In late 2018, the Food and Drug Administration (FDA) outlined a framework for evaluating the possible use of real-world evidence (RWE) to support regulatory decision-making. This framework was created to facilitate studies that would generate high-quality RWE, including pragmatic clinical trials (PCTs), which are randomized trials designed to inform clinical or policy decisions by assessing the real-world effectiveness of an intervention. There is general agreement among experts that the use of existing healthcare and patient-generated data holds promise for making randomized trials more efficient, less costly, and more generalizable. Yet the benefits of relying on real-world data sources must be weighed against difficulties with ensuring data integrity and completeness. Additionally, appropriately monitoring patient safety in randomized trials of new drugs using healthcare system data that might not be available in real time can be quite difficult. Recognizing that these and other concerns are critical to the development and acceptability of PCTs, a group of stakeholders from academia, industry, professional organizations, regulatory bodies, government agencies, and patient advocates discussed a path forward for PCT growth and sustainability at a think tank meeting entitled "Monitoring and Analyzing Data from Pragmatic Streamlined Randomized Clinical Trials," which took place in January 2019 (Washington, DC). The goals of this meeting were to: (1) evaluate study design and methodological options specific to PCTs that have the potential to yield high-quality evidence; (2) discuss best practices to ensure data quality in PCTs; and (3) identify appropriate methods for study monitoring. Proceedings from the think tank meeting are summarized in this manuscript.

Objective— Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) and statins are known to lower plasma LDL (low-density lipoprotein)-cholesterol concentrations. However, the comparative effects of these treatments on the postprandial metabolism of TRLs (triglyceride-rich lipoproteins) remain to be investigated. Approach and Results— We performed a 2-by-2 factorial trial of the effects of 8 weeks of subcutaneous evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on postprandial TRL metabolism in 80 healthy, normolipidemic men after ingestion of an oral fat load. We evaluated plasma total and incremental area under the curves for triglycerides, apo (apolipoprotein)B-48, and VLDL (very-LDL)-apoB-100. We also examined the kinetics of apoB-48 using intravenous D3-leucine administration, mass spectrometry, and multicompartmental modeling. Atorvastatin and evolocumab independently lowered postprandial VLDL-apoB-100 total area under the curves (P<0.001). Atorvastatin, but not evolocumab, reduced fasting plasma apoB-48, apoC-III, and angiopoietin-like 3 concentrations (P<0.01), as well as postprandial triglyceride and apoB-48 total area under the curves (P<0.001) and the incremental area under the curves for plasma triglycerides, apoB-48, and VLDL-apoB-100 (P<0.01). Atorvastatin also independently increased TRL apoB-48 fractional catabolic rate (P<0.001) and reduced the number of apoB-48–containing particles secreted in response to the fat load (P<0.01). In contrast, evolocumab did not significantly alter the kinetics of apoB-48. Conclusions— In healthy, normolipidemic men, atorvastatin decreased fasting and postprandial apoB-48 concentration by accelerating the catabolism of apoB-48 particles and reducing apoB-48 particle secretion in response to a fat load. Inhibition of PCSK9 with evolocumab had no significant effect on apoB-48 metabolism.

AimsLipoprotein(a) [Lp(a)], a low-density lipoprotein (LDL) particle covalently bound to apolipoprotein(a) [apo(a)], is a potentially potent heritable risk factor for cardiovascular disease. We investigated the mechanism whereby evolocumab, a monoclonal antibody against proprotein convertase subtilisin-kexin type 9 (PCSK9), lowers Lp(a).Methods and resultsWe studied the kinetics of Lp(a) particles in 63 healthy men, with plasma apo(a) concentration >5 nmol/L, participating in an 8-week factorial trial of the effects of evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on lipoprotein metabolism. Lipoprotein(a)-apo(a) kinetics were studied using intravenous D3-leucine administration, mass spectrometry, and compartmental modelling; Lp(a)-apoB kinetics were also determined in 16 subjects randomly selected from the treatment groups. Evolocumab, but not atorvastatin, significantly decreased the plasma pool size of Lp(a)-apo(a) (-36%, P < 0.001 for main effect). As monotherapy, evolocumab significantly decreased the production of Lp(a)-apo(a) (-36%, P < 0.001). In contrast, in combination with atorvastatin, evolocumab significantly increased the fractional catabolism of Lp(a)-apo(a) (+59%, P < 0.001), but had no effect on the production of Lp(a)-apo(a). There was a highly significant association between the changes in the fractional catabolism of Lp(a)-apo(a) and Lp(a)-apoB in the substudy of 16 subjects (r = 0.966, P < 0.001).ConclusionsEvolocumab monotherapy lowered the plasma Lp(a) pool size by decreasing the production of Lp(a) particles. In combination with atorvastatin, evolocumab lowered the plasma Lp(a) pool size by accelerating the catabolism of Lp(a) particles. This dual mechanism may relate to an effect of PCSK9 inhibition on Lp(a)-apo(a) production and to marked up-regulation of LDL receptor activity on Lp(a) holoparticle clearance.Clinical Trial Registration InformationNCT02189837.

