Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: A multicenter Fabry Registry study.

BACKGROUND: The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease. METHODS: To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events. RESULTS: In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25-34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55-64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17% of p.N215S males (mostly in patients aged 65-74 years), and rarely in females (3%). CONCLUSION: p.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males.

Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease.

BACKGROUND: Fabry disease results from deficient α-galactosidase A activity and globotriaosylceramide accumulation causing renal insufficiency, strokes, hypertrophic cardiomyopathy and early demise. We assessed the 10-year outcome of recombinant α-galactosidase A therapy. METHODS: The outcomes (severe clinical events, renal function, cardiac structure) of 52/58 patients with classic Fabry disease from the phase 3 clinical trial and extension study, and the Fabry Registry were evaluated. Disease progression rates for patients with low renal involvement (LRI, n=32) or high renal involvement (HRI, n=20) at baseline were assessed. RESULTS: 81% of patients (42/52) did not experience any severe clinical event during the treatment interval and 94% (49/52) were alive at the end of the study period. Ten patients reported a total of 16 events. Patients classified as LRI started therapy 13 years younger than HRI (mean 25 years vs 38 years). Mean slopes for estimated glomerular filtration rate for LRI and HRI were -1.89 mL/min/1.73 m(2)/year and -6.82 mL/min/1.73 m(2)/year, respectively. Overall, the mean left ventricular posterior wall thickness and interventricular septum thickness remained unchanged and normal. Patients who initiated treatment at age ≥ 40 years exhibited significant increase in left ventricular posterior wall thickness and interventricular septum thickness. Mean plasma globotriaosylceramide normalised within 6 months. CONCLUSIONS: This 10-year study documents the effectiveness of agalsidase beta (1 mg/kg/2 weeks) in patients with Fabry disease. Most patients remained alive and event-free. Patients who initiated treatment at a younger age and with less kidney involvement benefited the most from therapy. Patients who initiated treatment at older ages and/or had advanced renal disease experienced disease progression.

Health Resource Utilization and Direct Costs Associated with Angina for Patients with Coronary Artery Disease in a US Managed Care Setting.

BACKGROUND: Angina is often a first symptom of coronary artery disease (CAD); however, the specific burden of illness for patients with CAD-associated angina in managed care has not been reported. OBJECTIVE: To determine the clinical and cost burden of illness for patients with CAD-associated angina in a managed care environment. STUDY DESIGN: A retrospective database analysis in a nationwide commercial managed care plan. METHODS: This study included patients with International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic or procedure codes for CAD between July 1, 2004, and June 30, 2006, who had data available for the period 6 months before and 12 months after the index date. The primary analyses for patients classified as having CAD with angina were based on a 3-algorithm patient-identification model (combined positive predictive value of 89%, 95% confidence interval, 0.79-0.95). Utilization measures for the 12-month postindex period, annual CAD-related direct costs, and total all-cause costs (ie, medical plus pharmacy) were determined. A generalized linear model was used to compare CAD-related costs and overall costs. RESULTS: Of the 246,227 patients with CAD, the 3-algorithm model assigned 230,919 patients (93.8%) to the CAD-without-angina cohort and 15,308 (6.2%) to the CAD-with-angina cohort. Patients with angina were more likely than patients without angina to be hospitalized (41% vs 11%, respectively; P <.001), to visit the emergency department (34% vs 12%, respectively; P <.001), to have office visits (94% vs 79%, respectively; P <.001), and to have more revascularization procedures (35% vs 8%, respectively; P <.001). Average CAD-related inpatient costs were $9536 versus $2169, and pharmacy costs were $1499 versus $891, for patients with and without angina, respectively. Total average CAD-related medical and pharmacy costs for patients with angina were $14,851 versus $4449 for patients with CAD without angina, and the average all-cause per-patient cost was $28,590 versus $14,334, respectively. CONCLUSION: Based on these results, US patients with CAD plus angina in a managed care setting use significantly more healthcare services and incur higher costs than patients who have CAD without angina. Revascularization procedures are a major driver of these increased costs for those with CAD and angina.

The coprescription of contraindicated drugs with statins: continuing potential for increased risk of adverse events.

