Principles in the Evaluation of Systematic Reviews.

Literature reviews summarize information from individual studies and are an important tool in the practice of evidence-based medicine. Various types of reviews, including narrative and systematic reviews, may be found within the biomedical literature. Systematic reviews are the strongest type and are often rated as the highest level of evidence. Thus it is important that clinicians understand how to evaluate them critically. This article is intended to enhance clinicians' understanding of the unique methods commonly used in systematic reviews by using the reporting standards to formulate evaluation principles. Explanations of the statistical tests and types of biases that are frequently encountered in systematic reviews are discussed. Lastly, an evaluation of a meta-analysis using these principles is provided.

Remifentanil, fentanyl, or the combination in surgical procedures in the United States: predictors of use in patients with organ impairment or obesity.

INTRODUCTION: Remifentanil has a rapid onset and short duration of action, predictable pharmacokinetic/pharmacodynamic profile, and unlike fentanyl, does not accumulate with repeated or prolonged administration. This study evaluated predictors of remifentanil use in surgical patients with renal or hepatic impairment, or obesity in the United States who received remifentanil, fentanyl, or the combination. METHODS: Data (2010) from the US Healthcare National Inpatient Database, State Inpatient Database, State Ambulatory Surgery Database, and private hospital and Medicaid databases were used in this analysis. Patients included had presence of hepatic or renal disease, and/or obesity and were >5 and ≤80 years of age. RESULTS: In 2010, 9,274 patients with renal impairment, 1,896 with hepatic impairment, and 6,278 with obesity were identified. The percentage of surgical patients diagnosed with renal disease, hepatic disease, or obesity who received remifentanil was 41, 28, and 35%, respectively; 29, 17, and 22% received both remifentanil and fentanyl, and 30, 55, and 43% received fentanyl alone, respectively. In patients with renal or hepatic disease the probability of remifentanil use was greater for persons aged >50 years, with Medicare as primary payer, or who were diagnosed with obesity (p < 0.05 all comparisons). In obese patients, the probability of remifentanil use was greater for persons aged >50 years or female (both p < 0.05). For all 3 disease states, the probability of remifentanil use was lower for those receiving epidural anesthesia or with Medicaid as primary payer (p < 0.05 all comparisons). CONCLUSION: Remifentanil in combination with fentanyl is used less than fentanyl in surgical patients with hepatic impairment or obesity. This is inconsistent with the fact that the pharmacokinetic/pharmacodynamic features of remifentanil suggest it is the preferred intraoperative opioid in these patients. Predictors of remifentanil use in patients with renal or hepatic impairment, or obesity include older age, obesity, and Medicare as primary payer. Remifentanil in combination with fentanyl was significantly less utilized than fentanyl in persons with Medicaid as primary payer even though there was a disproportionate enrollment of beneficiaries with renal or hepatic disease, or obesity in state Medicaid programs.

Bioequivalence evaluation of epinephrine autoinjectors with attention to rapid delivery.

Timely and proper injection of epinephrine is critical to prevent serious consequences relating to anaphylaxis. In a recent bioavailability study comparing epinephrine delivery from the Auvi-Q™ and EpiPen(®) epinephrine autoinjectors, the Auvi-Q failed to meet the bioequivalence threshold when using partial area under the curve (AUC) analyses based on zero to Tmax recommended for highly variable drugs such as epinephrine. Peak plasma epinephrine concentrations for the EpiPen occurred 10 minutes (median Tmax) after dosing, while peak concentrations for the Auvi-Q occurred 20 minutes after dosing. Though bioequivalence may be concluded for Cmax, AUCinf, and AUC0-t, for fast-acting therapeutics used to treat life-threatening conditions, such as epinephrine, additional pharmacokinetic parameters such as AUC zero to Tmax may be important to evaluate when assessing bioequivalence.

Fidaxomicin for Clostridium difficile-associated diarrhoea: epidemiological method for estimation of warranted price.

