Acalabrutinib plus venetoclax and rituximab in treatment-naive mantle cell lymphoma: 2-year safety and efficacy analysis.

This phase 1b study (NCT02717624) evaluated the safety and efficacy of acalabrutinib, venetoclax, and rituximab (AVR) in treatment-naive mantle cell lymphoma (TN MCL). Patients received acalabrutinib from cycle 1 until progressive disease or undue toxicity, rituximab for 6 cycles with maintenance every other cycle through cycle 24 or until progressive disease, and venetoclax, beginning at cycle 2, for 24 cycles. Twenty-one patients were enrolled, 95.2% completed induction (6 AVR cycles), and 47.6% continued maintenance with acalabrutinib. Thirteen (61.9%) patients had grade 3-4 adverse events (AEs), most commonly neutropenia (33.3%). Seven (33.3%) patients had COVID-19 infection (6 [28.6%] serious AEs; 5 [23.8%] deaths, all among unvaccinated patients). There were no grade ≥ 3 events of atrial fibrillation, ventricular tachyarrhythmias, major hemorrhages, or tumor lysis syndrome. Overall response rate (ORR) by Lugano criteria was 100% (95% confidence interval [CI]: 83.9, 100.0) with 71.4% complete response (CR). With median follow-up of 27.8 months, median progression-free survival (PFS) and overall survival (OS) were not reached. PFS rates at 1 and 2 years were 90.5% (95% CI: 67.0, 97.5) and 63.2% (34.7, 82.0), respectively; both were 95% after censoring COVID-19 deaths. OS rates at 1 and 2 years were 95.2% (95% CI: 70.7, 99.3) and 75.2% (50.3, 88.9), respectively; both were 100% after censoring COVID-19 deaths. Overall, 87.5% of patients with available minimal residual disease (MRD) data achieved MRD negativity (10-6; next-generation sequencing) during treatment. AVR represents a chemotherapy-free regimen for TN MCL and resulted in high ORR and high rates of MRD negativity.

Phase I/II results of ceralasertib as monotherapy or in combination with acalabrutinib in high-risk relapsed/refractory chronic lymphocytic leukemia.

Background: Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) have limited treatment options. Ceralasertib, a selective ataxia telangiectasia and Rad-3-related protein (ATR) inhibitor, demonstrated synergistic preclinical activity with a Bruton tyrosine kinase (BTK) inhibitor in TP53- and ATM-defective CLL cells. Acalabrutinib is a selective BTK inhibitor approved for treatment of CLL. Objectives: To evaluate ceralasertib ± acalabrutinib in R/R CLL. Design: Nonrandomized, open-label phase I/II study. Methods: In arm A, patients received ceralasertib monotherapy 160 mg twice daily (BID) continuously (cohort 1) or 2 weeks on/2 weeks off (cohort 2). In arm B, patients received acalabrutinib 100 mg BID continuously (cycle 1), followed by combination treatment with ceralasertib 160 mg BID 1 week on/3 weeks off from cycle 2. Co-primary objectives were safety and pharmacokinetics. Efficacy was a secondary objective. Results: Eleven patients were treated [arm A, n = 8 (cohort 1, n = 5; cohort 2, n = 3); arm B, n = 3 (acalabrutinib plus ceralasertib, n = 2; acalabrutinib only, n = 1)]. Median duration of exposure was 3.5 and 7.2 months for ceralasertib in arms A and B, respectively, and 15.9 months for acalabrutinib in arm B. Most common grade ⩾3 treatment-emergent adverse events (TEAEs) in arm A were anemia (75%) and thrombocytopenia (63%), with four dose-limiting toxicities (DLTs) of grade 4 thrombocytopenia. No grade ⩾3 TEAEs or DLTs occurred in arm B. Ceralasertib plasma concentrations were similar when administered as monotherapy or in combination. At median follow-up of 15.1 months in arm A, no responses were observed, median progression-free survival (PFS) was 3.8 months, and median overall survival (OS) was 16.9 months. At median follow-up of 17.2 months in arm B, overall response rate was 100%, and median PFS and OS were not reached. Conclusion: Ceralasertib alone showed limited clinical benefit. Acalabrutinib plus ceralasertib was tolerable with preliminary activity in patients with R/R CLL, though findings are inconclusive due to small sample size. Registration: NCT03328273.