Aim: Lp(a), a LDL particle covalently bound to apo(a), is associated with an increased risk of premature coronary heart disease. Apo(a) is polymorphic and plasma Lp(a) concentrations are inversely related to the apo(a) size; yet the effect of apo(a) isoform size on Lp(a) metabolism is unclear.

Aim: Experimental studies suggest that proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important regulator of lipoprotein metabolism, particularly LDL, because of its ability to facilitate degradation of the LDL receptor. However, the association between plasma free PCSK9 concentration with very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and Lp(a) metabolism is unclear.

Callaway and Sunde1 are right when they advise caution in adoption of extracorporeal cardiopulmonary resuscitation (ECPR) given the varying definitions of what ECPR constitutes. However, we believe ECPR is not coming ‘too fast and furious’ but rather like a Formula One car, dependent on focused high performance teams, bespoke with narrow specifications and at the cutting edge.Current survival for cardiac arrest by conventional cardiopulmonary resuscitation (CCPR) is indeed dismal at around 10%.2 ECPR has led to improved outcomes compared with CCPR in many regions.3–6 ECPR consideration is in some ways analogous to resuscitative thoracotomy (RT) in trauma. Despite moderate quality of evidence, RT is strongly recommended in pulseless penetrating torso trauma with signs of life in ED.7 …

Callaway and Sunde1 are right when they advise caution in adoption of extracorporeal cardiopulmonary resuscitation (ECPR) given the varying definitions of what ECPR constitutes. However, we believe ECPR is not coming ‘too fast and furious’ but rather like a Formula One car, dependent on focused high performance teams, bespoke with narrow specifications and at the cutting edge. Current survival for cardiac arrest by conventional cardiopulmonary resuscitation (CCPR) is indeed dismal at around 10%.2 ECPR has led to improved outcomes compared with CCPR in many regions.3–6 ECPR consideration is in some ways analogous to resuscitative thoracotomy (RT) in trauma. Despite moderate quality of evidence, RT is strongly recommended in pulseless penetrating torso trauma with signs of life in ED.7 …

Purpose The need for novel approaches to cardiovascular drug development served as the impetus to convene an open meeting of experts from the pharmaceutical industry and academia to assess the challenges and develop solutions for drug discovery in cardiovascular disease. Methods The Novel Cardiovascular Therapeutics Summit first reviewed recent examples of ongoing or recently completed programs translating basic science observations to targeted drug development, highlighting successes (protein convertase sutilisin/kexin type 9 [PCSK9] and neprilysin inhibition) and targets still under evaluation (cholesteryl ester transfer protein [CETP] inhibition), with the hope of gleaning key lessons to successful drug development in the current era. Participants then reviewed the use of innovative approaches being explored to facilitate rapid and more cost-efficient evaluations of drug candidates in a short timeframe. Results We summarize observations gleaned from this summit and offer insight into future cardiovascular drug development. Conclusions The rapid development in genetic and high-throughput drug evaluation technologies, coupled with new approaches to rapidly evaluate potential cardiovascular therapies with in vitro techniques, offer opportunities to identify new drug targets for cardiovascular disease, study new therapies with better efficiency and higher throughput in the preclinical setting, and more rapidly bring the most promising therapies to human testing. However, there must be a critical interface between industry and academia to guide the future of cardiovascular drug development. The shared interest among academic institutions and pharmaceutical companies in developing promising therapies to address unmet clinical needs for patients with cardiovascular disease underlies and guides innovation and discovery platforms that are significantly altering the landscape of cardiovascular drug development.

