James H. Revkin

Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial

BACKGROUND Patients with mixed dyslipidaemia have raised triglycerides, low high-density lipoprotein (HDL) cholesterol, and high low-density lipoprotein (LDL) cholesterol. Augmentation of HDL cholesterol by inhibition of the cholesteryl ester transfer protein (CETP) could benefit these patients. We aimed to investigate the effect of the CETP inhibitor, torcetrapib, on carotid atherosclerosis progression in patients with mixed dyslipidaemia. METHODS We did a randomised double-blind trial at 64 centres in North America and Europe. 752 eligible participants completed an atorvastatin-only run-in period for dose titration, after which they all continued to receive atorvastatin at the titrated dose. 377 of these patients were randomly assigned to receive 60 mg of torcetrapib per day and 375 to placebo. We made carotid ultrasound images at baseline and at 6-month intervals for 24 months. The primary endpoint was the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Analysis was restricted to 683 patients who had at least one dose of treatment and had at least one follow-up carotid intima-media measurement; they were analysed as randomised. Mean follow-up for these patients was 22 (SD 4.8) months. This trial is registered with ClinicalTrials.gov, number NCT00134238. FINDINGS The change in maximum carotid intima-media thickness was 0.025 (SD 0.005) mm per year in patients given torcetrapib with atorvastatin and 0.030 (0.005) mm per year in those given atorvastatin alone (difference -0.005 mm per year, 95% CI -0.018 to 0.008, p=0.46). Patients in the combined-treatment group had a 63.4% relative increase in HDL cholesterol (p<0.0001) and an 17.7% relative decrease in LDL cholesterol (p<0.0001), compared with controls. Systolic blood pressure increased by 6.6 mm Hg in the combined-treatment group and 1.5 mm Hg in the atorvastatin-only group (difference 5.4 mm Hg, 95% CI 4.3-6.4, p<0.0001). INTERPRETATION Although torcetrapib substantially raised HDL cholesterol and lowered LDL cholesterol, it also increased systolic blood pressure, and did not affect the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further.

Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients

BACKGROUND Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and reduces levels of low‐density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODS In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow‐up was 10 months. RESULTS At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of ‐56.0% in the bococizumab group and +2.9% in the placebo group, for a between‐group difference of –59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower‐risk, shorter‐duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow‐up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P=0.94). In the higher‐risk, longer‐duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow‐up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P=0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P=0.08). Injection‐site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001). CONCLUSIONS In two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower‐risk patients but did have a significant benefit in the trial involving higher‐risk patients. (Funded by Pfizer; SPIRE‐1 and SPIRE‐2 ClinicalTrials.gov numbers, NCT01975376 and NCT01975389.)

Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab

BACKGROUND Bococizumab, a humanized monoclonal antibody targeting proprotein convertase subtilisin–kexin type 9 (PCSK9), reduces levels of low‐density lipoprotein (LDL) cholesterol. However, the variability and durability of this effect are uncertain. METHODS We conducted six parallel, multinational lipid‐lowering trials enrolling 4300 patients with hyperlipidemia who were randomly assigned to receive 150 mg of bococizumab or placebo subcutaneously every 2 weeks and who were followed for up to 12 months; 96% were receiving statin therapy at the time of enrollment. The patients were assessed for lipid changes over time, stratified according to the presence or absence of antidrug antibodies detected during the treatment period. RESULTS At 12 weeks, patients who received bococizumab had a reduction of 54.2% in the LDL cholesterol level from baseline, as compared with an increase of 1.0% among those who received placebo (absolute between‐group difference, ‐55.2 percentage points). Significant between‐group differences were also observed in total cholesterol, non–high‐density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) (P<0.001 for all comparisons). However, high‐titer antidrug antibodies developed in a substantial proportion of the patients who received bococizumab, which markedly diminished the magnitude and durability of the reduction in LDL cholesterol levels. In addition, among patients with no antidrug antibodies, there was wide variability in the reduction in LDL cholesterol levels at both 12 weeks and 52 weeks. Major cardiovascular events occurred in 57 patients (2.5%) who received bococizumab and in 55 (2.7%) who received placebo (hazard ratio, 0.96; 95% confidence interval, 0.66 to 1.39; P=0.83). The most common adverse event among patients who received bococizumab was injection‐site reaction (12.7 per 100 person‐years). CONCLUSIONS In six multinational trials evaluating bococizumab, antidrug antibodies developed in a large proportion of the patients and significantly attenuated the lowering of LDL cholesterol levels. Wide variation in the relative reduction in cholesterol levels was also observed among patients in whom antidrug antibodies did not develop. (Funded by Pfizer; SPIRE ClinicalTrials.gov numbers, NCT01968954, NCT01968967, NCT01968980, NCT02100514, NCT02135029, and NCT02458287.)