Effects of serelaxin on the outcome of patients with or without substantial peripheral edema: A subgroup analysis from the RELAX-AHF trial.

BACKGROUND: Acute heart failure (AHF) is a heterogeneous disorder, with most of the patients presenting with breathlessness along with varying degrees of peripheral edema. The presence of peripheral edema suggests that volume overload is the cause of decompensation leading to AHF, whereas breathlessness in the absence of edema may reflect a "vascular phenotype." This analysis investigated the characteristics, therapeutic response, and outcome of patients with AHF, with and without overt peripheral edema in the RELAX-AHF trial. METHODS: Physician-assessed edema scores at baseline were used to categorize the population into those with no/mild edema (score 0 or 1+) and moderate/severe edema (score 2+ or 3+). The effect of serelaxin vs placebo was assessed within each subgroup. RESULTS: Patients with moderate/severe edema (n = 583; 50.5%) were more likely to have severe dyspnea, orthopnea (>30°), rales (≥1/3), and elevated jugular venous pressure (>6 cm) than the patients with little or no peripheral edema (n=571; 49.5%). The relative benefits of serelaxin in terms of reduction in breathlessness, lower diuretic requirements, decreased length of initial hospital stay and days in intensive care unit/cardiac care unit, and improved prognosis (180-day cardiovascular and all-cause mortality) were generally similar for patients with or without peripheral edema. However, because patients with moderate/severe peripheral edema had worse outcomes, the absolute benefit was generally greater than in patients with no/mild edema. CONCLUSIONS: Overall, patients with AHF and moderate/severe peripheral edema have a worse prognosis but appear to receive similar relative benefit and perhaps greater absolute benefit from serelaxin administration.

Visit-to-visit low-density lipoprotein cholesterol variability and risk of cardiovascular outcomes: insights from the TNT trial.

BACKGROUND: Studies demonstrate that lowering low-density lipoprotein cholesterol (LDL-C) using a statin is associated with significant reduction in cardiovascular events. Whether visit-to-visit variability in LDL-C levels affects cardiovascular outcomes is unknown. OBJECTIVES: This study sought to evaluate the role of visit-to-visit variability in LDL-C levels on cardiovascular outcomes. METHODS: We evaluated patients with coronary artery disease and LDL-C <130 mg/dl enrolled in the TNT (Treating to New Targets) trial, randomly assigned to receive atorvastatin 80 mg/day versus 10 mg/day and with at least one post-baseline measurement of LDL-C. Visit-to-visit LDL-C variability was evaluated from 3 months into random assignment through the use of various measurements of LDL-C variability: SD, average successive variability (ASV), coefficient of variation, and variation independent of mean, with the first 2 measurements used as the primary measurements. Primary outcome was any coronary event, and secondary outcomes were any cardiovascular event, death, myocardial infarction, or stroke. RESULTS: Among 9,572 patients, SD and ASV were significantly lower with atorvastatin 80 mg/day versus 10 mg/day (SD: 12.03 ± 9.70 vs. 12.52 ± 7.43; p = 0.005; ASV: 12.84 ± 10.48 vs. 13.76 ± 8.69; p < 0.0001). In the adjusted model, each 1-SD increase in LDL-C variability (by ASV) increased the risk of any coronary event by 16% (hazard ratio [HR]: 1.16; 95% confidence interval [CI]: 1.10 to 1.23; p < 0.0001), any cardiovascular event by 11% (HR: 1.11; 95% CI: 1.07 to 1.15; p < 0.0001), death by 23% (HR: 1.23; 95% CI: 1.14 to 1.34; p < 0.0001), myocardial infarction by 10% (HR: 1.10; 95% CI: 1.02 to 1.19; p = 0.02), and stroke by 17% (HR: 1.17; 95% CI: 1.04 to 1.31; p = 0.01), independent of treatment effect and achieved LDL-C levels. Results were largely consistent when adjusted for medication adherence. CONCLUSIONS: In subjects with coronary artery disease, visit-to-visit LDL-C variability is an independent predictor of cardiovascular events.

LADA and CARDS: a prospective study of clinical outcome in established adult-onset autoimmune diabetes.

