Lipoprotein(a) is similar to LDL cholesterol but contains apolipoprotein(a). A trial tested the effects of an oligonucleotide drug targeting apo(a) mRNA on lipoprotein(a) concentrations in patients ...with CVD.
Summary Background New oral anticoagulants for stroke prevention in atrial fibrillation were developed to be given in fixed doses without the need for the routine monitoring that has hindered usage ...and acceptance of vitamin K antagonists. A concern has emerged, however, that measurement of drug concentration or anticoagulant activity might be needed to prevent excess drug concentrations, which significantly increase bleeding risk. In the ENGAGE AF-TIMI 48 trial, higher-dose and lower-dose edoxaban were compared with warfarin in patients with atrial fibrillation. Each regimen incorporated a 50% dose reduction in patients with clinical features known to increase edoxaban drug exposure. We aim to assess whether adjustment of edoxaban dose in this trial prevented excess drug concentration and the risk of bleeding events. Methods We analysed data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. We correlated edoxaban dose, plasma concentration, and anti-Factor Xa (FXa) activity and compared efficacy and safety outcomes with warfarin stratified by dose reduction status. Patients with atrial fibrillation and at moderate to high risk of stroke were randomly assigned in a 1:1:1 ratio to receive warfarin, dose adjusted to an international normalised ratio of 2·0–3·0, higher-dose edoxaban (60 mg once daily), or lower-dose edoxaban (30 mg once daily). Randomisation was done with use of a central, 24 h, interactive, computerised response system. International normalised ratio was measured using an encrypted point-of-care device. To maintain masking, sham international normalised ratio values were generated for patients assigned to edoxaban. Edoxaban (or placebo-edoxaban in warfarin group) doses were halved at randomisation or during the trial if patients had creatinine clearance 30–50 mL/min, bodyweight 60 kg or less, or concomitant medication with potent P-glycoprotein interaction. Efficacy outcomes included the primary endpoint of all-cause stroke or systemic embolism, ischaemic stroke, and all-cause mortality. Safety outcomes included the primary safety endpoint of major bleeding, fatal bleeding, intracranial haemorrhage, and gastrointestinal bleeding. This trial is registered with ClinicalTrials.gov , number NCT00781391. Findings Between Nov 19, 2008 and Nov 22, 2010, 21 105 patients were recruited. Patients who met clinical criteria for dose reduction at randomisation (n=5356) had higher rates of stroke, bleeding, and death compared with those who did not have a dose reduction (n=15 749). Edoxaban dose ranged from 15 mg to 60 mg, resulting in a two-fold to three fold gradient of mean trough drug exposure (16·0–48·5 ng/mL in 6780 patients with data available) and mean trough anti-FXa activity (0·35–0·85 IU/mL in 2865 patients). Dose reduction decreased mean exposure by 29% (from 48·5 ng/mL SD 45·8 to 34·6 ng/mL 30·9) and 35% (from 24·5 ng/mL 22·7 to 16·0 ng/mL 14·5) and mean anti-FXa activity by 25% (from 0·85 IU/mL 0·76 to 0·64 IU/mL 0·54) and 20% (from 0·44 IU/mL 0·37 to 0·35 IU/mL 0·28) in the higher-dose and lower-dose regimens, respectively. Despite the lower anti-FXa activity, dose reduction preserved the efficacy of edoxaban compared with warfarin (stroke or systemic embolic event: higher dose pinteraction =0·85, lower dose pinteraction =0·99) and provided even greater safety (major bleeding: higher dose pinteraction 0·02, lower dose pinteraction =0·002). Interpretation These findings validate the strategy that tailoring of the dose of edoxaban on the basis of clinical factors alone achieves the dual goal of preventing excess drug concentrations and helps to optimise an individual patient's risk of ischaemic and bleeding events and show that the therapeutic window for edoxaban is narrower for major bleeding than thromboembolism. Funding Daiichi-Sankyo Pharma Development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
BACKGROUND:Edoxaban, an oral factor Xa inhibitor with 50% renal clearance, was noninferior to well-managed warfarin for stroke or systemic embolism (S/SE) prevention and reduced bleeding in patients ...with atrial fibrillation. We evaluated the efficacy and safety of edoxaban versus warfarin across the range of baseline creatinine clearance (CrCl) in the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction Study 48) with a focus on the higher-dose edoxaban regimen (HDER) and the upper range of CrCl.
