Cardioprotective effects of PCSK9 inhibitor evolocumab against doxorubicin-trastuzumab sequential treatments and ipilimumab-induced cardiotoxicity: the role of MyD88/NF-KB/mTORC1 pathways

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
V Quagliariello ◽  
A Caronna ◽  
C Lombari ◽  
A Bonelli ◽  
G Conforti ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Cell Viability ◽  
Statin Therapy ◽  
Cardiovascular Events ◽  
Lipid Lowering ◽  
Funding Source ◽  
Pcsk9 Inhibitor ◽  
Fetal Cardiomyocytes ◽  
Cardioprotective Effects ◽  
Sequential Treatments

Abstract Introduction Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel therapy to treat hypercholesterolaemia and related cardiovascular diseases. Evolocumab, a PCSK9 inhibitor, reduced the risk of cardiovascular events in patients with atherosclerotic cardiovascular diseases when added to maximally tolerated statin therapy (± ezetimibe), and recent data from the ODYSSEY OUTCOMES trial indicate that alirocumab added to maximally tolerated statin therapy (± other lipid-lowering drugs) reduces the risk of cardiovascular events in patients with a recent acute coronary syndrome. Purpose Considering the expression of PCSK9 in heart tissue, we aimed to study for the first time the direct biochemical effects of evolocumab in cardiomyocytes during exposure to doxorubicin, trastuzumab, their sequential treatments, and immune checkpoint inhibitor ipilmumab. Methods Human fetal cardiomyocytes (HFC cell line) were exposed to subclinical concentration of doxorubicin, trastuzumab, sequential treatment of both ( all 100 nM), alone or in combination with evolocumab (50 nM) for 48h. In another experiment, in co-coltures of human fetal cardiomyocytes and lymphocytes, we incubated ipilimumab (200 nM) alone or in combination with evolocumab for 48h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). Results Evolocumab co-incubated with doxorubicin alone or in sequence with trastuzumab exerts cardioprotective effects, enhancing cell viability of 35–43% compared to untreated cells (p<0,05 for all); Cardiomyocytes co-incubated withevolocumab and ipilimumab (in co-colture of cardiomyocytes and lymphocytes) reduces significantly the cardiotoxicity phenomena through MyD88/NF-KB/cytokines axis and mTORC1 Fox01/3α mediated mechanisms. Conclusion We demonstrated, for the firts time, that PCSK9 inhibitor evolocumab exerts direct effects in cardiomyocytes during doxorubicin, trastuzumab and ipilimumab mediated cardiotoxicity turning on a new light on its possible use in the management of the cardiotoxic effects of antineoplastic drugs in cancer patients Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was funded by the “Ricerca Corrente” grant from the Italian Ministry of Health

PCSK9 inhibitor evolocumab to increase anticancer activities and reduce cardiotoxicity during doxorubicin and trastuzumab, as sequential treatment, through MyD88/NF-kB/mTORC1 pathways.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15039-e15039
Author(s):  
Vincenzo Quagliariello ◽  
Simona Buccolo ◽  
Martina Iovine ◽  
Andrea Paccone ◽  
Annamaria Bonelli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cardiovascular Diseases ◽  
Cell Viability ◽  
Statin Therapy ◽  
Cancer Cells ◽  
Cardiovascular Events ◽  
Breast Cancer Cells ◽  
Sequential Treatment ◽  
Pcsk9 Inhibitor ◽  
Her2 Breast Cancer

e15039 Background: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel therapy to treat hypercholesterolaemia and related cardiovascular diseases. Evolocumab, a PCSK9 inhibitor, reduced the risk of cardiovascular events in patients with atherosclerotic cardiovascular diseases when added to maximally tolerated statin therapy (± ezetimibe), and recent data from the ODYSSEY OUTCOMES trial indicate that alirocumab added to maximally tolerated statin therapy (± other lipid-lowering drugs) reduces the risk of cardiovascular events in patients with a recent acute coronary syndrome. Methods: Human fetal cardiomyocytes (HFC cell line), human HER2+ breast cancer cells were exposed to subclinical concentration of doxorubicin, trastuzumab, sequential treatment of both (all 100 nM), alone or in combination with evolocumab (50 nM) for 24 and 48h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). Results: Evolocumab co-incubated with doxorubicin alone or in sequence with trastuzumab exerts cardioprotective effects, enhancing cell viability of 35-43% compared to untreated cells (p < 0,05 for all); in cardiomyocytes Evolocumab reduced significantly the cardiotoxicity through MyD88/NF-KB/cytokines axis and mTORC1 Fox01/3α mediated mechanisms. In human HER2+ breast cancer cells, co-exposure of Evolocumab with doxorubicin and trastuzumab increased significantly cell apoptosis and necrosis through the involvement of key cytokines involved in chemoresistence. Conclusions: We demonstrated, for the first time, that the PCSK9 inhibitor evolocumab exerts direct effects in cardiomyocytes and human HER2+ breast cancer cells during doxorubicin and trastuzumab exposure turning on a new light on its possible use in the management of breast cancer therapies.

