Abstract Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein receptor, escorting it to its destruction in the lysosome and thereby preventing the recirculation ...of the low-density lipoprotein receptor to the hepatocyte cell surface. Both gain-of-function mutations in PCSK9 (causing marked increases in low-density lipoprotein cholesterol LDL-C concentration and premature atherosclerosis) and loss-of-function mutations (causing modest LDL-C reduction with low rates of coronary heart disease) have been described. Several monoclonal antibodies to PCSK9 have achieved LDL-C reductions of 50% to 70% across various patient populations and background lipid therapies. Phase 2/3 trials have demonstrated good tolerability without clear drug-related toxicity, although the number and duration of patients treated to date is modest. Currently, 4 phase 3 trials involving >70,000 patients are testing whether these drugs reduce cardiovascular events. The U.S. Food and Drug Administration is currently reviewing the existing data to determine whether these agents could be made available prior to the completion of these cardiovascular endpoint trials expected in 2018.
Permeability glycoprotein (P-gp) mediates the export of drugs from cells located in the small intestine, blood-brain barrier, hepatocytes, and kidney proximal tubule, serving a protective function ...for the body against foreign substances. Intestinal absorption, biliary excretion, and urinary excretion of P-gp substrates can therefore be altered by either the inhibition or induction of P-gp. A wide spectrum of drugs, such as anticancer agents and steroids, are known P-gp substrates and/or inhibitors, and many cardiovascular drugs have recently been observed to have clinically relevant interactions as well. We review the interactions among commonly prescribed cardiovascular drugs that are P-gp substrates and observe interactions involving P-gp that may be relevant to clinical practice. Cardiovascular drugs with narrow therapeutic indexes (e.g., antiarrhythmic agents, anticoagulant agents) have demonstrated large increases in concentrations when coadministered with potent P-gp inhibitors, thus increasing the risk for drug toxicity. Therefore, dose adjustment or use of alternative agents should be considered when strong P-gp-mediated drug-drug interactions are present. Finally, interactions between novel drugs and known P-gp inhibitors are now being systematically evaluated during drug development, and recommended guidelines for the administration of P-gp substrate drugs will be expanded.
In two randomized trials, evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9), reduced LDL cholesterol levels by 61%. In an exploratory analysis, the ...incidence of cardiovascular events was reduced in the evolocumab group.
Reduction in low-density lipoprotein (LDL) cholesterol levels has proved to be highly effective in reducing rates of major cardiovascular events in numerous large outcome trials.
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For this reason, LDL cholesterol reduction has been incorporated into practice guidelines as a fundamental means of reducing cardiovascular morbidity and mortality.
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During the past 3 years, monoclonal antibodies that inhibit proprotein convertase subtilisin–kexin type 9 (PCSK9) have emerged as a new class of drugs that very effectively lower LDL cholesterol levels.
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One of the members of this class is evolocumab, a fully human monoclonal antibody that typically achieves approximately a 60% reduction . . .
