Mary Ann McLaughlin

The impact of post-operative pain on outcomes following hip fracture.

&NA; Untreated pain is a major health care issue and very little is known about the treatment of pain and the effect of pain on post‐operative outcomes in older adults. This study was performed to identify the impact of pain on outcomes following hip fracture in older adults. Four hundred and eleven consecutive cognitively intact patients admitted with hip fracture to four New York hospitals were enrolled in a prospective cohort study. Patients were interviewed daily using standardized pain assessments. We used multiple logistic regression and ordinary least squares linear regression to examine the association of post‐operative pain on immediate post‐operative outcomes (duration of stay, physical therapy sessions missed or shortened, ambulation following surgery, and post‐operative complications) and outcomes 6 months following fracture (locomotion, mortality, return to the community, residual pain). Patients with higher pain scores at rest had significantly longer hospital lengths of stay (P=0.03), were significantly more likely to have physical therapy sessions missed or shortened (P=0.002), were significantly less likely to be ambulating by post‐operative day 3 (P<0.001), took significantly longer to ambulate past a bedside chair (P=0.01), and had significantly lower locomotion scores at 6 months (P=0.02). Pain at rest was not significantly associated with post‐operative complications, nursing home placement, survival at 6 months, or residual pain at 6 months. Post‐operative pain is associated with increased hospital length of stay, delayed ambulation, and long‐term functional impairment. Whereas appropriate caution is warranted in administering opioid analgesics to older adults, these data suggest that improved pain control may decrease length of stay, enhance functional recovery, and improve long‐term functional outcomes.

Gender Disparities in Blood Pressure Control and Cardiovascular Care in a National Sample of Ambulatory Care Visits

The purpose of this study was to provide an analysis of gender-based disparities in hypertension and cardiovascular disease care in ambulatory practices across the United States. Using data from the 2005 National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey, we conducted a cross-sectional analysis of patient visits with their primary care providers and examined the association between gender and blood pressure control, use of any antihypertensive medication or initiation of new therapy for patients with uncontrolled hypertension, and receipt of recommended therapy for select cardiovascular conditions. Multivariable models were estimated to examine the association between gender and each outcome controlling for other variables. A total of 12 064 patient visits were identified (7786 women and 4278 men). Among patients with hypertension, women were less likely than men to meet blood pressure control targets (54.0% versus 58.7%; P<0.02). In multivariate analyses, women aged 65 to 80 years were less likely than men to have controlled hypertension (odds ratio: 0.62; 95% CI: 0.45 to 0.85). There was no association between gender and use of any antihypertensive medication or initiating a new therapy among patients with uncontrolled hypertension. In multivariate analyses, women were less likely than men to receive aspirin (odds ratio: 0.43; 95% CI: 0.27 to 0.67) and &bgr;-blockers (odds ratio: 0.60; 95% CI: 0.36 to 0.99) for secondary prevention of cardiovascular disease. Our study highlights the persistent gender disparities in blood pressure control and cardiovascular disease management and also reveals the inadequate delivery of cardiovascular care to all patients.

Review of Cardiovascular Risk Factors in Women

BACKGROUND Although cardiovascular disease (CVD) is the leading cause of death in women in the United States, a knowledge gap persists regarding the mechanisms and management of CVD in women. Before treatment can be optimized, the role of cardiovascular risk factors must be elucidated. OBJECTIVE This review provides an updated assessment of cardiovascular risk factors in women, with a focus on cardiometabolic risk. METHODS MEDLINE and Cochrane Library databases, and statistics from the National Health and Nutrition Examination Survey and the American Heart Association, were searched from 1990 to September 2008 using the following terms: cardiovascular risk factors, women, gender, cardiometabolic risk, abdominal obesity, and metabolic syndrome. Publications were classified as English-only original data, reviews, and clinical guidelines. Nonpublished data were excluded. Data were extracted by 2 reviewers independently. RESULTS Investigators performing multivariable predictive models have estimated that traditional risk factors account for approximately 70% of the variance in estimating cardiovascular events. However, substantial sex differences exist in the prevalence of traditional risk factors as well as in cardiovascular outcomes. Hypertension is more prevalent in men until the age of 59 years, but then contributes to greater morbidity in older women. Low levels of high-density lipoprotein and elevated triglyceride levels pose more of a threat to women, yet high levels of low-density lipoprotein pose equal risk for women and men. The CVD mortality rate is -3 times greater in people with diabetes than in those without diabetes. Among diabetic individuals, CVD mortality is slightly higher in women compared with men. CONCLUSIONS Increased knowledge of gender-specific risks for CVD has led to national campaigns to educate women. In addition to traditional risk factors, cardiometabolic risk is an important consideration in women. Controversy exists regarding the exact definitions and usefulness of the term metabolic syndrome, but it is clear that the presence of certain factors contributes to increased morbidity and mortality in affected individuals. Abdominal obesity links insulin resistance, dyslipidemia, and hypertension through complex endocrine pathways. Current research is identifying gene x gender interactions, and continued research is necessary to explore the relationship of sex steroids and cardiovascular risk in both men and women.