Background: Monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9), such as evolocumab, lower plasma low-density lipoprotein (LDL)-cholesterol concentrations. Evolocumab is under investigation for its effects on cardiovascular outcomes in statin-treated, high-risk patients. The mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism remains to be fully evaluated. Stable isotope tracer kinetics can effectively elucidate the mode of action of new lipid-regulating pharmacotherapies. Methods: We conducted a 2-by-2 factorial trial of the effects of atorvastatin (80 mg daily) and subcutaneous evolocumab (420 mg every 2 weeks) for 8 weeks on the plasma kinetics of very-low-density lipoprotein (VLDL)–apolipoprotein B-100 (apoB), intermediate-density lipoprotein–apoB, and LDL-apoB in 81 healthy, normolipidemic, nonobese men. The kinetics of apoB in these lipoproteins was studied using a stable isotope infusion of D3-leucine, gas chromatography/mass spectrometry, and multicompartmental modeling. Results: Atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL-apoB ( P <0.001 and P .032, respectively), intermediate-density lipoprotein–apoB ( P =0.021 and P =.002, respectively), and LDL-apoB ( P <0.001, both interventions). Evolocumab but not atorvastatin decreased the production rate of intermediate-density lipoprotein–apoB ( P =0.043) and LDL-apoB ( P <0.001), which contributed to the reduction in the plasma pool sizes of these lipoprotein particles. The reduction in LDL-apoB and LDL-cholesterol concentrations was significantly greater with combination versus either monotherapy ( P <0.001). Whereas evolocumab but not atorvastatin lowered the concentration of free PCSK9, atorvastatin lowered the lathosterol/campesterol ratio (a measure of cholesterol synthesis/absorption) and apoC-III concentration. Both interventions decreased plasma apoE, but neither significantly altered lipoprotein lipase and cholesteryl ester protein mass or measures of insulin resistance. Conclusions: In healthy, normolipidemic subjects, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism. Reductions in intermediate-density lipoprotein and LDL production also contributed to the decrease in LDL particle concentration with evolocumab by a mechanism distinct from that of atorvastatin. These kinetic findings provide a metabolic basis for understanding the potential benefits of PCSK9 monoclonal antibodies incremental to statins in on-going clinical end point trials. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02189837.

IMPORTANCE Levels of proprotein convertase subtilisin kexin type 9 (PCSK9) vary markedly across the population and are influenced by genetic and nongenetic factors. Evolocumab is a fully human, monoclonal antibody against PCSK9 that reduces low-density lipoprotein cholesterol (LDL-C) levels by 55% to 75%. Whether the efficacy of evolocumab varies based on an individual's baseline PCSK9 level remains unknown.OBJECTIVE To characterize variability in PCSK9 levels and determine whether the LDL-C level reduction achieved with evolocumab differs based on PCSK9 levels.DESIGN, SETTING, AND PARTICIPANTS This study included pooled data from 3016 patients from 4 phase 3 randomized clinical trials of evolocumab as part of the Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 in Different Populations. Circulating PCSK9 levels were measured at baseline using quantitative enzyme-linked immunosorbent assays and used to stratify patients into quartiles, and LDL-C level was measured at baseline and weeks 10 and 12. In an additional 138 patients enrolled in a pharmacokinetic and pharmacodynamic substudy from 4 phase 2 trials, circulating PCSK9 levels were measured at baseline and then weekly at weeks 8 through 12.MAIN OUTCOMES AND MEASURES Placebo-controlled percentage change in LDL-C level with evolocumab, 140mg every 2 weeks and 420mg once monthly, across quartiles of baseline PCSK9 levels.RESULTS Of the 3016 patients, 1492 (49.5%) were female and 2758 (91.4%) were white. The median baseline circulating PCSK9 level was 323 ng/mL (interquartile range, 258-406 ng/mL). Patients with higher levels of PCSK9 were more likely to be receiving intensive statin therapy (56%, 36%, 25%, and 13% in the fourth through first quartiles; P <.001) and had significantly lower baseline LDL-C level (123mg/dL, 124mg/dL, 128mg/dL, and 137mg/dL in the fourth through first quartiles; P <.001). After stratifying by statin use, there was no correlation between PCSK9 levels and LDL-C levels (rho= 0.03 [95% CI,-0.04 to 0.10] for nonstatin users, P =.39, and. = 0.03 [95% CI,-0.01 to 0.08] for statin users, P =.12). Across all quartiles of baseline PCSK9 levels, both evolocumab 140mg every 2 weeks and 420mg once monthly suppressed circulating PCSK9 levels by 90% to 100% within 1 week of administration. Both evolocumab 140mg every 2 weeks and 420mg once monthly were associated with significant reductions in LDL-C levels between 64% and 71%(P <.001), regardless of PCSK9 levels (P for interaction =.76 and.21, respectively).CONCLUSIONS AND RELEVANCE Regardless of baseline PCSK9 levels, the doses of evolocumab being studied in a large cardiovascular outcomes trial suppress PCSK9 levels and consistently and substantially reduce LDL-C levels.

