Rachel Laskey

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.

Prevalence, predictors, and outcomes in treatment-resistant hypertension in patients with coronary disease.

BACKGROUND Increasingly, apparent treatment-resistant hypertension has been recognized. However, much of the prevalence, predictors, and outcomes are largely unknown, especially in patients with coronary artery disease. METHODS We evaluated 10,001 patients with coronary artery disease who were enrolled in the Treating to New Targets trial. Apparent treatment-resistant hypertension was defined as blood pressure ≥ 140 mm Hg despite 3 antihypertensive agents or <140 mm Hg with ≥ 4 antihypertensive agents. The primary outcome was major cardiovascular events (composite of fatal coronary heart disease, nonfatal myocardial infarction, resuscitated cardiac arrest, and stroke). RESULTS Among the 10,001 patients in the trial, 1112 (11.1%) had apparent treatment-resistant hypertension. In a multivariable model adjusting for baseline differences, the treatment-resistant hypertension group had a 64% increase in primary outcome (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.39-1.94; P < .001), driven by a 69% increase in coronary heart disease death (HR, 1.69; 95% CI, 1.22, 2.34; P = .001) and 73% increase in nonfatal myocardial infarction (HR, 1.73; 95% CI, 1.39-2.16, P < .0001) when compared with the no apparent treatment-resistant hypertension group. In addition, patients with apparent treatment-resistant hypertension had a 71% increase in major coronary event (P < .0001), 45% increase in death (P = .001), 33% increase in heart failure (P = .05), 53% increase in any cardiovascular event (P < .0001), 60% increase in any coronary event (P < .0001), 68% increase in angina (P < .0001), and 51% increase in coronary revascularization (P < .0001) when compared with the no apparent treatment-resistant hypertension group. Results were largely similar whether the definition of apparent treatment-resistant hypertension was based on a blood pressure ≥ 140 mm Hg despite 3 agents or a blood pressure <140 mm Hg with ≥ 4 agents. CONCLUSIONS In patients with coronary artery disease, apparent treatment-resistant hypertension is associated with a marked increase in the risk of cardiovascular morbidity and mortality, including an increase in all-cause death.

Relationship of Oxidized Phospholipids on Apolipoprotein B-100 to Cardiovascular Outcomes in Patients Treated With Intensive Versus Moderate Atorvastatin Therapy: The TNT Trial

BACKGROUND Oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) is a biomarker of increased risk for major adverse cardiovascular events (MACE) in community cohorts, but its role in patients with stable coronary heart disease (CHD) is unknown. OBJECTIVES This study sought to examine the relationship between these oxidative biomarkers and cardiovascular outcomes in patients with established CHD. METHODS In a random sample from the TNT (Treating to New Targets) trial, OxPL-apoB levels were measured in 1,503 patients at randomization (after an 8-week run-in period taking atorvastatin 10 mg) and 1 year after being randomized to atorvastatin 10 or 80 mg. We examined the association between baseline levels of OxPL-apoB and MACE, defined as death from CHD, nonfatal myocardial infarction, resuscitation after cardiac arrest, and fatal/nonfatal stroke, as well as the effect of statin therapy on OxPL-apoB levels and MACE. RESULTS Patients with events (n = 156) had higher randomization levels of OxPL-apoB than those without events (p = 0.025). For the overall cohort, randomization levels of OxPL-apoB predicted subsequent MACE (hazard ratio [HR]: 1.21; 95% confidence interval: 1.04 to 1.41; p = 0.018) per doubling and tertile 3 versus tertile 1 (hazard ratio: 1.69; 95% confidence interval [CI]: 1.14 to 2.49; p = 0.01) after multivariate adjustment for age, sex, body mass index, among others, and treatment assignment. In the atorvastatin 10-mg group, tertile 3 was associated with a higher risk of MACE compared to the first tertile (HR: 2.08; 95% CI: 1.20 to 3.61; p = 0.01) but this was not significant in the atorvastatin 80-mg group (HR: 1.40; 95% CI: 0.80 to 2.46; p = 0.24). CONCLUSIONS Elevated OxPL-apoB levels predict secondary MACE in patients with stable CHD, a risk that is mitigated by atorvastatin 80 mg. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691).