scholarly journals Real-world data on metabolic effects of PCSK9 inhibitors in a tertiary care center in patients with and without diabetes mellitus

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Laurenz T. Fischer ◽  
Daniel A. Hochfellner ◽  
Lisa Knoll ◽  
Tina Pöttler ◽  
Julia K. Mader ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Real World ◽  
Cardiovascular Events ◽  
Care Center ◽  
Tertiary Care ◽  
Lipid Lowering ◽  
Tertiary Care Center ◽  
Pcsk9 Inhibitors ◽  
Real World Data ◽  
Pcsk9 Inhibitor

Abstract Background The lipid-lowering and positive cardiovascular effect of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors was shown in several studies, hence, they are more widely used in the lipid-lowering management of individuals with high cardiovascular risk. As real-world data are still scarce, specifically in patients with type 2 diabetes (T2D), the aim of this retrospective analysis was to investigate the efficacy of PCSK9 inhibitors in lowering low-density lipoprotein cholesterol (LDL-C) in an outpatient clinic of a tertiary care center in routine care. Methods A retrospective analysis of data extracted from the electronic patient record was performed. Patients who were routinely prescribed with PCSK9 inhibitor therapy (alirocumab or evolocumab) during the years 2016 and 2019 were included in the analysis. Characteristics of the patient population, the effects on LDL-C and HbA1c levels as well as subsequent cardiovascular events were assessed over an observation period of 18 months. Results We identified 237 patients treated with PCSK9 inhibitors between January 2016 and September 2019. Almost all patients (97.5%) received PCSK9 inhibitors for secondary prevention. 26.2% of the population had a concomitant diabetes diagnosis. Intolerance to statins (83.1%), ezetimibe (44.7%) or both agents (42.6%) was reported frequently. Three months after initiation of PCSK9 inhibitor therapy, 61.2% of the patients achieved LDL-C levels < 70 mg/dl, and 44.1% LDL-C levels < 55 mg/dl. The median LDL-C was lowered from 141 mg/dl at baseline, to 60 mg/dl after 3 months and 66 mg/dl after 12 months indicating a reduction of LDL-C as follows: 57.5% after 3 months and 53.6% after 12 months. After 3 months of observation, target achievement of LDL-C was higher in patients with T2D compared to non-diabetes patients; < 55 mg/dl: 51% vs. 41.5%; < 70 mg/dl 69.4 vs. 58.5%. After 12 months even more pronounced target LDL achievement in T2D was demonstrated < 55 mg/dl: 58.8% vs. 30.1%; < 70 mg/dl 70.6 vs. 49.6%. Patients with insufficiently controlled T2D (HbA1c > 54 mmol/mol) had a higher reduction in LDL-C but still were more likely to subsequent cardiovascular events. Conclusions Significant reductions in LDL-C and a high percentage of patients achieving recommended treatment targets were observed. The percentage of patients with T2D meeting recommended LDL-C targets was higher than in those without T2D. Still some patients did not achieve LDL-C levels as recommended in current guidelines. Special attention to the characteristics of these patients is required in the future to enable achievement of treatment goals and avoid adverse cardiovascular outcomes.

scholarly journals Pooled safety and efficacy of inclisiran in patients with statin intolerance (ORION-10 and ORION-11)

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R.S Wright ◽  
D Kallend ◽  
F.J Raal ◽  
R Stoekenbroek ◽  
W Koenig ◽  
...  
Keyword(s):  
Statin Therapy ◽  
Therapeutic Option ◽  
Lipid Lowering ◽  
Funding Source ◽  
Lipid Lowering Therapy ◽  
Statin Intolerance ◽  
Private Company ◽  
Phase 3 ◽  
Absolute Reduction ◽  
Secondary Endpoints