The objectives of this study were to determine the extent of coprescribing of statins with medications that may increase the risk of adverse events and to identify associated patient and prescriber characteristics. The authors conducted a retrospective cohort study in a large database representative of the U.S. prescription-filling population. The authors studied the U.S. retail prescription environment as reflected in prescriptions dispensed. Patients filling a prescription for a statin between October 1, 2001, and September 30, 2002 were studied. A coprescription for medications of interest as reflected in the warnings and precautions of statin product package inserts was studied: fibric acid, niacin, azole antifungal, macrolide antibiotics, nefazodone, protease inhibitors, verapamil, or warfarin within 3 weeks of a statin prescription. Patient and prescriber characteristics and proportion of coprescribing events attributable to the same prescriber were examined.A total of 5,637,918 patients filled a statin prescription during the 12-month study period. Nearly 19% had concomitant use of a medication with warnings and/or precautions for coprescribing (coprescription event). Coprescription was highest for fibrates, macrolides, and niacin accounting for 19.3%, 17.4%, and 9.4%, respectively, and did not differ across statins. One-third of coprescribing events involved same-day prescriptions, 57% occurred within 7 days of the index statin prescription, and 71.2% of all coprescription events originated from the same prescriber. Coprescribing of medications not compatible with statins occurs frequently. The extent of coprescribing indicates the need for additional intervention to assure that the risk of untoward effects is mitigated.

Racial differences in reaching target low-density lipoprotein goal among individuals treated with prescription statin therapy.

BACKGROUND: Studies indicate that, overall, African Americans are less likely to achieve control of hyperlipidemia compared with whites. No population-based studies have examined the effect of race on achieving target low-density lipoprotein (LDL) goals among treated individuals. METHODS: Using computerized encounter and laboratory result data, we identified all African American and white patients in a Midwestern health system filling a statin prescription from January 1, 1997, through June 30, 2001 (index prescription), with no prescriptions filled 1 year before index prescription. We followed LDL results for 1 year after index prescription. RESULTS: A total of 16052 new statin users (32.5% African American) were identified. Mean baseline LDL was higher for African Americans (170.2 +/- 36.6) than for whites (161.8 +/- 37.2) (P < .001). Whites were more adherent to therapy, with 48.6% of white patients exposed to statins >80% of follow-up time (31.2% of African Americans) (P < .001). By the end of follow-up, 49.5% of African Americans and 71.1% of whites reached LDL goal. A proportional hazards model adjusting for age, sex, median household income, physician specialty, clinic site, baseline LDL, starting dose, and target LDL indicated that African Americans were less likely to reach goal compared with whites (hazard ratio 0.64, 95% CI 0.61-0.68). Results persisted after controlling for racial differences in statin adherence and LDL testing (hazard ratio 0.60, 95% CI 0.57-0.63). CONCLUSIONS: African American patients initiating statin therapy are less likely to achieve LDL goal, even after controlling for adherence differences and other factors, suggesting that African Americans may require different pharmacologic management.

Elevations in markers of liver injury and risk of type 2 diabetes: the insulin resistance atherosclerosis study.

A limited number of studies have reported associations of markers of liver injury, including elevated concentrations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), with prospective risk of type 2 diabetes. However, only one study has adjusted for a detailed measure of insulin sensitivity (insulin sensitivity index [S(i)]), which is important given associations of obesity and S(i) with nonalcoholic fatty liver disease (NAFLD). Our objective was to investigate the associations of elevated AST and ALT with incident type 2 diabetes among 906 participants in the Insulin Resistance Atherosclerosis Study who were nondiabetic at baseline. S(i) and acute insulin response (AIR) were measured directly from the frequently sampled intravenous glucose tolerance test among black, Hispanic, and non-Hispanic white participants aged 40-69 years. After 5.2 years, 148 individuals had developed type 2 diabetes. Baseline AST and ALT were positively correlated with fasting insulin (r = 0.22 and r = 0.35, respectively), waist circumference (r = 0.18 and r = 0.34), and fasting glucose (r = 0.13 and r = 0.29) and inversely with S(i) (r = -0.18 and r = -0.30; all P < 0.0001). In separate logistic regression models adjusting for age, sex, ethnicity, clinical center, and alcohol consumption, participants in the highest quartiles (Q4) of AST and ALT were at significantly increased risk of incident type 2 diabetes compared with those in the lowest three quartiles (Q1-Q3): AST: odds ratio (OR) 1.73 (95% CI 1.17-2.57); ALT: OR 2.32 (1.36-3.75). After further adjustment for smoking, waist circumference, triglyceride, HDL, impaired glucose tolerance, S(i), and AIR, both AST and ALT remained significantly associated with incident type 2 diabetes: AST, Q4 vs. Q1-Q3: OR 1.98 (1.23-3.17); ALT, Q4 vs. Q1-Q3: OR 2.00 (1.22-3.28). There were no interactions of sex, ethnicity, obesity, impaired glucose tolerance, or S(i) with AST or ALT in the prediction of type 2 diabetes. When entered into the same model with adjustment for demographic variables, both C-reactive protein and ALT independently predicted type 2 diabetes. In addition, AST and ALT were positively associated with incident type 2 diabetes after excluding former and moderate to heavy drinkers. In conclusion, AST and ALT independently predict type 2 diabetes. Baseline elevations of these markers may reflect NAFLD or related pathologies.