Nonalcoholic Steatohepatitis and Hepatic Fibrosis in HIV-1–Monoinfected Adults With Elevated Aminotransferase Levels on Antiretroviral Therapy

BACKGROUND Persistent aminotransferase elevations are common in human immunodeficiency virus (HIV)-infected patients on antiretroviral therapy (ART), including those without hepatitis B or C coinfection, but their clinical significance is unknown. METHODS HIV-infected adults with aminotransferase levels elevated above the upper limit of normal for ≥6 months while receiving ART, and without chronic viral hepatitis or other known causes of chronic liver disease, underwent a detailed metabolic assessment and liver biopsy. RESULTS Sixty-two HIV-infected subjects completed the study. Forty (65%) had clinically significant liver pathology, including 34 (55%) with nonalcoholic steatohepatitis (NASH) and 11 (18%) with bridging fibrosis, 10 of whom also had NASH. Nonspecific abnormalities alone were seen in 22 (35%) subjects, including mild steatosis, mild to moderate inflammation, and evidence of drug adaptation. Insulin resistance, obesity, and the presence of either of 2 minor alleles in the PNPLA3 gene were significantly associated with increased risk of NASH and fibrosis. NASH and/or fibrosis were not associated with duration of HIV infection or ART, specific antiretroviral drugs, history of opportunistic infection, immune status, or duration of aminotransferase elevation. CONCLUSIONS HIV-infected adults with chronic aminotransferase elevations while receiving ART have a high rate of liver disease. Noninvasive testing can help identify liver disease in such patients, but liver biopsy is necessary to definitively identify those at risk for liver disease progression and complications. Longitudinal follow-up of this cohort will better characterize the natural history of aminotransferase elevations in this population and identify noninvasive biomarkers of liver disease progression.

Differential antiviral effect of PEG-interferon-α-2b on HIV and HCV in the treatment of HIV/HCV co-infected patients

Objective:The major antiviral effect of interferon (IFN)-α on hepatitis C virus (HCV) is blocking of virion production from infected cells. We now investigate the previously unknown mechanism of action of IFN-α against HIV. Methods:HIV kinetics in parallel to HCV kinetics and IFN pharmacokinetics during pegylated-IFN-α-2b (1.5 μg/Kg q.w., PEG–IFN) and ribavirin (1–1.2 g daily) treatment in nine HIV patients co-infected with HCV genotype 1 were analyzed. In vivo modeling predictions of suppression of HIV replication by PEG–IFN in CD8-depleted peripheral blood mononuclear cells were verified by in vitro experiments. Results:HCV and HIV show different viral decline patterns after administration of PEG–IFN. Unlike the bi-phasic decline shown by HCV, HIV shows a slow continuous decline during the first week, with no rebound when PEG–IFN levels decline. Fitting of HIV kinetics with known half-lives of free virus and infected cells indicates that the major effect of IFN on HIV is to block de novo infection rather than to block virion production. The magnitude of the antiviral effect is similar (mean 1.1 log10 decline at 7 days) to those of direct anti-HIV drugs, but shows an inverse correlation with baseline viremia. In vitro studies show that preincubation with IFN renders a suppression of HIV replication superior to that of treatment postinfection, thus corroborating the mathematical analysis in vivo. Conclusion:The complimentary antiviral properties of IFN-α and antiretroviral therapy suggest a role for pharmacokinetically improved formulations of IFN as part of salvage therapy for HIV-infected individuals.

Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial

Chronic liver injury can result in fibrosis that may progress over years to end‐stage liver disease. The most effective anti‐fibrotic therapy is treatment of the underlying disease, however when not possible, interventions to reverse or slow fibrosis progression are needed.

Arterial Effects of Canakinumab in Patients With Atherosclerosis and Type 2 Diabetes or Glucose Intolerance.

Background Evidence suggests that interleukin (IL)-1β is important in the pathogenesis of atherosclerosis and its complications and that inhibiting IL-1β may favorably affect vascular disease progression. Objectives The goal of this study was to evaluate the effects of IL-1β inhibition with canakinumab versus placebo on arterial structure and function, determined by magnetic resonance imaging. Methods Patients (N = 189) with atherosclerotic disease and either type 2 diabetes mellitus or impaired glucose tolerance were randomized to receive placebo (n = 94) or canakinumab 150 mg monthly (n = 95) for 12 months. They underwent magnetic resonance imaging of the carotid arteries and aorta. Results There were no statistically significant differences between canakinumab compared with placebo in the primary efficacy and safety endpoints. There was no statistically significant change in mean carotid wall area and no effect on aortic distensibility, measured at 3 separate anatomic sites. The change in mean carotid artery wall area was –3.37 mm2 after 12 months with canakinumab versus placebo. High-sensitivity C-reactive protein was significantly reduced by canakinumab compared with placebo at 3 months (geometric mean ratio [GMR]: 0.568; 95% confidence interval [CI]: 0.436 to 0.740; p < 0.0001) and 12 months (GMR: 0.56; 95% CI: 0.414 to 0.758; p = 0.0002). Lipoprotein(a) levels were reduced by canakinumab compared with placebo (–4.30 mg/dl [range: –8.5 to –0.55 mg/dl]; p = 0.025] at 12 months), but triglyceride levels increased (GMR: 1.20; 95% CI: 1.046 to 1.380; p = 0.01). In these patients with type 2 diabetes mellitus or impaired glucose tolerance, canakinumab had no effect compared with placebo on any of the measures assessed by using a standard oral glucose tolerance test. Conclusions There were no statistically significant effects of canakinumab on measures of vascular structure or function. Canakinumab reduced markers of inflammation (high-sensitivity C-reactive protein and interleukin-6), and there were modest increases in levels of total cholesterol and triglycerides. (Safety & Effectiveness on Vascular Structure and Function of ACZ885 in Atherosclerosis and Either T2DM or IGT Patients; NCT00995930)

Four-Week Direct-Acting Antiviral Regimens in Noncirrhotic Patients With Hepatitis C Virus Genotype 1 Infection: An Open-Label, Nonrandomized Trial

BACKGROUND Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) for 6 weeks achieves sustained virologic response (SVR) rates of 95% in some patients. If effective, shorter therapeutic courses could improve adherence and treatment costs. OBJECTIVE To determine factors predictive of SVR to 4 weeks of DAA treatment in patients with stage F0 to F2 liver fibrosis. DESIGN Open-label, nonrandomized, phase 2a trial. (Clinical Trials.gov: NCT01805882). SETTING Single-center. PATIENTS 50 treatment-naive and predominantly African American patients with HCV genotype 1 infection and early-stage liver fibrosis were sequentially enrolled into 2 treatment groups. INTERVENTION 25 participants received a 3-drug regimen consisting of ledipasvir and sofosbuvir plus GS-9451 for 4 weeks, and 25 received a 4-drug regimen consisting of ledipasvir, sofosbuvir, GS-9451, and GS-9669 for 4 weeks. MEASUREMENTS The primary efficacy end point was SVR12 (HCV RNA level below the lower limit of quantification at posttreatment week 12). RESULTS Forty percent (10 of 25) (95% CI, 21% to 61%) of patients in the 3-drug group and 20% (5 of 25) (CI, 7% to 41%) of those in the 4-drug group achieved SVR12. Exploratory analysis suggested that lower baseline HCV viral load, younger age, and HCV genotype 1b were associated with SVR12. Ten patients had baseline HCV variants conferring greater than 20-fold resistance in vitro to at least 1 study DAA; all had viral relapse. Forty-eight percent (12 of 25) of patients receiving the 3-drug regimen and 72% (18 of 25) of those receiving the 4-drug regimen had adverse events, most of which were mild. One participant was lost to follow-up. LIMITATION Nonrandomized study design and small sample of patients with early-stage fibrosis. CONCLUSION Combination DAA therapy with 3 or 4 drugs for 4 weeks was well-tolerated but resulted in limited cure rates. PRIMARY FUNDING SOURCE National Institute of Allergy and Infectious Diseases, National Cancer Institute, and Clinical Center Intramural Program; supported in part by a cooperative research and development agreement between the National Institutes of Health and Gilead Sciences.