Abstract Introduction Statin-associated side effects prevent a substantial proportion of patients from being adequately treated with statin therapy and achieving adequate LDL-C reductions. Phase 3 trials showed that inclisiran, a new siRNA, durably lowers LDL-C by ≥50% on top of maximally tolerated statin therapy. Purpose To evaluate inclisiran's tolerability and LDL-C lowering effects among individuals who were not receiving statin therapy mainly because of statin intolerance. Methods The Phase 3 ORION-10 and ORION-11 trials randomized patients with established ASCVD (or risk-equivalents) with LDL-C &gt;70 mg/dl despite maximally tolerated statins to inclisiran or placebo (1:1). Inclisiran sodium 300 mg was administered s.c. at baseline, three months later, then every six months. The primary efficacy endpoints were % change in LDL-C from baseline to Day 510 and time adjusted % change in LDL-C from baseline after Day 90 and up to Day 540. Absolute LDL-C reductions were secondary endpoints. This analysis included individuals who were not on statin therapy at baseline. Results The trials included 252 (7.9% of the pooled trial populations; mean age 68; male 62%; lipid-lowering therapy 28%). AE rates and LDL-C reductions are shown in the Table. Overall, 12 (4.7%) patients had myalgia (4.8% in the inclisiran groups, 4.7% in the placebo groups). There were 8 discontinuations in the inclisiran groups (6.5%) and 3 in the placebo groups (2.3%). The placebo-adjusted mean reduction in LDL-C at Day 510 was 45.8%, an absolute reduction of 68.0 mg/dL (p&lt;0.0001). Conclusion Among statin intolerant individuals in ORION-10 and 11, inclisiran potently and durably lowered LDL-C with an adverse event profile comparable to placebo. Inclisiran may represent a new and potent therapeutic option for patients with elevated LDL-C unable to tolerate statins. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): The Medicines Company

Prognostic impact of cascade screening for familial hypercholesterolemia on cardiovascular events

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Tada ◽  
H Okada ◽  
A Nomura ◽  
A Nohara ◽  
M Yamagishi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Familial Hypercholesterolemia ◽  
Cardiovascular Events ◽  
Lipid Lowering ◽  
Funding Source ◽  
Atherosclerotic Cardiovascular Disease ◽  
Prognostic Impact ◽  
Cascade Screening ◽  
Ascvd Risk ◽  
The Impact

Abstract Background Early diagnosis and timely treatment for the patients with familial hypercholesterolemia (FH) can substantially lower the risk of atherosclerotic cardiovascular disease (ASCVD). In this sense, cascade screening could be one of the most useful options. However, few data exist regarding the impact of cascade screening for FH on the reduction of risk of ASCVD events. Objectives We aimed to evaluate the prognostic impact of cascade screening for FH. Methods We retrospectively investigated the health records of 1,050 patients with clinically diagnosed FH, including probands and their relatives who were cascade-screened. We used Cox models that were adjusted for established ASCVD risk factors to assess the association between cascade screening and major adverse cardiovascular events (MACE). The median period of follow-up was 12.3 years (interquartile range [IQR] = 9.1–17.5 years), and MACE included death from any causes or hospitalization due to ASCVD events. Results During the observation period, 246 participants experienced MACE. The mean age of patients identified through cascade screening was 18-years younger than that of the probands (38.7 yr vs. 57.0 yr, P&lt;0.001), with a lower proportion of ASCVD risk factors. Interestingly, patients identified through cascade screening under milder lipid-lowering therapies were at reduced risk for MACE (hazard ratio [HR] = 0.36; 95% CI = 0.22 to 0.60; P&lt;0.001) when compared with the probands, even after adjusting for those known risk factors. Conclusions The identification of patients with FH via cascade screening appeared to result in better prognoses. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Scientific research grants from the Ministry of Education, Science and Culture of Japan (no. 16K19394, 18K08064, and 19K08575)

P5015Efficacy of lipid lowering therapy beyond statins to prevent cardiovascular events: A meta-analysis