OBJECTIVE: Diabetes-associated autoantibodies can be detected in adult-onset diabetes, even when initially non-insulin requiring, i.e., with latent autoimmune diabetes. We aimed to identify adult-onset autoimmune diabetes in patients with established "type 2 diabetes" participating in the Collaborative Atorvastatin Diabetes Study (CARDS) to characterize their phenotype and clinical outcome. RESEARCH DESIGN AND METHODS: We prospectively studied 2,425 European patients with presumed type 2 diabetes (mean age 62 years, diabetes duration 7.9 years) for outcomes at 3.9 years after randomization to either atorvastatin or placebo. Subjects were screened for autoantibodies to GAD (GADA), insulinoma-associated antigen-2 (IA-2A), and zinc-transporter 8 (ZnT8A). RESULTS: A total of 173 patients (7.1%) had GADA, of whom 11 (0.5%) and 5 (0.2%) were also positive for IA-2A and ZnT8A, respectively. At baseline, 44% of GADA-positive patients were not on insulin. Fewer autoantibody-positive than autoantibody-negative patients had metabolic syndrome (64 vs. 80%), and more were on insulin (56 vs. 17%) (P < 0.0001 for each) without lower HbA1c (69 mmol/mol [8.5%] vs. 62 mmol/mol [7.8%]). The frequency of microvascular and macrovascular events was similar in both cohorts, independent of atorvastatin. CONCLUSIONS: Adult-onset autoimmune diabetes was prevalent, even in patients with established diabetes presumed to have type 2 diabetes. After 11.8 years' diabetes duration, nearly half the patients with autoimmune diabetes were not on insulin treatment and almost two-thirds had metabolic syndrome. The type of diabetes, whether autoimmune diabetes or type 2 diabetes, did not impact the risk of microvascular disease.

Effect of intensive lipid lowering with atorvastatin on cardiovascular outcomes in coronary heart disease patients with mild-to-moderate baseline elevations in alanine aminotransferase levels.

BACKGROUND: Statins may reduce cardiovascular (CV) morbidity in patients with mild-to-moderate elevations in liver enzyme levels. This post-hoc analysis of the IDEAL study compared intensive versus moderate statin therapy for the prevention of CV events in coronary heart disease patients with normal and elevated baseline levels of serum alanine aminotransferase (ALT). METHODS: Cox regression analysis was used to investigate the effect of atorvastatin 80 mg/day versus simvastatin 20-40 mg/day on the risk of IDEAL study end points in patients with normal baseline ALT (defined as ALT < ULN [upper limit of normal]) versus elevated baseline ALT (ALT ≥ ULN). RESULTS: Of 8863 IDEAL patients with non-missing baseline ALT values, 7782 (87.8%) had an ALT < ULN and 1081 (12.2%) had an ALT ≥ ULN. In patients with elevated baseline ALT, major CV event rates were 11.5% for simvastatin and 6.5% for atorvastatin, indicating a significant risk reduction with intensive statin therapy (hazard ratio, 0.556; 95% confidence interval, 0.367-0.842; p = 0.0056). Significant heterogeneity of treatment effect was observed for major CV events, cerebrovascular events, and major coronary events, with a trend towards treatment difference for the other outcomes, indicating a greater benefit with atorvastatin in the elevated ALT group. CONCLUSIONS: The CV benefit of intensive lipid lowering with atorvastatin compared with a more moderate regimen with simvastatin was generally greater in patients with mildly-to-moderately elevated baseline ALT than patients with normal baseline ALT. Moderate elevations in liver enzyme levels should not present a barrier to prescribing statins, even at higher doses, in high-risk patients.

A meta-analysis of factors impacting detection of antidepressant efficacy in clinical trials: the importance of academic sites.

Variability in placebo response greatly complicates the design, conduct, and interpretation of clinical trials of antidepressant medications. To identify factors that impact detection of antidepressant-placebo differences, we conducted a meta-analysis of all relevant phase II-IV clinical trials for major depressive disorder conducted by the manufacturer of venlafaxine and desvenlafaxine completed by March 2011. We examined 15 factors potentially relevant to trial outcomes, using the standardized mean difference on the Hamilton Rating Scale for Depression (HAM-D17) score as the primary outcome. Thirty trials comprising 8933 patients were included. In univariate analyses, antidepressant efficacy (ie, drug vs placebo difference) was predicted most strongly (ß=3.74, p=0.0002) by the proportion of patients in the trial enrolled from academic sites. Other factors predicting larger drug-placebo differences included lower participant completion rate, fewer post-baseline study visits, earlier year of study, and study drug (venlafaxine>desvenlafaxine). In multivariate meta-regression modeling, only the proportion of patients from academic sites maintained statistical significance as a predictor of drug-placebo separation for both HAM-D17 continuous score change (ß=2.24, p=0.034) and response rate (ß=2.26, p=0.035). Including a higher proportion of academic sites may increase the ability to detect differences between active drug and placebo in clinical trials of major depressive disorder.