The success of recruiting minorities, women, and elderly into a randomized controlled effectiveness trial

BACKGROUND Heart failure, a leading cause of hospitalization among elderly people, disproportionately afflicts African-American and other non-White populations. Studies of health care interventions often do not include these groups in proportion to numbers in the patient population. Our objective was to assess whether a randomized controlled effectiveness trial enrolled patients by ethnicity/race, gender, and age in proportion to those eligible. METHODS We conducted a randomized controlled trial comparing nurse management and usual care among ambulatory heart failure patients at the four hospitals in East and Central Harlem, New York. We incorporated culturally sensitive and age-appropriate strategies to enroll a demographically representative group into the trial. Recruitment proceeded in several steps: identifying patients with billing code and visit criteria, documenting systolic dysfunction, obtaining clinician permission and correct addresses, contacting patients, and enrolling eligible patients. We assessed differences by ethnicity/race and gender at successive steps in the recruitment process, and differences between enrollees and refusals regarding overall health, evaluation of medical care, and difficulty receiving care. RESULTS We enrolled 406 ambulatory patients by ethnicity/race and gender in proportion to the numbers eligible to be contacted (46% African-American/Black, 33% Hispanic, and 47% female). Among patients contacted, however, those 18 through 74 years were 2.0 to 3.3 times more likely than those > or = 75 years to enroll (p < 0.001). CONCLUSIONS The recruitment strategy successfully enrolled patients by ethnicity/race, gender, and age through 74 years, but not those > or = 75 years. Registries of patients who refuse to enroll in trials could provide guidance for clinical and public policy.

Therapeutic response to peg-IFN-alpha-2b and ribavirin in HIV/HCV co-infected African-American and Caucasian patients as a function of HCV viral kinetics and interferon pharmacodynamics

Method: In this study we sought to characterize the relationship between several pharmacokinetic and pharmacodynamic parameters and virologic responses among HIV/hepatitis C virus genotype-1 co-infected patients receiving pegylated interferon-alpha-2b (peg-IFN2b) and ribavirin. We also tried to establish the underlying mechanisms that lead to poor sustained virologic responder rates observed with African-Americans against Caucasians and compared their results with those observed in a cohort of hepatitis C virus mono-infected patients. Results: Among our studied population, a viral decline of more than 1.0 log at day 3 combined with viral load of less than 5.0 log IU/ml at day 28 predicted sustained virologic responders with negative predictive value 100% and positive predictive value 100%. African-Americans had significantly (P < 0.01) slower hepatitis C virus viral kinetics as compared to Caucasians. However, peg-IFN2b concentrations and pharmacokinetic parameters, peg-IFN2bmax and peg-IFN2b half-life, were similar in both groups and did not predict sustained virologic responders. Nevertheless, the pharmacodynamic parameter EC50, estimated from nonlinear fitting of the viral kinetics together with peg-IFN2b concentration data, showed that HIV/ hepatitis C virus co-infected African-Americans have lower sensitivity to interferon-alpha thus giving rise to slower viral decline. The combined pharmacokinetic/pharmacodynamic parameter IFNmax/EC90 was an excellent predictor of sustained virologic responders, thus showing the importance of maintaining peg-IFN2b levels above EC90 to achieve successful treatment. Conclusion: Further studies are needed to evaluate whether these pharmacodynamic predictions are a result of differential host response to peg-IFN2b or other viral factors conferring relative resistance to peg-IFN2b.