Statins are the accepted standard for lowering low‐density lipoprotein cholesterol (LDL‐C). However, 5% to 10% of statin‐treated patients report intolerance, mostly due to muscle‐related adverse effects. Challenges exist to objective identification of statin‐intolerant patients. Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in marked LDL‐C reduction. We report the design of Goal Achievement After Utilizing an Anti‐PCSK9 Antibody in Statin‐Intolerant Subjects 3 (GAUSS‐3), a phase 3, multicenter, randomized, double‐blind, ezetimibe‐controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose. The study incorporates a novel atorvastatin‐controlled, double‐blind, crossover phase to objectively identify statin intolerance. Eligible patients had LDL‐C above the National Cholesterol Education Project Adult Treatment Panel III target level for the appropriate coronary heart disease risk category and were unable to tolerate ≥3 statins or 2 statins (one of which was atorvastatin ≤10 mg/d) or had a history of marked creatine kinase elevation accompanied by muscle symptoms while on 1 statin. This trial has 2 co‐primary endpoints: mean percent change from baseline in LDL‐C at weeks 22 and 24 and percent change from baseline in LDL‐C at week 24. Key secondary efficacy endpoints include change from baseline in LDL‐C, percent of patients attaining LDL‐C <70 mg/dL (1.81 mmol/L), and percent change from baseline in total cholesterol, non–high‐density lipoprotein cholesterol, and apolipoprotein B. Recruitment of 511 patients was completed on November 28, 2014.

IMPORTANCE:Muscle-related statin intolerance is reported by 5% to 20% of patients.OBJECTIVE:To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab.DESIGN, SETTING, AND PARTICIPANTS:Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks.INTERVENTIONS:Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily).MAIN OUTCOME AND MEASURES:Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels.RESULTS:Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, -16.7% (95% CI, -20.5% to -12.9%), absolute change, -31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, -54.5% (95% CI, -57.2% to -51.8%); absolute change, -106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, -16.7% (95% CI, -20.8% to -12.5%); absolute change, -31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, -52.8% (95% CI, -55.8% to -49.8%); absolute change, -102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was -37.8%; absolute difference, -75.8 mg/dL. For week 24, between-group difference in LDL-C was -36.1%; absolute difference, -71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%).CONCLUSIONS AND RELEVANCE:Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety.TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT01984424.

Lipoprotein (a) [Lp(a)] is independently associated with CVD risk. Evolocumab, a monoclonal antibody (mAb) to proprotein convertase subtilisin/kexin type 9 (PCSK9), decreases Lp(a). The potential mechanisms were assessed. A pooled analysis of Lp(a) and LDL cholesterol (LDL-C) in 3,278 patients from 10 clinical trials (eight phase 2/3; two extensions) was conducted. Within each parent study, biweekly and monthly doses of evolocumab statistically significantly reduced Lp(a) at week 12 versus control (P < 0.001 within each study); pooled median (quartile 1, quartile 3) percent reductions were 24.7% (40.0, 3.6) and 21.7% (39.9, 4.2), respectively. Reductions were maintained through week 52 of the open-label extension, and correlated with LDL-C reductions [with and without correction for Lp(a)-cholesterol] at both time points (P < 0.0001). The effect of LDL and LDL receptor (LDLR) availability on Lp(a) cell-association was measured in HepG2 cells: cell-associated LDL fluorescence was reversed by unlabeled LDL and Lp(a). Lp(a) cell-association was reduced by coincubation with LDL and PCSK9 and reversed by adding PCSK9 mAb. These studies support that reductions in Lp(a) with PCSK9 inhibition are partly due to increased LDLR-mediated uptake. In most situations, Lp(a) appears to compete poorly with LDL for LDLR binding and internalization, but when LDLR expression is increased with evolocumab, particularly in the setting of low circulating LDL, Lp(a) is reduced.