Prediction of cardiovascular events in patients with ankylosing spondylitis and psoriatic arthritis: role of lipoproteins in a high-risk population.

OBJECTIVE: To evaluate lipids and apolipoproteins as predictors of cardiovascular mortality and morbidity (CVD) in patients with spondyloarthritis (SpA). METHODS: In the pooled cohort of participants in the IDEAL, TNT, and CARDS trials, 50 had ankylosing spondylitis (AS), 36 had psoriatic arthritis (PsA), and 21,641 did not have AS or PsA (non-SpA). We compared lipid levels at baseline between AS or PsA and non-SpA, and hazard ratios (HR) for CVD were calculated in a Cox proportional hazard model. RESULTS: Atherogenic lipids were lower in samples from AS, but not in PsA, compared to non-SpA. The HR for 1 SD increase in baseline lipids for future CVD was for total cholesterol 1.39 (95% CI 0.82, 2.36) in AS, 1.01 (95% CI 0.44, 2.31) in PsA, and 1.10 (95% CI 1.07, 1.14) in non-SpA. Both high-density lipoprotein (HDL) and apolipoprotein (ApoA-1) were significantly associated with CVD in AS (HR 3.67, 95% CI 1.47, 9.06, and HR 1.89, 95% CI 1.02, 3.54, respectively), in contrast to PsA (HDL: HR 1.03, 95% CI 0.49, 2.15; ApoA-1: HR 0.79, 95% CI 0.34, 1.89) and non-SpA (HDL: HR 0.86, 95% CI 0.84, 0.89; ApoA-1: HR 0.88, 95% CI 0.85, 0.91). CONCLUSION: HDL and ApoA-1 were surprisingly associated with increased risk of future CVD in patients with AS, whereas these lipids were protective in non-SpA.

Effect of intensive lipid-lowering therapy on cardiovascular outcome in patients with and those without inflammatory joint disease.

OBJECTIVE: To examine the effect of intensive lipid-lowering therapy on a composite cardiovascular outcome (cardiovascular disease [CVD]), consisting of mortality and morbidity end points, in patients with inflammatory joint disease (rheumatoid arthritis [RA], ankylosing spondylitis [AS], or psoriatic arthritis [PsA]) by post hoc analysis of 2 prospective trials of statins with a secondary end point of CVD outcome (the Treating to New Targets [TNT] and Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL] studies). METHODS: Of the 18,889 patients participating in the 2 trials, 199 had RA, 46 had AS, and 35 had PsA. Lipid-lowering therapy consisted of an intensive regimen of atorvastatin 80 mg or a conventional/low-dose regimen of atorvastatin 10 mg or simvastatin 20-40 mg. The median duration of followup was nearly 5 years. Changes in lipid levels were examined by analyses of covariance. The effect on CVD was examined by Cox regression analyses, and heterogeneity tests were performed. RESULTS: Patients with RA and those with AS had lower baseline cholesterol levels than patients without inflammatory joint disease (least squares mean ± SEM 180.7 ± 2.3 mg/dl and 176.5 ± 4.7 mg/dl, respectively, versus 185.6 ± 0.2 mg/dl; P = 0.03 and P = 0.05, respectively). Statin treatment led to a comparable decrease in lipid levels and a 20% reduction in overall risk of CVD in both patients with and those without inflammatory joint disease. CONCLUSION: Our findings indicate that patients with and those without inflammatory joint disease experience comparable lipid-lowering effects and CVD risk reduction after intensive treatment with statins.

Relation of improvement in estimated glomerular filtration rate with atorvastatin to reductions in hospitalizations for heart failure (from the Treating to New Targets [TNT] study).