BACKGROUND: Fidaxomicin is a macrocyclic antibiotic approved in 2011 by the US Food and Drug Administration for treatment of Clostridium difficile-associated diarrhoea (CDAD). OBJECTIVE: Herein, we present an epidemiological method to estimate, on a case mix basis, and from the perspective of the US health system, the warranted (justifiable) price per day for fidaxomicin, as a percent of the wholesale acquisition cost (WAC) per day for fidaxomicin ($US280). METHODS: Data from two randomized controlled studies (Optimer-003 [n = 596] and Optimer-004 [n = 509]) were used to discern the number-needed-to-treat (NNT = 7.1) for sustained clinical response. Sustained clinical response was defined as clinical response at the end of treatment, and survival without proven or suspected CDAD recurrence through 25 days beyond the end of treatment. National data for primary and secondary cases (the case mix) of CDAD (mean hospital length of stay [LOS], and mean cost) were derived from the 2009 US Healthcare Cost and Utilization Project. The method for attribution of hospital LOS for secondary cases of CDAD was derived from a study published by O'Brien et al. in 2007. Comparative regimens of vancomycin were: (i) injectable used orally, 125 mg four times daily (qid; WAC of $US6/day), with use of vancomycin hydrochloride (HCl) capsules, 125 mg qid (WAC of $US106/day) post-hospital discharge; (ii) vancomycin HCl capsules, 125 mg qid; and (iii) vancomycin HCl capsules, 250 mg qid (WAC of $US196/day). Findings are expressed in 2011 US dollars. The study perspective is that of the US health system. RESULTS: The warranted price per day for fidaxomicin represented 95% of the WAC per day for fidaxomicin compared with use of injectable vancomycin (orally) 125 mg qid (with subsequent use of vancomycin HCl capsules, 125 mg qid post-hospital discharge); 109% of the WAC per day for fidaxomicin compared with use of vancomycin HCl capsules, 125 mg qid; and 141% of the WAC per day for fidaxomicin when compared with use of vancomycin HCl capsules, 250 mg qid. CONCLUSION: From the perspective of the US health system, fidaxomicin represents value for money in the treatment of CDAD. The methodology employed in this research has application beyond antimicrobial pharmacotherapy.

α1-Proteinase inhibitor (human) in the treatment of hereditary emphysema secondary to α1-antitrypsin deficiency: number and costs of years of life gained.

BACKGROUND: α(1)-Antitrypsin deficiency (α-ATD) is a disorder inherited in an autosomal recessive pattern, with co-dominant alleles known as the protease inhibitor system (Pi). The main function of α(1)-antitrypsin (α-AT) is to protect the lungs against a powerful elastase released from neutrophil leucocytes. α-ATD typically presents with a serum α-AT level of <50 mg/dL. In severe α-ATD, phenotype PiZZ, protection of the lungs is compromised, leading to an accelerated decline in forced expiratory volume in 1 second (FEV(1)). As a result, a patient may develop pulmonary emphysema of the panacinar type at a young age (third to fourth decades of life), with cigarette smoking being the most significant additional risk factor. It has been shown that weekly or monthly infusion of human α-AT is effective in raising serum α-AT levels to desired levels (>80 mg/dL), with few, if any, adverse effects. OBJECTIVE: The present study was designed to discern the number of years of life gained, and the expense per year of life gained, associated with use of α-AT augmentation therapy (α(1)-proteinase inhibitor [human]), relative to 'no therapeutic intervention' in persons with α-ATD. METHODS: Monte Carlo simulation (MCS) was used to: (i) estimate the number of years of life gained; and (ii) estimate the health service expenditures per year of life gained for persons receiving, or not receiving, α-AT augmentation therapy. MCS afforded a decision-analytical framework parameterized with both stochastic (random) and deterministic (fixed) components, and yielded a fiscal risk-profile for each simulated cohort of interest (eight total: by sex, smoking status [non-smoker; or past use (smoker)]; and use of α-AT augmentation therapy). The stochastic components employed in the present inquiry were: (i) age-specific body weight, and height; (ii) age-specific mortality; and (iii) the probability distribution for receipt of a lung transplant, as a function of FEV(1). The deterministic components employed in the present inquiry were: (i) age in years for the simulated cohort; (ii) outlays for α-AT augmentation therapy; (iii) health service expenditures associated with receipt of a lung transplant; (iv) annual decline in FEV(1); (v) percent predicted FEV(1); (vi) initiation of α-AT augmentation therapy as a function of percent predicted FEV(1); (vii) need for a lung transplant as a function of percent predicted FEV(1); (viii) annual rate of lung infection; and (ix) mortality as a function of percent predicted FEV(1). Results are reported from a payer perspective ($US, year of costing 2010). RESULTS: Receipt of α-AT augmentation therapy was associated with a significant increase (p < 0.05) in years of life gained, with female smokers gaining an estimated mean 7.14 years (cost per year: $US248 361 [95% CI 104 531, 392 190]); female non-smokers gained an estimated mean 9.19 years (cost per year: $US160 502 [95% CI 37 056, 283 947)]); male smokers gained an estimated mean 5.93 years (cost per year: $US142 250 [95% CI 48 467, 236 032]); and male non-smokers gained an estimated mean 10.60 years (cost per year: $US59 234 [95% CI 20 719, 97 548]). CONCLUSION: Use of α-AT augmentation therapy was associated with an increase in years of life gained by sex and history of tobacco use, and at a cost per year of life gained comparable to that of other evidenced-based interventions.

