Correlation Between Blue Fundus Autofluorescence and SD-OCT Measurements of Geographic Atrophy in Dry Age-Related Macular Degeneration.

PURPOSE: To compare fundus autofluorescence (FAF) and spectral domain optical coherence tomography (OCT) measurements of geographic atrophy (GA) area and to analyze lesion area changes measured by spectral domain OCT in GATHER1. DESIGN: An assessment reliability analysis using prospective, randomized, double-masked phase 2/3 clinical trial data. METHODS: GATHER1 examined the efficacy and safety of avacincaptad pegol (ACP) for GA treatment. A post hoc analysis was performed to identify correlations between FAF- and OCT-based measurements of GA. GA area was measured on blue-light FAF images using semiautomatic segmentation software with support from OCT and near-infrared imaging. Machine-learning enhanced, multilayer segmentation of OCT scans were reviewed by human readers, and segmentation errors were corrected as needed. GA area was defined as total RPE loss on cross-sectional B scans. Time points included Months 0, 6, 12, and 18. Additionally, OCT-based GA-area changes between ACP and sham were analyzed. RESULTS: There was a strong correlation (r = 0.93) between FAF and OCT GA area measurements that persisted through 18 months. Mean (SD) differences between OCT and FAF GA measurements were negligible: 0.11 mm2 (1.42) at Month 0, 0.03 mm2 (1.62) at Month 6, -0.17 mm2 (1.81) at Month 12, and -0.07 mm2 (1.78) at Month 18. OCT assessments of GA growth revealed a 30% and 27% reduction at Months 12 and 18, respectively, between ACP and sham, replicating FAF measurements from GATHER1. CONCLUSIONS: The strong correlation between blue FAF and OCT measurements of GA area supports OCT as a reliable method to measure GA lesion area in clinical trials.

Limited impact of IL28B genotype on response rates in telaprevir-treated patients with prior treatment failure.

BACKGROUND & AIMS: Nucleotide polymorphisms upstream of the interleukin 28B (IL28B) gene are strongly associated with hepatitis C virus (HCV) clearance in treatment-naïve patients treated with peginterferon/ribavirin (PegIFN/RBV). This subanalysis of the REALIZE study evaluated the impact of IL28B polymorphisms on sustained virologic response (SVR) in telaprevir-treated, HCV genotype 1-infected patients with prior PegIFN/RBV treatment failure. METHODS: Treatment-experienced patients were randomized to 12 weeks of telaprevir (750 mg every 8h) with/without a 4-week PegIFN/RBV lead-in, or placebo, each with PegIFN-α-2a (180 µg/week) and ribavirin (1000-1200 mg/day) for 48 weeks overall. Data from telaprevir arms were pooled. RESULTS: Eighty percent (527/662) of patients consented to genetic testing and were included. Similar proportions of patients had IL28B CC, CT and TT genotypes across treatment arms; baseline characteristics were generally well balanced. SVR rates were higher in the pooled telaprevir versus placebo group for all IL28B genotypes; CC: 79% versus 29%, respectively; CT: 60% versus 16%, respectively; TT: 61% versus 13%, respectively. Within each prior response category (relapse, partial or null response), SVR and viral breakthrough rates with telaprevir-based treatment were comparable across IL28B genotypes. IL28B genotype did not significantly affect SVR (2-step multivariate analyses; p >0.16 in pairwise comparison among CC, TT, and CT). Variations in rapid virologic response and relapse rates were noted in certain patient subgroups. CONCLUSIONS: Our findings suggest that IL28B genotype has a limited impact on SVR rates with telaprevir-based therapy in treatment-experienced patients. IL28B genotyping may have limited utility in the baseline evaluation of similar patients considered for telaprevir-based therapy.

Futility rules for telaprevir combination treatment for patients with hepatitis C virus infection.

For patients treated with telaprevir, peginterferon, and ribavirin, futility rules have been developed to prevent needless drug exposure and minimize development of drug-resistant variants for patients who have little or no chance of achieving a sustained virologic response. We performed retrospective analyses of data from phase 3 trials and validated the current futility rule. All therapy should be stopped for treatment-naive and treatment-experienced patients if hepatitis C virus RNA levels are greater than 1000 IU/mL at weeks 4 or 12, or if hepatitis C virus RNA is detectable at week 24.

Sustained virologic response rates with telaprevir by response after 4 weeks of lead-in therapy in patients with prior treatment failure.