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
I Dykun ◽  
R Mincu ◽  
M Totzeck ◽  
T Rassaf ◽  
A A Mahabadi
Keyword(s):  
Myocardial Infarction ◽  
Relative Risk ◽  
Statin Therapy ◽  
Risk Reduction ◽  
Cardiovascular Events ◽  
Ldl Cholesterol ◽  
Meta Analysis ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Lowering Therapy

Abstract Background Lipid lowering therapy is a key cornerstone in secondary prevention of patients with coronary artery disease. However, only a minority of patients with statin therapy reach LDL thresholds as suggested by the ESC. Ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors allow for reduction in LDL-cholesterol in addition to statin therapy. Purpose To perform a meta-analysis of existing trials, evaluating how lipid lowering therapy beyond statins impacts cardiovascular outcome. Methods We performed a systematic search using the Pubmed, Cochrane, SCOPUS, and Web of Science databases for studies, evaluating the impact of an intensified lipid lowering therapy via ezetimibe or PCSK-9 inhibitor in addition to statin therapy compared to statin therapy alone. Manuscript and congress presentations, published until 1st of November 2018, were included. We made our search specific and sensitive using Medical Subject Headings terms and free text and considered studies published in English language. Search terms used were “ezetimibe”, “evolocumab”, “alirocumab”, or “bococizumab” and “cardiovascular events”. Results A total of 100,610 patients from 9 randomized controlled trials (IMPROVE-IT, FOURIER, ODYSSEY Outcomes, SIPRE I, SPIRE II, ODYSSEY LONG TERM, OSLER-1 and OSLER-2, HIJ-PROPER) were included. Treatment with ezetimibe or a PCSK-9 inhibitor was associated with a 18% risk reduction in cardiovascular events (OR [95% CI]: 0.82 [0.75–0.89]). Effect sizes were similar for myocardial infarction (0.84 [0.76–0.92]) and even more pronounced for ischemic stroke (0.77 [0.67–0.83]). In contrast, all-cause mortality was not improved by the intensified lipid lowering therapy (0.94 [0.85–1.05]). No relevant heterogeneity and inconsistency between groups was present in all analyses (detailed data not shown). Comparing efficacy of LDL-reduction and relative risk redaction of cardiovascular events, a linear relationship was observed (figure). Figure 1. Correlation of reduction of LDL-cholesterol at one year with relative risk reduction (95% confidence interval) of cardiovascular events in included trials. Conclusion Intensified LDL-lowering therapy with ezetimibe or PCSK-9 inhibitors, in addition to statins, reduces the risk of myocardial infarction and stroke, however, does not impact overall mortality. There is a linear relationship between LDL reduction and cardiovascular risk reduction, confirming the beneficial effects of LDL lowering therapy beyond statins in secondary prevention.

scholarly journals Cardiovascular outcomes trials with statins in diabetes

2018 ◽  
Vol 18 (1) ◽  
pp. 7-13 ◽  
Author(s):  
Fariha Naeem ◽  
Gerard McKay ◽  
Miles Fisher
Keyword(s):  
Cardiovascular Disease ◽  
Side Effects ◽  
Primary Prevention ◽  
Secondary Prevention ◽  
Statin Therapy ◽  
Cardiovascular Events ◽  
Atherosclerotic Disease ◽  
Lipid Lowering ◽  
High Dose ◽  
Drug Side Effects

Treatment with statins is one of the most effective ways of reducing cardiovascular events in those with diabetes. Many studies containing thousands of subjects with diabetes have demonstrated that statins reduce cardiovascular events when there is no known cardiovascular disease (primary prevention) and in those with confirmed atherosclerotic disease (secondary prevention). High-dose statins appear to be even more effective in established cardiovascular disease, but at the expense of increased drug side effects. In this paper we review the evidence for the benefits of statins in diabetes. In a second review we will examine the evidence for possible benefits of other lipid-lowering therapies when these are added to background statin therapy in diabetes.

scholarly journals PCSK9 inhibitors for in-hospital treatment of patients with acute coronary syndrome and severe lipid metabolism disorders

2020 ◽  
Vol 25 (8) ◽  
pp. 4010
Author(s):  
O. L. Barbarash ◽  
N. V. Fedorova ◽  
D. Yu. Sedykh ◽  
O. V. Gruzdeva ◽  
O. N. Khryachkova ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Statin Therapy ◽  
Lipid Lowering ◽  
High Density Lipoproteins ◽  
Hospital Treatment ◽  
Lipid Lowering Therapy ◽  
Pcsk9 Inhibitor ◽  
Coronary Syndrome ◽  
Lowering Therapy ◽  
Baseline Values