Impaired kidney function often accompanies heart failure (HF) and is associated with a worse prognosis. This post hoc analysis of the Treating to New Targets (TNT) trial examined whether the observed decrease in HF hospitalizations with high- compared to low-dose atorvastatin could be related to improvements in kidney function. Of 10,001 TNT participants, 9,376 had estimated glomerular filtration rate (eGFR) measurements at baseline and 1 year and were included in this analysis. The association of change in year-1 eGFR and subsequent HF hospitalization was examined using Cox regression models. In total 218 participants developed subsequent HF hospitalization. Little change in eGFR occurred over 1 year in the atorvastatin 10-mg group, whereas eGFR improved in the 80-mg group by 1.48 ml/min/1.73 m(2) (95% confidence interval 1.29 to 1.67, p <0.0001). Subsequent HF was preceded by a decrease in eGFR over 1 year compared to modest improvement in those without subsequent HF (-0.09 ± 7.89 vs 0.81 ± 6.90 ml/min/1.73 m(2), p = 0.0015). After adjusting for baseline eGFR, each 5-ml/min/1.73 m(2) increase in eGFR at 1 year was associated with a lower risk of subsequent HF hospitalization (hazard ratio 0.85, 95% confidence interval 0.77 to 0.94, p = 0.002). This relation was independent of treatment effect or change in low-density lipoprotein cholesterol level at 1 year. In conclusion, treatment with high- compared to low-dose atorvastatin was associated with improvement in eGFR at 1 year, which was related to a decrease in subsequent HF hospitalization. This suggests that improvement in kidney function may be related to the beneficial effect of high-dose atorvastatin on HF hospitalization.

Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials.

OBJECTIVES: We sought to examine the incidence and clinical predictors of new-onset type 2 diabetes mellitus (T2DM) within 3 large randomized trials with atorvastatin. BACKGROUND: Statin therapy might modestly increase the risk of new-onset T2DM. METHODS: We used a standard definition of diabetes and excluded patients with prevalent diabetes at baseline. We identified baseline predictors of new-onset T2DM and compared the event rates in patients with and without new-onset T2DM. RESULTS: In the TNT (Treating to New Targets) trial, 351 of 3,798 patients randomized to 80 mg of atorvastatin and 308 of 3,797 randomized to 10 mg developed new-onset T2DM (9.24% vs. 8.11%, adjusted hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.94 to 1.29, p = 0.226). In the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial, 239 of 3,737 patients randomized to atorvastatin 80 mg/day and 208 of 3,724 patients randomized to simvastatin 20 mg/day developed new-onset T2DM (6.40% vs. 5.59%, adjusted HR: 1.19, 95% CI: 0.98 to 1.43, p = 0.072). In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, new-onset T2DM developed in 166 of 1,905 patients randomized to atorvastatin 80 mg/day and in 115 of 1,898 patients in the placebo group (8.71% vs. 6.06%, adjusted HR: 1.37, 95% CI: 1.08 to 1.75, p = 0.011). In each of the 3 trials, baseline fasting blood glucose, body mass index, hypertension, and fasting triglycerides were independent predictors of new-onset T2DM. Across the 3 trials, major cardiovascular events occurred in 11.3% of patients with and 10.8% of patients without new-onset T2DM (adjusted HR: 1.02, 95% CI: 0.77 to 1.35, p = 0.69). CONCLUSIONS: High-dose atorvastatin treatment compared with placebo in the SPARCL trial is associated with a slightly increased risk of new-onset T2DM. Baseline fasting glucose level and features of the metabolic syndrome are predictive of new-onset T2DM across the 3 trials.

Impact of smoking on cardiovascular events in patients with coronary disease receiving contemporary medical therapy (from the Treating to New Targets [TNT] and the Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL] trials).