The association between class of antipsychotic and rates of hospitalization: results of a retrospective analysis of data from the 2005 Medicare current beneficiary survey.

BACKGROUND: When second-generation antipsychotics (SGAs), also called atypical antipsychotics, were introduced in the 1990s, early research suggested that these drugs offered better tolerability and adherence than first-generation antipsychotics (FGAs), or typical antipsychotics. This presumably would reduce the need for hospital services. However, health research to test this hypothesis has focused mostly on psychiatric readmissions. OBJECTIVE: The objective of this study was to compare rates of all-cause hospitalization among patients receiving different classes of antipsychotics (SGAs, FGAs, both, or neither) in a large, all-ages sample of both institutionalized and noninstitutionalized Medicare beneficiaries. METHODS: We examined the 2005 Medicare Current Beneficiary Survey Cost and Use file for 11,236 survey participants. Antipsychotic utilization was characterized in terms of class: FGA (ie, chlorpromazine, fluphenazine, haloperidol, loxapine, perphenazine, thiothixene, thioridazine, or trifluoperazine) or SGA (ie, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, or ziprasidone). Hospitalization was defined in terms of whether a Medicare beneficiary was admitted to the hospital for any reason in 2005, and was measured in terms of the number of hospital visits. In our final model, we included the following confounding variables: disability status (> or =1 limitation in activities of daily living), Rosow-Breslau impairment score (difficulty with walking, stooping, crouching, kneeling, or doing heavy housework), cognitive impairment (diagnosis of Alzheimer's disease or memory loss that interfered with daily activity), and health behavior variables (body mass index and smoking status). RESULTS: A total of 3.5% of Medicare beneficiaries (1.3 million) filled > or =1 prescription for an antipsychotic medication in 2005. Controlling for demographic, socioeconomic, health, and disability variables, SGA-only users were more than twice as likely (odds ratio [OR] = 2.2 [95% CI, 1.7-2.9]) and combination users were more than 6 times as likely (OR = 6.3 [95% CI, 2.4-16.2]) as nonusers to be hospitalized. The odds of FGA users being hospitalized were not significantly different from nonusers (OR = 1.4 [95% CI, 0.7-2.8]). CONCLUSIONS: This analysis yielded provocative, but by no means conclusive, evidence that SGAs as a class are not necessarily superior to FGAs in mitigating patient's use of hospital services under real-world conditions. Systematic analysis of this relationship with a large, multiple-year sample of Medicare beneficiaries is warranted.

The use of anticholinergic medications in homebound elderly patients with dementia.

OBJECTIVE: Identify the number of homebound older adults admitted to a home-based health care agency in 2003 with a diagnosis of dementia. Compare the use of anticholinergic medications in older adults with a diagnosis of dementia to a matched comparison group without a diagnosis of dementia. DESIGN: Retrospective, cohort study. SETTING: Home health care agency in the eastern part of Washington State serving the homebound. PARTICIPANTS: Homebound subjects 60 years of age or older with or without a diagnosis of dementia. INTERVENTIONS: N/A. MAIN OUTCOME MEASURES: Number of homebound subjects with a diagnosis of dementia. Comparison of those in the group diagnosed with dementia (n = 50) to a matched cohort in the group with no dementia diagnosis (n = 50) in regard to use of drugs with anticholinergic activity. RESULTS: From a population of 1,746 patients served in 2003 who met the study criteria, 107 (6.1%) patients had a diagnosis of dementia. Of these, 50 were studied. Of the subjects with dementia, 62% were prescribed a drug with anticholinergic activity, compared with 80% of subjects without dementia. Fewer patients in the study group were prescribed anticholinergic drugs than in the comparison group. The primary drugs with anticholinergic activity cited most often were olanzapine, hydroxyzine, and mirtazapine. CONCLUSION: Drugs with anticholinergic activity are used frequently in an older homebound population, irrespective of a dementia diagnosis.