Abstract Background Ezetimibe improves cardiovascular (CV) outcomes in patients stabilized after acute coronary syndrome (ACS) when added to statin therapy. After ACS, patients vary considerably in ...their risk for recurrent CV events. Objectives This study tested the hypothesis that atherothrombotic risk stratification may be useful to identify post-ACS patients who have the greatest potential for benefit from the addition of ezetimibe to statin therapy. Methods The TIMI (Thrombolysis In Myocardial Infarction) Risk Score for Secondary Prevention (TRS 2°P) is a simple 9-point risk stratification tool, previously developed in a large population with atherothrombosis to predict CV death, myocardial infarction (MI), and ischemic stroke (CV death/MI/ischemic cerebrovascular accident iCVA). The current study applied this tool prospectively to 17,717 post-ACS patients randomized either to ezetimibe and simvastatin or to placebo and simvastatin in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Treatment efficacy was assessed by baseline risk for CV death/MI/iCVA, the IMPROVE-IT composite endpoints (CE), and individual component endpoints at 7 years. Results All 9 clinical variables in the TRS 2°P were independent risk indicators for CV death/MI/iCVA (p < 0.001). The integer-based scheme showed a strong graded relationship with the rate of CV death/MI/iCVA, the trial CE, and the individual components (p trend <0.0001 for each). High-risk patients (n = 4,393; 25%), defined by ≥3 risk indicators, had a 6.3% (95% confidence interval: 2.9% to 9.7%) absolute risk reduction in CV death/MI/iCVA at 7 years with ezetimibe/simvastatin, thus translating to a number-needed-to-treat of 16. Intermediate-risk patients (2 risk indicators; n = 5,292; 30%) had a 2.2% (95% confidence interval: −0.3% to 4.6%) absolute risk reduction. Low-risk patients (0 to 1 risk indicators; n = 8,032; 45%) did not appear to derive benefit from the addition of ezetimibe (p interaction = 0.010). Similar findings were observed for the IMPROVE-IT primary CE. Conclusions Atherothrombotic risk stratification using the TRS 2°P identifies high-risk patients who derive greatest benefit from the addition of ezetimibe to statin therapy for secondary prevention after ACS. (Improved Reduction of Outcomes: Vytorin Efficacy International Trial IMPROVE-IT; NCT00202878 )
Summary Background Four new oral anticoagulants compare favourably with warfarin for stroke prevention in patients with atrial fibrillation; however, the balance between efficacy and safety in ...subgroups needs better definition. We aimed to assess the relative benefit of new oral anticoagulants in key subgroups, and the effects on important secondary outcomes. Methods We searched Medline from Jan 1, 2009, to Nov 19, 2013, limiting searches to phase 3, randomised trials of patients with atrial fibrillation who were randomised to receive new oral anticoagulants or warfarin, and trials in which both efficacy and safety outcomes were reported. We did a prespecified meta-analysis of all 71 683 participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF–TIMI 48 trials. The main outcomes were stroke and systemic embolic events, ischaemic stroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial haemorrhage, and gastrointestinal bleeding. We calculated relative risks (RRs) and 95% CIs for each outcome. We did subgroup analyses to assess whether differences in patient and trial characteristics affected outcomes. We used a random-effects model to compare pooled outcomes and tested for heterogeneity. Findings 42 411 participants received a new oral anticoagulant and 29 272 participants received warfarin. New oral anticoagulants significantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR 0·81, 95% CI 0·73–0·91; p<0·0001), mainly driven by a reduction in haemorrhagic stroke (0·49, 0·38–0·64; p<0·0001). New oral anticoagulants also significantly reduced all-cause mortality (0·90, 0·85–0·95; p=0·0003) and intracranial haemorrhage (0·48, 0·39–0·59; p<0·0001), but increased gastrointestinal bleeding (1·25, 1·01–1·55; p=0·04). We noted no heterogeneity for stroke or systemic embolic events in important subgroups, but there was a greater relative reduction in major bleeding with new oral anticoagulants when the centre-based time in therapeutic range was less than 66% than when it was 66% or more (0·69, 0·59–0·81 vs 0·93, 0·76–1·13; p for interaction 0·022). Low-dose new oral anticoagulant regimens showed similar overall reductions in stroke or systemic embolic events to warfarin (1·03, 0·84–1·27; p=0·74), and a more favourable bleeding profile (0·65, 0·43–1·00; p=0·05), but significantly more ischaemic strokes (1·28, 1·02–1·60; p=0·045). Interpretation This meta-analysis is the first to include data for all four new oral anticoagulants studied in the pivotal phase 3 clinical trials for stroke prevention or systemic embolic events in patients with atrial fibrillation. New oral anticoagulants had a favourable risk–benefit profile, with significant reductions in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding. The relative efficacy and safety of new oral anticoagulants was consistent across a wide range of patients. Our findings offer clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population. Funding None.