To define the incremental risk of cigarette smoking in patients with coronary disease receiving contemporary medical therapy, we performed a post hoc analysis of 18,885 patients by combining data from the Treating to New Targets (TNT) and the Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) trials. These studies compared high-dose treatment (atorvastatin 80 mg/day) to moderate-dose treatment (atorvastatin 10 mg/day in TNT and simvastatin 20 to 40 mg/day in IDEAL) in patients with established coronary heart disease. The primary end point of this pooled analysis was major cardiovascular events, a composite of cardiac death, myocardial infarction, stroke, or resuscitated cardiac arrest. At baseline 4,196 patients had never smoked, 11,513 were ex-smokers, and 3,176 were current smokers. The adjusted hazard ratio for current smokers compared to never smokers was 1.68 (95% confidence interval 1.46 to 1.94) and that for current smokers compared to ex-smokers was 1.57 (95% confidence interval 1.41 to 1.76). Event rates for current smokers compared to ex-smokers were similarly increased in each treatment group. The difference in absolute event rates between current and ex-smokers in this pooled analysis was 4.5%, which is >2 times as large as the decrease in absolute event rates between high-dose and moderate-dose statin therapy found in the IDEAL (1.7%) and TNT (2.2%) trials, respectively. In conclusion, in patients with coronary disease receiving modern medical therapy, smoking cessation is of substantial benefit with a number needed to treat of 22 to prevent a major cardiovascular event over 5 years. Smoking cessation deserves greater emphasis in secondary prevention.

J-curve revisited: An analysis of blood pressure and cardiovascular events in the Treating to New Targets (TNT) Trial.

AIM: In patients with coronary artery disease (CAD), a J-curve relationship has been reported between blood pressure (BP) and future cardiovascular events. However, this is controversial. The purpose of the study was to determine the relationship between on-treatment BP and cardiovascular outcomes in patients with CAD. METHODS AND RESULTS: We evaluated 10 001 patients with CAD and a low-density lipoprotein (LDL) cholesterol level <130 mg/dL, randomized to atorvastatin 80 vs. 10 mg, enrolled in the TNT trial. The post-baseline, time-dependent BPs [systolic blood pressure (SBP) and diastolic blood pressure (DBP)] were categorized into 10 mmHg increments. The primary outcome was a composite of death from coronary disease, non-fatal myocardial infarction (MI), resuscitated cardiac arrest, and fatal or non-fatal stroke. Among the 10 001 patients, 982 (9.82%) experienced a primary outcome at 4.9 years (median) of follow-up. The relationship between SBP or DBP and primary outcome followed a J-curve with increased event rates above and below the reference BP range, both unadjusted and adjusted (for baseline covariates, treatment effect, and LDL levels). A time-dependent, non-linear, multivariate Cox proportional hazard model identified a nadir of 146.3/81.4 mmHg where the event rate was lowest. A similar non-linear relationship with a higher risk of events at lower pressures was found for most of the secondary outcomes of all-cause mortality, cardiovascular mortality, non-fatal MI, or angina. However, for the outcome of stroke, lower was better for SBP. CONCLUSION: In patients with CAD, a low BP (<110-120/<60-70 mmHg) portends an increased risk of future cardiovascular events (except stroke).

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.

Relationship between cardiovascular risk factors and atherosclerotic disease burden measured by intravascular ultrasound.

OBJECTIVES: The goal of this study was to determine the relationship between established cardiovascular risk factors and the extent of coronary atherosclerotic plaque. BACKGROUND: Few data exist correlating cardiovascular risk factors with volumetric measurements of coronary atheroma burden in patients with coronary artery disease. METHODS: Clinical characteristics, quantitative coronary angiography, and intravascular ultrasound (IVUS) were evaluated in subjects enrolled in a study comparing atorvastatin and pravastatin. Plaque areas were measured at 1-mm intervals to compute atheroma volume. The percent of cross sections with an abnormal intimal thickness (>0.5 mm) was determined. Data on cardiovascular risk factors were collected. RESULTS: In 654 subjects, atheroma volume averaged 174.5 mm3 and percent atheroma volume 38.9%. Atherosclerosis was present in 81.2% of 25,897 cross sections. In univariate analysis, there was a strong association between diabetes, male gender, and a history of either prior revascularization or stroke with percent atheroma volume. Hypertension or prior myocardial infarction was also predictive of more severe disease. Low-density lipoprotein and C-reactive protein were not significant predictors of greater disease burden. In multivariate analysis, diabetes, male gender, and a history of a prior interventional procedure remained strong predictors of increased atheroma volume. History of stroke, non-Caucasian race, and smoking status remained significant. Although multiple measures of IVUS disease burden were worse in subjects with diabetes, angiographic stenosis severity was not different. CONCLUSIONS: Male gender, diabetes, and a history of prior revascularization are strong independent predictors of atherosclerotic burden in coronary disease patients. Many risk factors did not predict angiographic disease severity, suggesting different mechanisms drive stenosis development and atheroma accumulation.