Aim. To assess the efficacy and safety of PCSK9 inhibitor alirocumab as part of a combination lipid-lowering therapy in patients with acute coronary syndrome (ACS).Material and methods. This prospective, open-label, single-center activetreatment study included 13 patients hospitalized due to ACS. The main inclusion criterion was nonachievement of target low-density lipoprotein cholesterol (LDL-C) values (<1,4 mmol/L) with high-intensity statin therapy prior to ACS. During the first 30 days after ACS, all patients received therapy with atorvastatin 40-80 mg/day or rosuvastatin 20-40 mg/day in combination with alirocumab 150 mg/ml (Praluent) administered by subcutaneous injection. Lipid and biochemical profiles were monitored. The first injection of the PCSK9 inhibitor was performed on days 3-5 of hospitalization, the second — after 2 weeks.Results. On admission, the median LDL-C was 4,3 [3,5;5,3] mmol/L. A day after administration, there was a decrease in LDL-C by 41,9% (median 2,5 [1,8;3,2] mmol/L; p=0,001) without a negative effect on high-density lipoproteins (HDL-C) (median 1,2 [0,8;1,4] mmol/L; p=0,270). Before the next injection, LDL-C decreased by another 8% (median 2,3 [1,1;4,1] mmol/L). A day after the second injection, a decrease in LDL-C from the baseline values was 69,8% (median 1,3 [0,7;1,5] mmol/L; p=0,010). Strengthening lipid-lowering therapy with a PCSK9 inhibitor within 30 days after ACS did not lead to clinical and biochemical deterioration.Conclusion. The use of subcutaneous 150-mg injections of alirocumab 2 times a week 30 days after ACS in patients who did not reach target LDL-C values with statin therapy, leads to a 69% decrease in LDL-C from baseline values and is safe.

scholarly journals Cardiovascular outcomes trials with non-statin lipid-lowering drugs in diabetes

2018 ◽  
Vol 18 (3) ◽  
pp. 101-105
Author(s):  
Fariha Naeem ◽  
Gerard McKay ◽  
Miles Fisher
Keyword(s):  
Statin Therapy ◽  
Cardiovascular Events ◽  
Ldl Cholesterol ◽  
Lipid Lowering ◽  
High Dose ◽  
Large Trial ◽  
Pcsk9 Inhibitors ◽  
Vascular Events ◽  
Lipid Lowering Drugs ◽  
Cardiovascular Morbidity And Mortality

Statin therapy is proven to reduce cardiovascular morbidity and mortality in people with diabetes, and high-dose statins are recommended for people with established atherosclerotic vascular disease. In two dedicated studies in people with diabetes, fibrates did not significantly reduce cardiovascular events and were associated with serious side effects. A similar lack of benefit was seen in two large studies of niacin. Ezetimibe, when added to statins, may further reduce LDL cholesterol and non-fatal vascular events. The PCSK9 inhibitors are a new class of subcutaneous lipid- lowering drugs which cause profound reductions in LDL cholesterol when added to statins. Evolocumab reduced non-fatal cardiovascular events when added to background statin therapy in a larger group of subjects and the benefits were confirmed in a diabetes subgroup. In another large trial alirocumab reduced major adverse cardiovascular events and total mortality. The clinical use of ezetimibe and PCSK9 inhibitors is currently limited by cost.

Effect of evolocumab on acute arterial events across all vascular territories : results from the FOURIER trial

2021 ◽  
Author(s):  
Kazuma Oyama ◽  
Robert P Giugliano ◽  
Minao Tang ◽  
Marc P Bonaca ◽  
Jeffrey L Saver ◽  
...  
Keyword(s):  
Statin Therapy ◽  
Lipid Lowering ◽  
Atherosclerotic Cardiovascular Disease ◽  
Limb Ischaemia ◽  
Lipid Lowering Therapy ◽  
Peripheral Vascular ◽  
Pcsk9 Inhibitor ◽  
Acute Limb Ischaemia ◽  
The Impact ◽  
Over Time