Body-Weight Fluctuations and Outcomes in Coronary Disease

Background Body‐weight fluctuation is a risk factor for death and coronary events in patients without cardiovascular disease. It is not known whether variability in body weight affects outcomes in patients with coronary artery disease. Methods We determined intraindividual fluctuations in body weight from baseline weight and follow‐up visits and performed a post hoc analysis of the Treating to New Targets trial, which involved assessment of the efficacy and safety of lowering low‐density lipoprotein cholesterol levels with atorvastatin. The primary outcome was any coronary event (a composite of death from coronary heart disease, nonfatal myocardial infarction, resuscitated cardiac arrest, revascularization, or angina). Secondary outcomes were any cardiovascular event (a composite of any coronary event, a cerebrovascular event, peripheral vascular disease, or heart failure), death, myocardial infarction, or stroke. Results Among 9509 participants, after adjustment for risk factors, baseline lipid levels, mean body weight, and weight change, each increase of 1 SD in body‐weight variability (measured according to average successive variability and used as a time‐dependent covariate) was associated with an increase in the risk of any coronary event (2091 events; hazard ratio, 1.04; 95% confidence interval [CI], 1.01 to 1.07; P=0.01), any cardiovascular event (2727 events; hazard ratio, 1.04; 95% CI, 1.02 to 1.07; P<0.001), and death (487 events; hazard ratio,1.09; 95% CI, 1.07 to 1.12; P<0.001). Among patients in the quintile with the highest variation in body weight, the risk of a coronary event was 64% higher, the risk of a cardiovascular event 85% higher, death 124% higher, myocardial infarction 117% higher, and stroke 136% higher than it was among those in the quintile with the lowest variation in body weight in adjusted models. Conclusions Among participants with coronary artery disease, fluctuation in body weight was associated with higher mortality and a higher rate of cardiovascular events independent of traditional cardiovascular risk factors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00327691.)

High-dose atorvastatin is superior to moderate-dose simvastatin in preventing peripheral arterial disease

Objectives To study whether high-dose versus usual-dose statin treatment reduces the incidence of peripheral artery disease (PAD) and what is the effect of high-dose statin treatment on cardiovascular disease (CVD) outcome in patients with PAD. Methods and results In the Incremental Decrease in End Points Through Aggressive Lipid Lowering trial, 8888 post-myocardial infarction patients were randomised to high-dose or usual-dose statin therapy (atorvastatin 80 mg/day vs simvastatin 20–40 mg/day). We investigated the effect of high-dose versus usual-dose statins on the pre-specified outcome PAD incidence, and additionally performed a posthoc analysis of the efficacy of high-dose statins in reducing CVD risk among patients with PAD. During a median follow-up of 4.8 years, 94 patients (2.2%) receiving atorvastatin and 135 patients (3.2%) receiving simvastatin developed PAD (HR=0.70, 95% CI 0.53 to 0.91; p=0.007). The risk of major coronary events was almost twofold higher in patients with PAD at baseline, but was no longer significant after adjusting for the adverse cardiovascular risk profile. In PAD patients, major coronary events occurred in fewer patients in the atorvastatin group (14.4%) than in the simvastatin group (20.1%), but the difference did not reach statistical significance. (HR=0.68, 95% CI 0.41 to 1.11; p=0.13). Atorvastatin treatment significantly reduced overall cardiovascular (p=0.046) and coronary events (p=0.004), and coronary revascularisation (p=0.007) in these patients. Conclusions High-dose statin therapy with atorvastatin significantly reduced the incidence of PAD compared with usual-dose statin therapy with simvastatin. Patients with a history of PAD at baseline were at higher risk of future coronary events and this risk was reduced by high-dose atorvastatin treatment. Trial registration number NCT00159835 (URL: http://clinicaltrials.gov/show/NCT00159835).

Impact of female sex on lipid lowering, clinical outcomes, and adverse effects in atorvastatin trials.

