressure (MAP) <50 mmHg, an episode of 40% decrease in MAP, and an episode of tachycardia (heart rate >100).

Bottom line: A combination of preoperative predictors and intraoperative elements can help improve risk assessment for perioperative CAEs after noncardiac surgery.

Citation: Kheterpal S, O’Reilly M, Englesbe M, et al. Preoperative and intraoperative predictors of cardiac adverse events after general, vascular, and urological surgery. Anesthesiology. 2009;110(1):58-66.

Early Feeding in the ICU Does Not Affect Hospital Mortality

Clinical question: Will implementing evidence-based feeding guidelines improve feeding practices and reduce mortality in ICU patients?

Background: There is evidence suggesting that providing nutritional support to ICU patients within 24 hours of admission may decrease mortality. It is widely understood that patient care varies between ICUs, and there exist no uniform, evidence-based guidelines for nutritional support. Many patients remain unfed after 48 hours.

Study design: Cluster, randomized-controlled trial.

Setting: ICUs in 27 community and tertiary-care hospitals in Australia and New Zealand.

Synopsis: Hospitals were randomized to intervention or control groups. Dietitian and intensivist co-investigators from intervention ICUs developed guidelines using the Clinical Practice Guideline Development Cycle. Control ICUs were requested to make no new ICU nutritional management changes. The study enrolled 1,118 eligible patients and included adults expected to stay longer than two days. Excluded were patients taking oral diets, patients receiving palliative care or with suspected brain death, and patients sent from other facilities.

Guidelines were implemented using several methods—educational outreach visits, one-on-one conversations, active reminders, passive reminders, and educational in-services. The guidelines were successful in evoking significant practice changes in all of the intervention ICUs. Significantly more patients received nutritional support during their ICU stays in guideline ICUs, and patients in these ICUs were fed significantly earlier. There were, however, no significant differences between guideline and control ICUs with regard to hospital discharge mortality (28.9% vs. 27.4%; 95% CI; -6.3% to 12.0%; P=0.75). The groups also showed no statistical difference in hospital or ICU length of stay.

Bottom line: Significantly more patients in the guideline ICUs were fed within 24 hours, but this did not translate into improvements in mortality or other clinical outcomes.

Citation: Doig G, Simpson F, Finfer S, et al. Effect of evidence-based feeding guidelines on mortality of critically ill adults: a cluster randomized controlled trial. JAMA. 2008;300(23):2731-2741.

Low-Dose Aspirin Doesn’t Reduce Cardiovascular Events in Type 2 Diabetes Patients

Clinical question: Is low-dose aspirin effective for the primary prevention of atherosclerotic events in patients with Type 2 diabetes?

Background: Diabetes is a significant risk factor for cardiovascular events. Several prior studies have shown that aspirin therapy is effective as a secondary prevention strategy for cardiovascular events. The American Diabetes Association also recommends use of aspirin as a primary prevention strategy. Clinical trial data is currently insufficient in this area.

Study design: Prospective, randomized, open-label, controlled trial with blinded endpoint assessment.

Setting: 163 institutions in Japan.

Synopsis: The study enrolled 2,539 diabetic patients between 30 and 85 years old—mean age was 65—and included patients without EKG changes or a significant history or ongoing treatment of atherosclerotic disease. Patients were randomly assigned into an aspirin group (81 mg or 100 mg once daily) or a nonaspirin group. Patients had a median follow up of 4.37 years.

The primary endpoint was any atherosclerotic event, ranging from sudden death to ischemic heart disease or stroke. The incidence of atherosclerotic events was not statistically different in the aspirin group (68 events, 5.4%) than in the nonaspirin group (86 events, 6.7%) (HR, 0.80; 95% CI; 0.58-1.10; log-rank test, P=0.16). However, there was a suggested benefit of primary prevention in the subgroup aged 65 years or older. In addition, the combined endpoint of fatal coronary and cerebrovascular events occurred in one patient in the aspirin group and 10 patients in the nonaspirin group (HR, 0.10; 95 % CI, 0.01-0.79; P=.0037). This study is limited by the low incidence of atherosclerotic disease in Japan.

Bottom line: Low-dose aspirin used in patients with Type 2 diabetes does not significantly demonstrate primary prevention of cardiovascular events.

Citation: Ogawa H, Nakayama M, Morimoto T, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA. 2008;300(18):2134-2141. TH

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