Abstract Aims We assessed the impact of the proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor evolocumab on acute arterial events across all vascular territories, including coronary, cerebrovascular, and peripheral vascular beds, in patients with established atherosclerotic cardiovascular disease (ASCVD). Methods and results In the FOURIER trial, 27 564 patients with stable ASCVD on statin therapy were randomly assigned to evolocumab or placebo. Acute arterial events were a composite of acute coronary (coronary heart disease death, myocardial infarction, or urgent coronary revascularization), cerebrovascular (ischaemic stroke, transient ischaemic attack, or urgent cerebral revascularization), or peripheral vascular (acute limb ischaemia, major amputation, or urgent peripheral revascularization) events. Of the 2210 first acute arterial events, 74% were coronary, 22% were cerebrovascular, and 4% were peripheral vascular. Evolocumab reduced first acute arterial events by 19% (hazard ratio [HR] 0.81 [95% confidence interval 0.74–0.88]; P &lt; 0.001), with significant individual reductions in acute coronary (HR 0.83 [0.75–0.91]), cerebrovascular (HR 0.77 [0.65–0.92]), and peripheral vascular (HR 0.58 [0.38–0.88]) events. There were 3437 total events (first plus recurrent), with evolocumab reducing total events by 24% (incidence rate ratio 0.76 [0.69–0.85]). The magnitude of reduction in acute arterial events with evolocumab numerically increased over time, with a 16% reduction (HR 0.84 [0.75–0.95]) in the first year followed by a 24% reduction (HR 0.76 [0.67–0.85]) thereafter. Conclusion The addition of the PCSK9 inhibitor evolocumab to statin therapy reduced acute arterial events across all vascular territories with a robust effect over time, indicating a pan-vascular impact of aggressive lipid-lowering therapy on these acute and clinically meaningful events. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633.

Abstract 15913: Two-year Results of the Getting to an Improved Understanding of Low-density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD) Registry of Patients With Atherosclerotic Cardiovascular Disease (ASCVD)

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Christopher P Cannon ◽  
James A De Lemos ◽  
Christie M Ballantyne ◽  
Robert S Rosenson ◽  
Shushama Alam ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Statin Therapy ◽  
Treatment Guidelines ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Atherosclerotic Cardiovascular Disease ◽  
Lipid Lowering Therapy ◽  
Pcsk9 Inhibitor ◽  
Statin Dose

Background: Atherosclerotic cardiovascular disease (ASCVD) treatment guidelines recommend intensive statin therapy and adding non-statin therapy if LDL-C ≥70 mg/dL. Methods: We designed the GOULD registry to assess lipid-lowering therapy (LLT) over time: At 120 U.S. centers, 5006 ASCVD patients on any (LLT) were enrolled in 1 of 3 cohorts: 1) currently on PCSK9 inhibitor (PCSK9i), 2) no PCSK9i and LDL-C ≥100 mg/dL, and 3) no PCSK9i and LDL-C 70-99 mg/dL. Results: Over the two years, only 16.8% had some type of LLT intensification, In the cohorts of patients with baseline LDL-C ≥ 100 and 70-99 mg/dL, LLT intensification was present in 21.9% and 14.3% respectively: statin dose was intensified in 6.1% and 6.1%, ezetimibe was added in 6.8% and 4.3% and PCSK9i was added in 6.3% and 2.2% respectively. Conversely, out of the total population, statins were discontinued in 246/4275 (5.8%), ezetimibe in 81/535 (15.1%), and PCSK9i in 47/544 (8.6%). At 24 months, 83.7% were on statin (43.4% high-intensity), with 14.2% on ezetimibe. Lipid panels were measured in 73% by 1 year and 84% by 2 years. Among Pts in the LDL-C ≥100 and 70-99 mg/dL cohorts, 18.6% and 30.4% achieved an LDL-C <70 mg/dL by 1 year, with little further change by 2 years: 21.3% and 33.5% respectively. In the PCSK9 cohort, 53.2% had LDL-C<70 mg/dl. Overall, only 31.7% had LDL-C <70 mg/dL at 2 years (an increase from 6.7% at baseline), while 25.0% had LDL-C >100 mg/dL. Conclusion: Of ASCVD patients with suboptimal LDL-C at baseline, even after 2 years of follow up, strikingly only 16% had LLT intensification, and thus most remained uncontrolled. Further intensive efforts are needed to achieve optimal LDL management in patients with ASCVD.

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