Biomarkers in the Prevention and Treatment of Atherosclerosis: Need, Validation, and Future

Cardiovascular disease (CVD) remains one of the leading causes of morbidity and mortality in the developed world, and there is a clear need to develop novel therapeutic strategies to reduce cardiovascular risk further than is currently possible. Traditionally, the effectiveness of new cardiovascular drugs has been evaluated in clinical trials using cardiovascular outcomes as endpoints. However, such trials require large numbers of patients followed over long periods of time. Clinical trials using surrogate markers for CVD may be shorter in duration and involve fewer participants. Measurement of atherosclerotic progression is an ideal surrogate marker as it is predictive of future cardiovascular events. The “gold standard” for detecting and defining the severity, extent, and rate of atherosclerotic progression has been quantitative coronary angiography. However, this technique has fundamental limitations. More recently, measurement of carotid intima-media thickness using B-mode ultrasound and measurement of atheroma volume using intravascular ultrasound have emerged as more accurate techniques for detecting atherosclerotic progression. Both of these techniques have potential utility as surrogate endpoints in place of cardiovascular outcomes in clinical trials. Their use might facilitate the more rapid development of novel, safe, and effective therapies.

Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiency

Composite endpoints are commonly used as the primary measure of efficacy in heart failure clinical trials to assess the overall treatment effect and to increase the efficiency of trials. Clinical trials still must enrol large numbers of patients to accrue a sufficient number of outcome events and have adequate power to draw conclusions about the efficacy and safety of new treatments for heart failure. Additionally, the societal and health system perspectives on heart failure have raised interest in ascertaining the effects of therapy on outcomes such as repeat hospitalization and the patients burden of disease. Thus, novel methods for using composite endpoints in clinical trials (e.g. clinical status composite endpoints, recurrent event analyses) are being applied in current and planned trials. Endpoints that measure functional status or reflect the patient experience are important but used cautiously because heart failure treatments may improve function yet have adverse effects on mortality. This paper discusses the use of traditional and new composite endpoints, identifies qualities of robust composites, and outlines opportunities for future research.

Designs of RADIANCE 1 and 2:carotid ultrasound studies comparing the effects of torcetrapib/atorvastatin with atorvastatin alone on atherosclerosis

ABSTRACT Objective: The RADIANCE studies were designed to assess the effects of torcetrapib/atorvastatin (T/A) compared with atorvastatin alone on slowing atherosclerotic progression in patients with heterozygous familial hypercholesterolemia (RADIANCE 1) or mixed hyperlipidemia (RADIANCE 2), as measured by change in carotid intima-media thickness (CIMT). Research design and methods: RADIANCE 1 and 2 were randomized, double-blind, controlled trials with a duration of 2 years. In both studies, eligible subjects began treatment with atorvastatin during a run-in period and were titrated to target LDL‑C levels defined by NCEP ATP III guidelines. Subjects then proceeded to a double-blind randomized treatment period where they received one of two regimens: (i) fixed combination T/A (torcetrapib dose, 60 mg), or (ii) atorvastatin alone. In both regimens, the dose of atorvastatin was established during the run-in period (20–80 mg, RADIANCE 1; 10–80 mg RADIANCE 2). B-mode ultrasonography was performed in duplicate at baseline and at end of study, and every 6 months in between. Main outcome measures: The primary efficacy measure in both studies was the annualized rate of change in maximum CIMT of 12 pre-defined carotid segments. Further outcome measures included lipid and safety assessments. Current status: The number of subjects randomized was 904 in RADIANCE 1 and 752 in RADIANCE 2. Results are anticipated in 2007. Trial registration: ClinicalTrials.gov identifier: NCT00136981. Trial registration: ClinicalTrials.gov identifier: NCT00134238.

Metabolic and functional effects of perfluorocarbon distal perfusion during coronary angioplasty.