BACKGROUND & AIMS: For hepatitis C virus (HCV)-infected patients who have not responded to previous PegIFN/ribavirin treatment, it is unclear whether subsequent direct-acting antiviral therapy outcomes are better predicted by prior treatment response or by on-treatment response to a PegIFN/ribavirin lead-in. METHODS: In REALIZE, treatment-experienced patients randomized to the lead-in telaprevir arm received 4 weeks of PegIFN-α-2a (180 µg/week) and ribavirin (1000-1200 mg/day), then 12 weeks of telaprevir (750 mg every 8h) plus PegIFN-α-2a/ribavirin, followed by 32 weeks of PegIFN-α-2a/ribavirin. This subanalysis only included patients in the lead-in telaprevir arm with available week 4 on-treatment response data (n=240). RESULTS: After 4weeks of PegIFN/ribavirin, 90% of relapsers, 60% of partial responders, and 41% of null responders in the lead-in telaprevir arm had ⩾1 log(10) HCV RNA reduction. Sustained virologic response (SVR) rates for telaprevir-treated patients with ≥1 versus <1 log(10) HCV RNA reduction after the PegIFN/ribavirin lead-in were 94% versus 62% in relapsers, 59% versus 56% in partial responders and 54% versus 15% in null responders. CONCLUSIONS: In prior relapsers and partial responders there is no apparent benefit of assessing response after a PegIFN/ribavirin lead-in with the aim of guiding telaprevir-based treatment. For patients known to be prior null responders, on-treatment response after a 4-week PegIFN/ribavirin lead-in may provide clinically useful prognostic information. However, withholding telaprevir-containing therapy in uncategorised treatment-experienced patient populations (i.e., that could include prior relapsers or partial responders), using response after a PegIFN/ribavirin lead-in could potentially exclude some patients with a high chance of SVR.

Telaprevir for retreatment of HCV infection.

BACKGROUND: Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin. METHODS: In this randomized, phase 3 trial, we evaluated the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response. A total of 663 patients were assigned to one of three groups: the T12PR48 group, which received telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks; the lead-in T12PR48 group, which received 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks; and the control group (PR48), which received peginterferon plus ribavirin for 48 weeks. The primary end point was the rate of sustained virologic response, which was defined as undetectable HCV RNA 24 weeks after the last planned dose of a study drug. RESULTS: Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (P<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%). CONCLUSIONS: Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase. (Funded by Tibotec and Vertex Pharmaceuticals; REALIZE ClinicalTrials.gov number, NCT00703118.).

Effects of increasing doses of atorvastatin on the atherogenic lipid subclasses commonly associated with hypertriglyceridemia.

The increased cardiovascular risk associated with hypertriglyceridemia is thought to be due in part to high levels of triglyceride (TG)-rich lipoproteins and small dense low-density lipoprotein (LDL). In this post hoc analysis, effects of increasing doses of atorvastatin (10, 20, 40, and 80 mg) on atherogenic lipid subclasses commonly associated with hypertriglyceridemia were evaluated in 191 men and women who were candidates for lipid-lowering therapy and had baseline TG levels >200 mg/dl (2.3 mmol/L). After 8 weeks of treatment, in addition to significantly decreasing LDL cholesterol and TG levels, atorvastatin significantly increased LDL peak particle diameter (p <0.01) and significantly decreased the concentration of small LDL subclasses IIIa and IIIb (p <0.0001) from baseline at all doses. These effects were more pronounced with higher compared with lower doses of atorvastatin. Each dose of atorvastatin also significantly lowered levels of very LDL, intermediate-density lipoprotein (p <0.0001), and small very LDL subclass 3 (p <0.0001). Greater decreases were achieved by those patients receiving higher doses of atorvastatin (20, 40, and 80 mg). The increase in LDL size correlated with the decrease in TG levels, but not with the decrease in LDL cholesterol levels. However, the decrease in small dense LDL cholesterol concentrations correlated significantly with TG and LDL cholesterol decreases. In conclusion, atorvastatin significantly lowered levels of TG-rich remnant lipoproteins and favorably changed LDL particle size in patients with hypertriglyceridemia. These effects may explain the benefits of statin therapy in high-risk patients with hypertriglyceridemia even when levels of LDL cholesterol are at goal.

Effects of intensive versus moderate lipid-lowering therapy on myocardial ischemia in older patients with coronary heart disease: results of the Study Assessing Goals in the Elderly (SAGE).