Aralast: a new alpha1-protease inhibitor for treatment of alpha-antitrypsin deficiency.

OBJECTIVE: To review the epidemiology, pathogenesis, and management of patients with alpha-antitrypsin (AAT) deficiency syndrome and compare Aralast with Prolastin, 2 of the 3 available human plasma-derived AAT agents. DATA SOURCES: Articles were identified using a MEDLINE (1966-September 2005) search with MESH headings that included alpha-antitrypsin and emphysema. STUDY SELECTION AND DATA EXTRACTION: All papers from peer-reviewed journals on the laboratory or clinical efficacy of plasma-derived AAT (eg, Prolastin, Aralast) for patients with this autosomal recessive disorder were reviewed. DATA SYNTHESIS: Clinical trials found that AAT augmentation prevents progression of AAT-deficient emphysema and thus its associated morbidity and mortality. Treatment with Aralast has been shown to be safe and well tolerated, with a low incidence of mild to moderate adverse events. Pharmacoeconomics studies of AAT augmentation demonstrated that the use of Aralast was cost-effective as lifelong augmentation therapy for AAT-deficient emphysema. CONCLUSIONS: Because of its effectiveness and extra safety measure compared with Prolastin, Aralast should be recommended for formulary inclusion.

Effectiveness of an osteoporosis intervention among older adults residing in assisted living facilities.

OBJECTIVES: To describe demographic and clinical risk factors for osteoporosis among persons aged 60 years and older residing in assisted living facilities and to compare the frequency of bone-mineral density (BMD) testing and initiation of pharmacotherapy for osteoporosis (prevention/treatment) in both a control and experimental cohort. DESIGN: Prospective cohort study. SETTING: Sixteen separate assisted living facilities from November 2001 through July 2002. PARTICIPANTS: Assisted living facility ambulatory residents (N = 111) aged 60 years and older. INTERVENTION: Based on the subject's risk factors for osteoporosis and FRACTURE Index score (female subjects only), written recommendations were made from a multidisciplinary team to increase the percentage of residents evaluated (via central dual-energy x-ray absorptiometry [DEXA] scan) and/or treated for osteoporosis. MAIN OUTCOME MEASURES: FRACTURE Index was calculated on all female participants and reported with BMD or without BMD results by convention. An investigator-developed osteoporosis risk-factor assessment questionnaire was used to evaluate risk factors present for each participant. Numbers of subjects being evaluated for osteoporosis via DEXA scan and numbers of subjects having pharmacotherapy altered to prevent or treat osteoporosis were recorded. RESULTS: One hundred eleven older adults (average age 84 [range 60-94], SD = 6.5 years) participated in the study. As a group the female cohort with no known previous diagnosis of osteoporosis were at high risk for fracture over the next five years as evidenced by an average FRACTURE Index score of 6.6 and 7.2 (control and intervention group, respectively) without BMD, and 9.9 and 10.3 (control and intervention group, respectively) with BMD, respectively. At study end, a significant number of participants in the intervention group had initiated the use of calcium or vitamin D supplements (P = 0.016 and P = 0.031, respectively). The initiation of bisphosphonates in eight subjects over the six-month study period was also significant (P = 0.008) in the intervention group. No significant changes in the use of calcium or vitamin D or specific osteoporosis therapies were realized in the control group. In the intervention group, physician contact did not result in a significant increase in the numbers of participants receiving a BMD evaluation. CONCLUSION: As a whole, residents residing in assisted living facilities are at high risk of having osteoporosis and/or sustaining a fracture. When assessment of osteoporosis and fracture risk is communicated to a physician, use of therapies aimed to improve bone health increases. In this study, there was a significant increase in the use of calcium, vitamin D, and bisphosphonates in the intervention cohort. However, physician contact did not result in more participants receiving a BMD evaluation.