METHODS:A total of 14 071 patients with atrial fibrillation at moderate to high risk for stroke were randomized to warfarin or HDER (60 mg daily or a 50% dose reduction to 30 mg daily for CrCl 30–50 mL/min, body weight of ≤60 kg, or use of a potent phosphorylated glycoprotein inhibitor). CrCl <30 mL/min was exclusionary. End points of S/SE, International Society on Thrombosis and Haemostasis major bleeding, and the net clinical outcome of S/SE/major bleeding or death were evaluated by intention-to-treat analysis using the prespecified CrCl cut point of 50 mL/min and additional exploratory cut points with the Cockcroft-Gault formula. A sensitivity analysis was performed with the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula for estimating renal function.
RESULTS:The relative risk of S/SE with HDER versus warfarin in patients with CrCl >50 mL/min (hazard ratio HR, 0.87; 95% confidence interval CI, 0.72–1.04) was similar to that in patients with CrCl ≤50 mL/min (HR, 0.87; 95% CI, 0.65–1.18; P for interaction=0.94). Several exploratory analyses suggested lower relative efficacy for the prevention of S/SE with HDER compared with warfarin at higher levels of CrCl (CrCl ≤50 mL/minHR, 0.87; 95% CI, 0.65–1.18; CrCl >50–95 mL/minHR, 0.78; 95% CI, 0.64–0.96; CrCl >95 mL/minHR, 1.36; 95% CI, 0.88–2.10; P for interaction=0.08). Bleeding rates were lower at all levels of CrCl with HDER (P for interaction=0.11). Because of the preserved effect on bleeding, the net clinical outcome was more favorable with HDER across the range of CrCl (P for interaction=0.73). Similar findings were observed in the sensitivity analysis using the CKD-EPI formula.
CONCLUSIONS:Although there was an apparent decrease in relative efficacy to prevent arterial thromboembolism in the upper range of CrCl, the safety and net clinical benefit of HDER compared with warfarin are consistent across the range of renal function.
CLINICAL TRIAL REGISTRATION:URLhttp://www.clinicaltrials.gov. Unique identifierNCT00781391.
In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), the proprotein convertase subtilisin-kexin type 9 inhibitor evolocumab reduced low-density ...lipoprotein cholesterol (LDL-C) and risk of cardiovascular events and was safe and well tolerated over a median of 2.2 years of follow-up. However, large-scale, long-term data are lacking.
The parent FOURIER trial randomized 27 564 patients with atherosclerotic cardiovascular disease and LDL-C ≥70 mg/dL on statin to evolocumab versus placebo. Patients completing FOURIER at participating sites were eligible to receive evolocumab in 2 open-label extension studies (FOURIER-OLE FOURIER Open-Label Extension) in the United States and Europe; primary analyses were pooled across studies. The primary end point was the incidence of adverse events. Lipid values and major adverse cardiovascular events were prospectively collected.
A total of 6635 patients were enrolled in FOURIER-OLE (3355 randomized to evolocumab and 3280 to placebo in the parent study). Median follow-up in FOURIER-OLE was 5.0 years; maximum exposure to evolocumab in parent plus FOURIER-OLE was 8.4 years. At 12 weeks in FOURIER-OLE, median LDL-C was 30 mg/dL, and 63.2% of patients achieved LDL-C <40 mg/dL on evolocumab. Incidences of serious adverse events, muscle-related events, new-onset diabetes, hemorrhagic stroke, and neurocognitive events with evolocumab long term did not exceed those for placebo-treated patients during the parent study and did not increase over time. During the FOURIER-OLE follow-up period, patients originally randomized in the parent trial to evolocumab versus placebo had a 15% lower risk of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina or coronary revascularization (hazard ratio, 0.85 95% CI, 0.75-0.96;
=0.008); a 20% lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80 95% CI, 0.68-0.93;
=0.003); and a 23% lower risk of cardiovascular death (hazard ratio, 0.77 95% CI, 0.60-0.99;
=0.04).
Long-term LDL-C lowering with evolocumab was associated with persistently low rates of adverse events for >8 years that did not exceed those observed in the original placebo arm during the parent study and led to further reductions in cardiovascular events compared with delayed treatment initiation.