BackgroundProprotein convertase subtilisin kexin 9 (PCSK9) inhibitors reduce low‐density lipoprotein cholesterol (LDL‐C) and improve outcomes in the general population. HIV‐infected individuals are at increased risk for cardiovascular events and have high rates of dyslipidemia and hepatitis C virus (HCV) coinfection, making PCSK9 inhibition a potentially attractive therapy. Methods and ResultsWe studied 567 participants from a clinic‐based cohort to compare PCSK9 levels in patients with HIV/HCV coinfection (n=110) with those with HIV infection alone (n=385) and with uninfected controls (n=72). The mean age was 49 years, and the median LDL‐C level was 100 mg/dL (IQR 77–124 mg/dL); 21% were taking statins. The 3 groups had similar rates of traditional risk factors. Total cholesterol, LDL‐C, and high‐density lipoprotein cholesterol levels were lower in coinfected patients compared with controls (P<0.001). PCSK9 was 21% higher in HIV/HCV‐coinfected patients versus controls (95% CI 9–34%, P<0.001) and 11% higher in coinfected individuals versus those with HIV infection alone (95% CI 3–20%, P=0.008). After adjustment for cardiovascular risk factors, HIV/HCV coinfection remained significantly associated with 20% higher PCSK9 levels versus controls (95% CI 8–33%, P=0.001). Interleukin‐6 levels increased in a stepwise fashion from controls (lowest) to HIV‐infected to HIV/HCV‐coinfected individuals (highest) and correlated with PCSK9 (r=0.11, P=0.018). ConclusionsDespite having lower LDL‐C, circulating PCSK9 levels were increased in patients coinfected with HIV and HCV in parallel with elevations in the inflammatory, proatherogenic cytokine interleukin‐6. Clinical trials should be conducted to determine the efficacy of targeted PCSK9 inhibition in the setting of HIV/HCV coinfection.

Statins are the accepted standard for lowering low‐density lipoprotein cholesterol (LDL‐C). However, 5% to 10% of statin‐treated patients report intolerance, mostly due to muscle‐related adverse effects. Challenges exist to objective identification of statin‐intolerant patients. Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in marked LDL‐C reduction. We report the design of Goal Achievement After Utilizing an Anti‐PCSK9 Antibody in Statin‐Intolerant Subjects 3 (GAUSS‐3), a phase 3, multicenter, randomized, double‐blind, ezetimibe‐controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose. The study incorporates a novel atorvastatin‐controlled, double‐blind, crossover phase to objectively identify statin intolerance …

RATIONALE:Vitamin E transport and steroidogenesis are closely associated with low-density lipoproteins (LDLs) metabolism, and evolocumab can lower LDL cholesterol (LDL-C) to low levels.OBJECTIVE:To determine the effects of evolocumab on vitamin E and steroid hormone levels.METHODS AND RESULTS:After titration of background lipid-lowering therapy per cardiovascular risk, 901 patients with an LDL-C ≥2.0 mmol/L were randomized to 52 weeks of monthly, subcutaneous evolocumab, or placebo. Vitamin E, cortisol, adrenocorticotropic hormone, and gonadal hormones were analyzed at baseline and week 52. In a substudy (n=100), vitamin E levels were also measured in serum, LDL, high-density lipoprotein, and red blood cell membranes at baseline and week 52. Absolute vitamin E decreased in evolocumab-treated patients from baseline to week 52 by 16% but increased by 19% when normalized for cholesterol. In the substudy, vitamin E level changes from baseline to week 52 mirrored the changes in the lipid fraction, and red blood cell membrane vitamin E levels did not change. Cortisol in evolocumab-treated patients increased slightly from baseline to week 52, but adrenocorticotropic hormone and the cortisol:adrenocorticotropic hormone ratio did not change. No patient had a cortisol:adrenocorticotropic hormone ratio <3.0 (nmol/pmol). Among evolocumab-treated patients, gonadal hormones did not change from baseline to week 52. Vitamin E and steroid changes were consistent across subgroups by minimum postbaseline LDL-C <0.4 and <0.6 mmol/L.CONCLUSIONS:As expected, vitamin E levels changed similarly to lipids among patients treated for 52 weeks with evolocumab. No adverse effects were observed in steroid or gonadal hormones, even at very low LDL-C levels.CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01516879.

Aim: Evolocumab, a fully human monoclonal antibody to PCSK9, markedly reduced LDL-C in clinical studies. Here, we evaluated the effects of evolocumab on vitamin E as well as adrenal and gonadal steroid hormone levels.

Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors are an effective strategy for lowering LDL-C. In an oral presentation from our group, we reported that PCSK9 is elevated in HIV infection, a state of heightened inflammation. Here, we aim to characterize the levels of PCSK9 in individuals

Despite the global burden of cardiovascular disease, investment in cardiovascular drug development has stagnated over the past 2 decades, with relative underinvestment compared with other therapeutic areas. The reasons for this trend are multifactorial, but of primary concern is the high cost of conducting cardiovascular outcome trials in the current regulatory environment that demands a direct assessment of risks and benefits, using clinically-evident cardiovascular endpoints. To work toward consensus on improving the environment for cardiovascular drug development, stakeholders from academia, industry, regulatory bodies, and government agencies convened for a think tank meeting in July 2014 in Washington, DC. This paper summarizes the proceedings of the meeting and aims to delineate the current adverse trends in cardiovascular drug development, understand the key issues that underlie these trends within the context of a recognized need for a rigorous regulatory review process, and provide potential solutions to the problems identified.