BACKGROUND: Clinical trials have demonstrated that, compared with placebo, intensive statin therapy reduces ischemia in patients with acute coronary syndromes and in patients with stable coronary artery disease. However, no studies to date have assessed intensive versus moderate statin therapy in older patients with stable coronary syndromes. METHODS AND RESULTS: A total of 893 ambulatory coronary artery disease patients (30% women) 65 to 85 years of age with > or = 1 episode of myocardial ischemia that lasted > or = 3 minutes during 48-hour ambulatory ECG at screening were randomized to atorvastatin 80 mg/d or pravastatin 40 mg/d and followed up for 12 months. The primary efficacy parameter (absolute change from baseline in total duration of ischemia at month 12) was significantly reduced in both groups at month 3 and month 12 (both P<0.001 for each treatment group) with no significant difference between the treatment groups. Atorvastatin-treated patients experienced greater low-density lipoprotein cholesterol reductions than did pravastatin-treated patients, a trend toward fewer major acute cardiovascular events (hazard ratio, 0.71; 95% confidence interval, 0.46, 1.09; P=0.114), and a significantly greater reduction in all-cause death (hazard ratio, 0.33; 95% confidence interval, 0.13, 0.83; P=0.014). CONCLUSIONS: Compared with moderate pravastatin therapy, intensive atorvastatin therapy was associated with reductions in cholesterol, major acute cardiovascular events, and death in addition to the reductions in ischemia observed with both therapies. The contrast between the therapies' differing efficacy for major acute cardiovascular events and death and their nonsignificant difference in efficacy for reduction of ischemia suggests that low-density lipoprotein cholesterol-lowering thresholds for ischemia and major acute cardiovascular events may differ. The Study Assessing Goals in the Elderly (SAGE) demonstrates that older men and women with coronary artery disease benefit from intensive statin therapy.

Effects of high-dose atorvastatin in patients > or =65 years of age with acute coronary syndrome (from the myocardial ischemia reduction with aggressive cholesterol lowering [MIRACL] study).

After acute coronary syndromes (ACSs), older patients are particularly susceptible to early complications, including death and recurrent ACS. Lipid management guidelines do not differentiate elderly from younger patients, and lack of evidence for statin benefits in older patients has led to underutilization of statins in the elderly. The MIRACL study randomized 3,086 patients to 16 weeks of 80 mg/day of atorvastatin or placebo 24 to 96 hours after ACS and demonstrated significant decreases in the combined primary end point (nonfatal acute myocardial infarction, resuscitated cardiac arrest, recurrent symptomatic myocardial ischemia). This post hoc analysis compared benefits of 80 mg of atorvastatin in older (> or =65 years) versus younger (<65 years) patients. Event rates were approximately two- to threefold higher in older than in younger patients. Treatment-by-age heterogeneity testing indicated no difference in treatment effect by age for any of the primary or secondary end points, and relative risk decreases in the primary end point with atorvastatin versus placebo were similar in younger and older patients (22% vs 14%, respectively). The safety profile of atorvastatin was similar between the 2 age groups. In conclusion, these results and a greater immediate cardiovascular risk in older patients argue for early, intensive atorvastatin therapy as routine practice after ACS.

Analysis of efficacy and safety in patients aged 65-75 years at randomization: Collaborative Atorvastatin Diabetes Study (CARDS).

OBJECTIVE: Rates of cardiovascular disease are highest in the elderly. Lipid-lowering statin therapy reduces the proportional risk as effectively in older patients as in younger individuals; however, limited data are available for elderly patients with type 2 diabetes. We conducted a post hoc analysis to compare the efficacy and safety of atorvastatin among 1,129 patients aged 65-75 years at randomization with 1,709 younger patients in the Collaborative Atorvastatin Diabetes Study (CARDS). RESEARCH DESIGN AND METHODS: CARDS was a randomized placebo-controlled trial of 10 mg/day atorvastatin for primary prevention of cardiovascular disease in patients aged 40-75 years with LDL cholesterol concentrations

Tolerability of atorvastatin in a population aged > or =65 years: a retrospective pooled analysis of results from fifty randomized clinical trials.