URL: https://www.
gov; Unique identifiers: NCT02867813 and NCT03080935.
Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety ...in the long term remains unknown.
In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels.
In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels-down to very low levels <20 mg/dL-and a lower risk of the primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted
<0.0001 for each end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years.
In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns.
URL: https://www.
gov; Unique identifier: NCT01764633.
BACKGROUND:Atrial fibrillation (AF) and atrial flutter (AFL) are associated with both diabetes mellitus and its related comorbidities, including hypertension, obesity, and heart failure (HF). SGLT2 ...(sodium-glucose cotransporter 2) inhibitors have been shown to lower blood pressure, reduce weight, have salutary effects on left ventricular remodeling, and reduce hospitalization for HF and cardiovascular death in patients with type 2 diabetes mellitus. We therefore investigated whether SGLT2 inhibitors could also reduce the risk of AF/AFL.
METHODS:DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) studied the efficacy and safety of the SGLT2 inhibitor dapagliflozin versus placebo in 17 160 patients with type 2 diabetes mellitus and either multiple risk factors for atherosclerotic cardiovascular disease (n=10 186) or known atherosclerotic cardiovascular disease (n=6974). We explored the effect of dapagliflozin on the first and total number of AF/AFL events in patients with (n=1116) and without prevalent AF/AFL using Cox and negative binomial models, respectively. AF/AFL events were identified by search of the safety database using MedDRA preferred terms (“atrial fibrillation,” “atrial flutter”).
RESULTS:Dapagliflozin reduced the risk of AF/AFL events by 19% (264 versus 325 events; 7.8 versus 9.6 events per 1000 patient-years; hazard ratio HR, 0.81 95% CI, 0.68–0.95; P=0.009). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (previous AF/AFLHR, 0.79 95% CI, 0.58–1.09; no AF/AFLHR, 0.81 95% CI, 0.67–0.98; P for interaction 0.89). Similarly, presence of atherosclerotic cardiovascular disease (HR, 0.83 95% CI, 0.66–1.04) versus multiple risk factors (HR, 0.78 95% CI, 0.62–0.99; P for interaction 0.72) or a history of HF (HFHR, 0.78 95% CI, 0.55–1.11; No HFHR, 0.81 95% CI, 0.68–0.97; P for interaction 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Moreover, there was no effect modification by sex, history of ischemic stroke, glycated hemoglobin A1c, body mass index, blood pressure, or estimated glomerular filtration rate (all P for interaction >0.20). Dapagliflozin also reduced the total number (first and recurrent) of AF/AFL events (337 versus 432; incidence rate ratio, 0.77 95% CI, 0.64–0.92; P=0.005).
CONCLUSIONS:Dapagliflozin decreased the incidence of reported episodes of AF/AFL adverse events in high-risk patients with type 2 diabetes mellitus. This effect was consistent regardless of the patient’s previous history of AF, atherosclerotic cardiovascular disease, or HF.
REGISTRATION:URLhttps://www.clinicaltrials.gov; Unique identifierNCT01730534.