Effects of obesity on lipid-lowering, anti-inflammatory, and antiatherosclerotic benefits of atorvastatin or pravastatin in patients with coronary artery disease (from the REVERSAL Study).

The effect of obesity on atherosclerotic burden and its modulation by lipid-lowering therapy is unknown. The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study was analyzed to determine the influence of increasing body mass index (BMI) on plasma lipids, C-reactive protein, plaque burden as determined by intravascular ultrasound, and the serial change in these parameters with a moderate or intensive lipid-lowering strategy. Patients with a higher BMI were younger, more likely to be women, and had a greater prevalence of hypertension, diabetes, and the metabolic syndrome. Although a higher BMI was associated with a lower high-density lipoprotein level and higher triglyceride and C-reactive protein levels, there was no apparent influence of BMI on plaque burden. However, with the intensive lipid-lowering strategy, a greater BMI was associated with a lower proportionate decrease in low-density lipoprotein (49.1 +/- 21.4% vs 43.0 +/- 22.4%, p = 0.008) and a greater proportionate decrease in C-reactive protein (39.7% vs 33.3%, p <0.04). Further, although moderate and intensive lipid-lowering strategies halted plaque progression in subjects with a lower BMI (median progression rates +1.5% and +1.2%, respectively), a significant effect on plaque progression rates was seen only with adoption of an intensive lipid-lowering strategy in the most obese subjects (median progression rate -1.88% vs +6.5% with the moderate lipid-lowering strategy, p = 0.01). In conclusion, plaque progression in obese patients is attenuated using an intensive, but not moderate, lipid-lowering strategy. These results highlight the need for aggressive risk factor modification and a decrease in vascular inflammation in obese patients.

Rationale and design of the avoiding cardiovascular events through combination therapy in patients living with systolic hypertension (ACCOMPLISH) trial: the first randomized controlled trial to compare the clinical outcome effects of first-line combination therapies in hypertension.

Reducing blood pressure (BP) to target levels is a major priority in preventing clinical events in hypertension. Typically this requires more than one drug, and recent guidelines on hypertension management therefore recommend starting with combination treatment in many patients. Diuretics have often been part of such therapy, usually paired with angiotensin converting enzyme (ACE) inhibitors or similar agents; but calcium channel blockers are also highly efficacious in reducing BP when combined with ACE inhibitors. In addition, these drug classes, separately and in combination, appear to have vasculoprotective properties. Because the primary goal of treating hypertension is to enhance survival and reduce cardiovascular outcomes, the Rationale and Design of Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial is designed as the first blinded and randomized study to prospectively compare the effects on these endpoints of two antihypertensive combinations, benazapril/hydrochlorothiazide (force titrated to 40/12.5 mg) and amlodipine besylate/benazapril (force titrated to 5/40 mg). The doses can be further titrated to 40/25 mg or 10/40 mg, and other classes of drugs can be added as needed for optimal BP control. The primary study endpoint is a composite of cardiovascular mortality and morbidity. The study will be performed in hypertensive patients (systolic BP > or = 160 mm Hg or currently on antihypertensive therapy) with risk factors for cardiovascular events (prior events, target organ damage, kidney disease, or diabetes). A total of 6300 subjects will be randomized to each group with the expectation that a total of 1642 primary endpoints will occur during a 5-year period, providing 90% power to detect the 15% relative reduction in events (alpha = 0.05) hypothesized to favor the amlodipine besylate/benazapril group. The ACCOMPLISH study will be performed in the United States and Europe. The first patient was randomizedduring 2003, and the trial should conclude in 2008.

Analysis of survival data with missing measurements of a time-dependent binary covariate.

The objective of this study was to investigate the influence of the number and timing of a binary time-dependent covariate on the bias using the last-observation carried forward in the proportional hazards model. Under various assumptions of censoring rates, transition probabilities of the time-dependent covariate, sample size, and the log hazard-ratio for the covariate, we empirically examined the impact that the number and timing have on the bias of the estimator of the covariate. An example from the Systolic Hypertension in the Elderly Program was used. Inference on the effect of systolic blood pressure on survival is strongly affected by the number and timing of systolic blood measurements.