Abstract Cardiovascular (CV) disease is a leading cause of death worldwide, accounting for approximately 31.4% of deaths globally in 2012. It is estimated that, from 1980 to 2000, reduction in total ...cholesterol accounted for a 33% decrease in coronary heart disease (CHD) deaths in the United States. In other developed countries, similar decreases in CHD deaths (ranging from 19%–46%) have been attributed to reduction in total cholesterol. Low-density lipoprotein cholesterol (LDL-C) has now largely replaced total cholesterol as a risk marker and the primary treatment target for hyperlipidemia. Reduction in LDL-C levels by statin-based therapies has been demonstrated to result in a reduction in the risk of nonfatal CV events and mortality in a continuous and graded manner over a wide range of baseline risk and LDL-C levels. This article provides a review of (1) the relationship between LDL-C and CV risk from a biologic, epidemiologic, and genetic standpoint; (2) evidence-based strategies for LDL-C lowering; (3) lipid-management guidelines; (4) new strategies to further reduce CV risk through LDL-C lowering; and (5) population-level and health-system initiatives aimed at identifying, treating, and lowering lifetime LDL-C exposure.
Abstract Background The use of non-vitamin K antagonist oral anticoagulants (NOACs) instead of vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and coexisting valvular heart ...disease (VHD) is of substantial interest. Objectives This study explored outcomes in patients with AF with and without VHD in the ENGAGE AF–TIMI 48 (Effective Anticoagulation with factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, comparing edoxaban with warfarin. Methods Valvular heart disease was defined as history or baseline echocardiography evidence of at least moderate aortic/mitral regurgitation, aortic stenosis, or prior valve surgery (bioprosthesis replacement, valve repair, valvuloplasty). Patients with moderate to severe mitral stenosis or mechanical heart valves were excluded from the trial. Comparisons were made of rates of stroke/systemic embolic event (SSEE), major bleeding, additional efficacy and safety outcomes, as well as net clinical outcomes, in patients with or without VHD treated with edoxaban or warfarin, using adjusted Cox proportional hazards. Results After adjustment for multiple baseline characteristics, compared with no-VHD patients (n = 18,222), VHD patients (n = 2,824) had a similar rate of SSEE but higher rates of death (hazard ratio HR: 1.40; 95% confidence interval CI:1.26 to 1.56; p <0.001), major adverse cardiovascular events (HR: 1.29; 95% CI: 1.16 to 1.43; p <0.001), and major bleeding (HR: 1.21; 95% CI: 1.03 to 1.42; p = 0.02). Higher-dose edoxaban regimen had efficacy similar to warfarin in the presence of VHD (for SSEE, HR: 0.69; 95% CI: 0.44 to 1.07, in patients with VHD, and HR: 0.91; 95% CI: 0.77 to 1.07, in patients without VHD; p interaction pint = 0.26; and for less major bleeding, HR: 0.74; 95% CI: 0.53 to 1.02 in patients with VHD, and HR: 0.82; 95% CI: 0.71 to 0.94, in patients with no VHD; pint = 0.57). Conclusions The presence of VHD increased the risk of death, major adverse cardiovascular events, and major bleeding but did not affect the relative efficacy or safety of higher-dose edoxaban versus warfarin in AF. (Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs. Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation ENGAGE AF-TIMI 48; NCT00781391 )
To address concerns about cognitive decline with the use of PCSK9 inhibitors, automated neuropsychological testing was performed in patients who received evolocumab or placebo. Evolocumab was ...noninferior to placebo with respect to cognitive changes from baseline over 19 months.
Patients with active cancer are at an increased risk of arterial and venous thromboembolism (VTE) and bleeding events. Historically, in patients with cancer, low molecular weight heparins have been ...preferred for treatment of VTE, whereas warfarin has been the standard anticoagulant for stroke prevention in patients with atrial fibrillation (AF). More recently, direct oral anticoagulants (DOACs) have been demonstrated to reduce the risk of venous and arterial thromboembolism in large randomized clinical trials of patients with VTE and AF, respectively, thus providing an attractive oral dosing option that does not require routine laboratory monitoring. In this review, we summarize available clinical trial data and guideline recommendations, and outline a practical approach to anticoagulation management of VTE and AF in cancer.
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