Abstract Background The PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In ...Myocardial Infarction 54) trial studied 2 doses of ticagrelor, 90 mg twice a day (bid) and 60 mg bid, for long-term prevention of ischemic events in patients with prior myocardial infarction. Both doses similarly reduced the rate of ischemic events versus placebo. The pharmacokinetics and pharmacodynamics of ticagrelor 60 mg bid have not been studied. Objectives In this study, the authors sought to study the pharmacokinetics and pharmacodynamics for ticagrelor 60 mg compared with 90 mg bid. Methods A total of 180 patients who received >4 weeks of study medication had blood sampling in the morning pre-maintenance dose and again 2 h post-dose. All patients received aspirin. Plasma levels of ticagrelor and its active metabolite AR-C124910XX were determined. P2Y12 inhibition was assessed by the VerifyNow P2Y12 assay (Accumetrics, Inc., San Diego, California) (P2Y12 reaction units PRU), light transmittance aggregometry (adenosine diphosphate 5 and 20 μmol/l and arachidonic acid), and vasodilator-stimulated phosphoprotein phosphorylation assays. VerifyNow Aspirin assays and serum thromboxane B2 measurements were performed. Results Mean pre- and post-dose plasma levels of ticagrelor were 35% and 38% lower, respectively, with 60 mg versus 90 mg. Both doses achieved high levels of platelet inhibition pre- and post-dose, with numerically slightly more variability with 60 mg: mean (SD) pre-dose PRU values were 59 ± 63 and 47 ± 43 for ticagrelor 60 and 90 mg, respectively (p = 0.34). High platelet reactivity, determined as PRU >208, was rare with the 60-mg pre-dose and was absent post-dose. Platelet reactivity pre- and post-dose, as measured by light transmittance aggregometry or vasodilator-stimulated phosphoprotein assays, was numerically but not significantly lower with 90 mg than with 60 mg. Aspirin response was not affected by either dose. Conclusions Ticagrelor 60 mg bid achieved high levels of peak and trough platelet inhibition in nearly all patients, similar to that with 90 mg bid, helping to explain the efficacy of the lower ticagrelor dose in PEGASUS-TIMI 54.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BACKGROUND:The FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) recently showed that the PCSK9 (proprotein convertase subtilisin-kexin ...type 9) inhibitor evolocumab significantly reduced major vascular events in patients with stable atherosclerotic cardiovascular disease, including patients with prior myocardial infarction (MI). Within the broad group of patients with prior MI, we hypothesized that readily ascertainable features would identify subsets who derive greater clinical risk reduction with evolocumab.
METHODS:The 22 351 patients with a prior MI were characterized on the basis of time from most recent MI, number of prior MIs, and presence of residual multivessel coronary artery disease (≥40% stenosis in ≥2 large vessels). The relative and absolute risk reductions in major vascular events, including the primary end point (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) and the key secondary end point (cardiovascular death, MI, or stroke), with evolocumab in these subgroups were compared.
RESULTS:A total of 8402 patients (38%) were within 2 years of their most recent MI; 5285 patients (24%) had ≥2 prior MIs; and 5618 patients (25%) had residual multivessel coronary artery disease. In a multivariable-adjusted model that simultaneously included all 3 high-risk features and other baseline covariates, more recent MI, multiple prior MIs, and residual multivessel coronary disease remained independent predictors of cardiovascular outcomes, with adjusted hazard ratios (HRs) for the primary end point of 1.37 (95% confidence interval CI,1.22–1.53), 1.78 (95% CI, 1.59–1.99), and 1.39 (95% CI, 1.24–1.56; all P<0.001). The relative risk reductions with evolocumab for the primary end point tended to be greater in the high-risk subgroups and were 20% (HR, 0.80; 95% CI, 0.71–0.91), 18% (HR, 0.82; 95% CI, 0.72–0.93), and 21% (HR, 0.79; 95% CI, 0.69–0.91) for those with more recent MI, multiple prior MIs, and residual multivessel coronary artery disease, whereas they were 5% (HR, 0.95; 95% CI, 0.85–1.05), 8% (HR, 0.92; 95% CI, 0.84–1.02), and 7% (HR, 0.93; 95% CI, 0.85–1.02) in those without, respectively. Given the higher baseline risk, the respective absolute risk reductions at 3 years exceeded 3% in the high-risk groups (3.4%, 3.7%, and 3.6%) versus ≈1% in the low-risk groups (0.8%, 1.3%, and 1.2%).
CONCLUSIONS:Patients closer to their most recent MI, with multiple prior MIs, or with residual multivessel coronary artery disease are at high risk for major vascular events and experience substantial risk reductions with low-density lipoprotein cholesterol lowering with evolocumab.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT01764633.
The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab reduced LDL cholesterol and cardiovascular events in the FOURIER trial. In this prespecified analysis of FOURIER, we ...investigated the efficacy and safety of evolocumab by diabetes status and the effect of evolocumab on glycaemia and risk of developing diabetes.