The aim of this study was to evaluate the effect of atorvastatin on lipid lowering, cardiovascular (CV) events, and adverse events in women compared with men in 6 clinical trials. In the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial (atorvastatin 80 mg vs simvastatin 20 to 40 mg), the Treating to New Targets (TNT) trial (atorvastatin 80 vs 10 mg), the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial (atorvastatin 80 mg vs placebo), and the Collaborative Atorvastatin Diabetes Study (CARDS), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), and the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) (atorvastatin 10 mg vs placebo), lipid changes on treatment were compared between genders with studies grouped by dose. The association of on-study low-density lipoprotein (LDL) cholesterol and CV events by gender was evaluated in the combined studies and the impact of gender on adverse events in each study separately. Major CV events occurred in 3,083 of 30,000 men (10.3%) and 823 of 9,173 women (9.0%). Changes in lipids were similar in women and men. Major CV events were associated with gender-specific quintiles of on-treatment LDL cholesterol for women and men. In women, LDL cholesterol was a significant predictor of stroke, but not in men. Discontinuation rates due to adverse events were higher in women in 4 of 6 trials, but in only 1 trial was a significant treatment-gender interaction seen. Myalgia rates were slightly higher in women in both statin and placebo groups. In conclusion, the response of women to atorvastatin was similar to that of men, with slightly more discontinuations due to adverse events. Higher on-treatment LDL cholesterol was significantly associated with more CV events in both genders, but the association was stronger for stroke in women and for coronary heart disease death in men.

Statin and the Risk of Renal-Related Serious Adverse Events: Analysis from the IDEAL, TNT, CARDS, ASPEN, SPARCL, and Other Placebo-Controlled Trials

A recent study has shown an association between high-potency statins and risk of acute kidney injury. However, these data are from observational studies, and it is not clear if similar signal is seen from randomized controlled trials. We evaluated the risk of renal-associated serious adverse events (SAEs) using statins versus placebo trials and the high-dose versus low-dose statin trials that were available to us. The outcome of interest was renal-related SAEs. The incidence of adverse events relating to kidney injury was determined through review of the adverse event database. The following outcomes were evaluated: (1) renal-related SAEs within 120 days of randomization (primary outcome), (2) renal-related SAEs after 120 days of randomization (secondary), and (3) drug discontinuation due to renal-related SAEs (secondary). There was no difference in the incidence of renal-related SAEs at 120 days (0.04% vs 0.10%, p = 0.162) between atorvastatin and placebo in the 24 placebo-controlled trials (10,345 patients on atorvastatin (10 to 80 mg/day) versus 8,945 patients on placebo) or in the high-dose versus low-dose statin trials including the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study (0.05% vs 0.02%, p = 0.625) or the Treating to New Targets (TNT) trial (0.0% vs 0.04%, p = 0.500) trial. Results were similar for renal-related SAEs after 120 days (placebo controlled trials [0.38% vs 0.36%, p = 0.905], IDEAL trial [0.56% vs 0.65%, p = 0.683], or the TNT trial [0.76% vs 1.04%, p = 0.168]) and for drug withdrawal due to renal-related SAE (placebo controlled trials [0.05% vs 0.04%, p = 1.00], IDEAL trial [0.02% vs 0.0%, p = 0.499], or the TNT trial [0.08% vs 0.12%, p = 0.754]). In conclusion, the results from clinical trials with data from 149,882 patient-years of follow-up fail to show any increase in renal-related SAEs with statins compared with controls.

Systemic Exposure to Atorvastatin Between Asian and Caucasian Subjects: A Combined Analysis of 22 Studies

The aim of the present study was to determine whether there is a differing pattern of systemic exposure to atorvastatin in Asian versus Caucasian subjects by comparison of data obtained from completed pharmacokinetic studies. Pharmacokinetic data were analyzed from completed single-dose (10–80 mg) studies in Asian and Caucasian subjects. Dose normalized area under the concentration-time curve (AUC) and maximum observed concentration (Cmax) (AUCdn and Cmaxdn) were obtained by dividing each value by the administered dose. Dose-per-bodyweight normalized AUC and Cmax (AUCdn,wt and Cmax,dn,wt) were obtained by dividing each value by the administered dose per unit bodyweight. Mean difference and 90% confidence intervals for Asian versus Caucasian comparisons were calculated for atorvastatin pharmacokinetic values based on the t statistic and expressed as ratios using Caucasians as the reference. Data were analyzed from 310 Asians and 579 Caucasians from 22 studies. AUCdn (Asian = 2.35, Caucasian = 2.06 [ng·hr·mL−1]/mg) and Cmaxdn (Asian = 0.39, Caucasian = 0.40 Cmaxdn,wt) and the equivalent dose-per-bodyweight normalized values for atorvastatin (AUCdn,wt: Asian = 157.5, Caucasian = 156.4 [ng·hr·mL−1]/[mg·kg−1]; Cmaxdn,wt: Asian = 26.2, Caucasian = 30.3 [ng·mL−1]/[mg·kg−1]) were similar in both ethnic groups. Mean differences and 90% confidence interval for the differences fell within the limits (0.8–1.25) except for Cmaxdn,wt, for which the lower limit was slightly below 80%. No differences were noted in the systemic exposure to atorvastatin between Asian and Caucasian subjects. These data therefore demonstrate that dosing considerations in the current labels for atorvastatin are similar for Asian compared with Caucasian subjects.