OBJECTIVE: The aim of this study was to compare the safety profile of atorvastatin calcium at 4 doses with that of placebo in elderly patients (age, > or =65 years). METHODS: A single pooled database (Pfizer Atorvastatin Clinical Program Database) of 50 published and unpublished completed clinical trials was analyzed retrospectively. Tolerability data from male and female study participants aged > or =65 years at the time of study enrollment were extracted from this database and grouped based on treatment: atorvastatin 10, 20, 40, or 80 mg/d, or placebo. Analyses included comparisons of treatment-related and serious adverse events (AEs) of the musculoskeletal, hepatic, and renal systems. Descriptive statistics were employed. No inferential statistical analyses were performed. RESULTS: A total of 5924 patients were included in the pooled analysis (range of mean age, 71-74 years; white race, 5437 [91.8%]; female sex, 2506 [42.3%]; treatment with atorvastatin 10 mg/d, n = 2042; atorvastatin 20 mg/d, n = 667; atorvastatin 40 mg/d, n = 522; atorvastatin 80 mg/d, n = 1698; and placebo, n = 995). The overall AE profiles appeared similar with all atorvastatin doses and placebo. The proportions of patients experiencing at least 1 treatment-related AE were 16.1%, 10.2%, 11.3%, 15.0%, and 15.3% in the atorvastatin 10-, 20-, 40-, and 80-mg/d, and placebo groups, respectively. The rates of discontinuation due to treatment-associated AEs appeared comparable between all doses of atorvastatin and placebo (2.1% vs 1.7%). Serious AEs were rare (< or =1.0%) and seldom led to withdrawal. The prevalence of treatment-associated myalgia was low in all treatment groups (< or =1.8%). None of the patients experienced persistent creatine kinase elevations >10-fold the upper limit of normal (x ULN), and no cases of myopathy or rhabdomyolysis were reported. The rates of patients with persistent elevation >3 x ULN) of hepatic aminotransferases were 0.1%, 0%, 0.2%, 0.5%, and 0.2% in the atorvastatin 10-, 20-, 40-, and 80-mg/d, and placebo groups, respectively. Although the prevalences of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations appeared slightly higher in the 80-mg/d group (3.2% vs < or =0.9% in all other groups), specific musculoskeletal and hepatic AEs were rare (< or =3.0%). CONCLUSIONS: This pooled analysis of 50 published and unpublished studies in elderly patients found that the overall prevalences of AEs did not appear to increase with dose and appeared comparable to that observed with placebo. Although the prevalences of ALT/AST elevations appeared slightly higher in the 80-mg/d group (3.2% vs < or =0.9% in all other groups), specific musculoskeletal and hepatic AEs were rare (< or =3.0%). The rates of discontinuation appeared comparable between all 4 doses of atorvastatin and placebo. The results of this analysis support the favorable safety profile of atorvastatin across the full dose range in patients aged > or =65 years.

Comparative safety of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed trials in 14,236 patients.

Atorvastatin has been shown to reduce coronary events and revascularization procedures in patients with multiple risk factors for coronary heart disease. Recent studies with atorvastatin 80 mg support the overall safety of this dose during long-term treatment. However, physicians appear reluctant to use high doses of statins. A retrospective analysis of pooled data from 49 clinical trials of atorvastatin in 14,236 patients treated for an average period of 2 weeks to 52 months was conducted. The study compared the safety of atorvastatin 10 mg (n = 7,258), atorvastatin 80 mg (n = 4,798), and placebo (n = 2,180) and included analyses on treatment-associated adverse events; nonserious and serious adverse events related to the musculoskeletal, hepatic, and renal systems; the incidence of elevations of creatine kinase >10 times the upper limit of normal (ULN); and hepatic transaminases >3 times ULN. Percentages of patients experiencing > or =1 adverse event were similar across all 3 groups. Withdrawals due to treatment-related adverse events were observed in 2.4%, 1.8%, and 1.2% of patients in the atorvastatin 10 mg, atorvastatin 80 mg, and placebo groups, respectively. Serious adverse events were rare and seldom led to treatment withdrawal with any dose. Treatment-associated myalgia was observed in 1.4%, 1.5%, and 0.7% of patients in the atorvastatin 10 mg, atorvastatin 80 mg, and placebo groups, respectively. No cases of rhabdomyolysis were reported in any group. Persistent elevations in hepatic transaminases >3 times ULN were observed in 0.1%, 0.6%, and 0.2% of patients in the atorvastatin 10 mg, atorvastatin 80 mg, and placebo groups, respectively. The incidence of treatment-associated adverse events for atorvastatin 80 mg was similar to that of atorvastatin 10 mg and placebo. In conclusion, the results of this analysis support the positive safety profile of atorvastatin at the highest dose.