FOURIER was a randomised trial of evolocumab (140 mg every 2 weeks or 420 mg once per month) versus placebo in 27 564 patients with atherosclerotic disease who were on statin therapy, followed up for a median of 2·2 years. In this prespecified analysis, we investigated the effect of evolocumab on cardiovascular events by diabetes status at baseline, defined on the basis of patient history, clinical events committee review of medical records, or baseline HbA
of 6·5% (48 mmol/mol) or greater or fasting plasma glucose (FPG) of 7·0 mmol/L or greater. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularisation. The key secondary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. We also assessed the effect of evolocumab on glycaemia, and on the risk of new-onset diabetes among patients without diabetes at baseline. HbA
was measured at baseline then every 24 weeks and FPG was measured at baseline, week 12, week 24, and every 24 weeks thereafter, and potential cases of new-onset diabetes were adjudicated centrally. In a post-hoc analysis, we also investigated the effects on glycaemia and diabetes risk in patients with prediabetes (HbA
5·7-6·4% 39-46 mmol/mol or FPG 5·6-6·9 mmol/L) at baseline. FOURIER is registered with ClinicalTrials.gov, number NCT01764633.
At study baseline, 11 031 patients (40%) had diabetes and 16 533 (60%) did not have diabetes (of whom 10 344 had prediabetes and 6189 had normoglycaemia). Evolocumab significantly reduced cardiovascular outcomes consistently in patients with and without diabetes at baseline. For the primary composite endpoint, the hazard ratios (HRs) were 0·83 (95% CI 0·75-0·93; p=0·0008) for patients with diabetes and 0·87 (0·79-0·96; p=0·0052) for patients without diabetes (p
=0·60). For the key secondary endpoint, the HRs were 0·82 (0·72-0·93; p=0·0021) for those with diabetes and 0·78 (0·69-0·89; p=0·0002) for those without diabetes (p
=0·65). Evolocumab did not increase the risk of new-onset diabetes in patients without diabetes at baseline (HR 1·05, 0·94-1·17), including in those with prediabetes (HR 1·00, 0·89-1·13). Levels of HbA
and FPG were similar between the evolocumab and placebo groups over time in patients with diabetes, prediabetes, or normoglycaemia. Among patients with diabetes at baseline, the proportions of patients with adverse events were 78·5% (4327 of 5513 patients) in the evolocumab group and 78·3% (4307 of 5502 patients) in the placebo group; among patients without diabetes at baseline, the proportions with adverse events were 76·8% (6337 of 8256 patients) in the evolocumab group and 76·8% (6337 of 8254 patients) in the placebo group.
PCSK9 inhibition with evolocumab significantly reduced cardiovascular risk in patients with and without diabetes. Evolocumab did not increase the risk of new-onset diabetes, nor did it worsen glycaemia. These data suggest evolocumab use in patients with atherosclerotic disease is efficacious and safe in patients with and without diabetes.
Amgen.
Abstract
Aims
To investigate the relationship between body mass index (BMI) and outcomes in patients with atrial fibrillation (AF).
Methods and results
In the ENGAGE AF-TIMI 48 trial, patients with ...AF were randomized to warfarin (international normalized ratio 2.0–3.0) or edoxaban. The cohort (N = 21 028) included patients across BMI categories (kg/m2): underweight (<18.5) in 0.8%, normal (18.5 to <25) in 21.4%, overweight (25 to <30) in 37.6%, moderately obese (30 to <35) in 24.8%, severely obese (35 to <40) in 10.0%, and very severely obese (≥40) in 5.5%. In an adjusted analysis, higher BMI (continuous, per 5 kg/m2 increase) was significantly and independently associated with lower risks of stroke/systemic embolic event (SEE) hazard ratio (HR) 0.88, P = 0.0001, ischaemic stroke/SEE (HR 0.87, P < 0.0001), and death (HR 0.91, P < 0.0001), but with increased risks of major (HR 1.06, P = 0.025) and major or clinically relevant non-major bleeding (HR 1.05, P = 0.0007). There was a significant interaction between sex and increasing BMI category, with lower risk of ischaemic stroke/SEE in males and increased risk of bleeding in women. Trough edoxaban concentration and anti-Factor Xa activity were similar across BMI groups >18.5 kg/m2, while time in therapeutic range for warfarin improved significantly as BMI increased (P < 0.0001). The effects of edoxaban vs. warfarin on stroke/SEE, major bleeding, and net clinical outcome were similar across BMI groups.
Conclusion
An increased BMI was independently associated with a lower risk of stroke/SEE, better survival, but increased risk of bleeding. The efficacy and safety profiles of edoxaban were similar across BMI categories ranging from 18.5 to >40.
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