Lipid lowering in patients with treatment-resistant hypertension: an analysis from the Treating to New Targets (TNT) trial

AIM Patients with resistant hypertension are at high risk for adverse cardiovascular events. Efforts have been focused on lowering the surrogate endpoint of blood pressure (BP) with scant focus on reduction of hard cardiovascular endpoints. However, whether or not intensive lipid lowering is beneficial for reducing the risk of cardiovascular events in this high-risk cohort is not known. METHODS AND RESULTS We evaluated 10 001 patients with coronary artery disease and a low-density lipoprotein cholesterol level <130 mg/dL, randomized to atorvastatin 80 vs. 10 mg, enrolled in the Treating to New Targets trial. Treatment-resistant hypertension (TRH) was defined as BP ≥140 mmHg despite being on three antihypertensive agents or <140 mmHg on four or more agents. Subjects were followed up for a median duration of 4.9 years. The primary outcome was major cardiovascular events (composite of non-fatal myocardial infarction (MI), fatal coronary heart disease (CHD), resuscitated cardiac arrest, and stroke). Among the 10 001 patients in the trial, 1112 (11.1%) patients had TRH. Atorvastatin 80 mg, in patients with TRH, was associated with a significant reduction in the risk of the primary outcome (HR = 0.70; 95% CI 0.52-0.93; P = 0.01), driven largely by a significant reduction in CHD deaths (HR = 0.55; 95% CI 0.32-0.97; P = 0.04). In addition, atorvastatin 80 mg was associated with a reduction in major coronary events (HR = 0.67; 95% CI 0.49-0.93; P = 0.02), and any cardiovascular or coronary event and with a trend (P = 0.05) towards reduction in all-cause mortality (HR = 0.68; 95% CI 0.46-1.01) when compared with atorvastatin 10 mg. The results were similar when analysed for the two separate components of the TRH cohort. CONCLUSION In subjects with TRH, intensive lipid lowering with atorvastatin 80 mg is associated with a significant reduction in cardiovascular events.

Safety of atorvastatin in Asian patients within clinical trials

Summary Introduction Data on statin safety in Asian patients are limited compared with evidence from Western populations. Aim This study assessed atorvastatin safety among Asian patients enrolled in 58 randomized clinical trials. Methods Data from 52 short‐term trials (median exposure 4–72 weeks) and six long‐term cardiovascular outcomes trials (median exposure 3.1–4.9 years) conducted across the atorvastatin 10–80‐mg dose range were analyzed retrospectively to assess the incidence of safety endpoints. Results A total of 77 952 patients were identified (49 974 received atorvastatin), among whom 3191 were Asian (2519 received atorvastatin). In the short‐term trials, the incidence of all‐causality adverse events (AEs) and serious AEs (SAEs) in Asian patients treated with atorvastatin was similar to or lower than that observed with other statins or placebo, and discontinuations due to treatment‐related AEs/SAEs were infrequent (2.0% across all doses). These observations were confirmed in the long‐term trials. Treatment‐related SAEs were rare (n = 4) among Asian patients receiving atorvastatin. No cases of rhabdomyolysis were observed in atorvastatin‐treated Asian patients, and the incidence of myalgia was 1.8% in the short‐term studies and 6.7% in the long‐term trials. Elevations (>3× the upper limit of normal) in liver transaminases were observed in ~2% of Asian patients receiving atorvastatin; renal AEs occurred in <2%. Conclusion The incidence of AEs/SAEs with atorvastatin 10–40‐mg in patients of Asian origin was low and comparable to placebo. Further evaluation of atorvastatin 80‐mg is required owing to the limited number of Asian patients (n = 281; 11.2%) who received this dose.