Myocardial lactate metabolism and left ventricular function were studied in 12 patients during angioplasty of the left anterior descending artery performed with distal coronary perfusion (oxygenated and nonoxygenated Fluosol) and by conventional technique without distal perfusion. Before balloon inflation there was net lactate extraction by the heart (31 +/- 6%). During balloon inflations performed with distal perfusion there was net lactate release into the great cardiac vein while the balloon was inflated; the great cardiac vein lactate concentration was approximately 25% lower during perfusion with oxygenated versus nonoxygenated Fluosol (p less than 0.02) indicating less myocardial lactate release. After balloon deflation washout of lactate into the great cardiac vein (net myocardial release) was observed in all 3 protocols. Left ventricular ejection fraction measured by echocardiography decreased markedly during nonperfused (53 +/- 3 to 36 +/- 3%, p less than 0.001) and nonoxygenated Fluosol (52 +/- 2 to 30 +/- 3%, p less than 0.001) inflations. This dysfunction was largely prevented by oxygenated Fluosol where only a minimal decrease in ejection fraction (51 +/- 2 vs 48 +/- 2%, p less than 0.02) occurred. Analysis of regional contractile function yielded similar results. Although oxygenated perfluorocarbons decrease cardiac lactate release during angioplasty, this study provides evidence for the onset of lactate production even when ventricular function is preserved.

Surrogate endpoints in randomized cardiovascular clinical trials

Surrogate endpoints predict the occurrence and timing of a clinical endpoint of interest (CEI). Substitution of a surrogate endpoint for a CEI can dramatically reduce the time and cost necessary to complete a Phase III clinical trial. However, assurance that use of a surrogate endpoint will result in a correct conclusion regarding treatment effect on a CEI requires prior rigorous validation of the surrogate. Surrogate endpoints can also be of substantial use in Phase I and II studies to assess whether the intended therapeutic pathway is operative, thus providing assurance regarding the reasonableness of proceeding to a Phase III trial. This paper discusses the uses and validation of surrogate endpoints.

Rate of change in carotid intima-media thickness and vascular events: meta-analyses can not solve all the issues. A point of view.

Whether a change in the rate of carotid intima–media thickness (CIMT) over time that is induced by a pharmaceutical intervention can be directly translated into change in future cardiovascular disease risk is an important issue. As this biomarker is increasingly used as primary outcome in many trials of the evaluation of novel cardiovascular treatments, this has become an important topic in cardiovascular drug development. Two recent meta-analyses using aggregated data from publication have attempted to address the issue. In our view both analyses suffer from considerable flaws. Flaws include the misuse of the concept of the atherosclerosis, pooling of trials carried out with treatments of heterogeneous efficacy and in patients, who had very different risk profiles; pooling of measurements from a wide variety of methodologies that shared a common name, ‘CIMT’; lack of power for detecting relationships using meta-regression techniques, and lastly, the ecologic fallacy. In this article, we discuss the concerns in more detail and offer strategies to get a valid answer on whether therapy-induced change in CIMT indeed relates to change in vascular risk

In vivo measurement of myocardial protein turnover using an indicator dilution technique.

We applied a nondestructive tracer technique, previously developed for measuring skeletal muscle protein turnover, to the measurement of myocardial protein turnover in vivo. During a continuous infusion of L-[ring-2,6-3H]phenylalanine to anesthetized, overnight-fasted dogs, we measured the uptake of radiolabeled phenylalanine from plasma and the release of unlabeled phenylalanine from myocardial proteolysis using arterial and coronary sinus catheterization and analytic methods previously applied to skeletal muscle. Using these measurements, together with a model of myocardial protein synthesis that assumes rapid equilibration of tracer specific activity between myocardial phenylalanyl-tRNA and circulating phenylalanine, we estimated the rates of heart protein synthesis and degradation. The rate of heart protein synthesis was also estimated directly from the incorporation of labeled phenylalanine into tissue protein. The use of [3H]phenylalanine was compared with L-[1-14C]leucine in the measurement of heart protein turnover in dogs given simultaneous infusion of both tracers. Leucine uptake and release by the myocardium exceeded that of phenylalanine by 3.1 +/- 0.4- and 1.7 +/- 0.3-fold, respectively, consistent with leucines 2.4-fold greater abundance in heart protein and its metabolism via other pathways. Phenylalanine is the preferred tracer for use with this method because of its limited metabolic fate in muscle. One theoretical limitation to the method, slow equilibration of circulating labeled phenylalanine with myocardial phenylalanyl-tRNA, was resolved by comparison of these specific activities after a 30-minute infusion of labeled phenylalanine in the rat. A second, empirical limitation involves precision in the measurement of the small decrements in phenylalanine specific activity that occur with each pass of blood through the coronary circulation. This was addressed by improving the precision of both the measurements of phenylalanine concentration and phenylalanine specific activity using high-performance liquid chromatography. We conclude that the in vivo measurement of phenylalanine tracer exchange across the myocardium permits the nondestructive estimation of heart protein turnover in the intact animal.