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Lipid-Lowering Therapy in Patients with Coronary Heart Disease and Prior Stroke: Mission Impossible?

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Lipid-Lowering Therapy in Patients with Coronary Heart Disease and Prior Stroke: Mission Impossible? Journal of Clinical Medicine Review Lipid-Lowering Therapy in Patients with Coronary Heart Disease and Prior Stroke: Mission Impossible? Pier Luigi Temporelli 1,*, Marcello Arca 2, Laura D’Erasmo 2 and Raffaele De Caterina 3,4 1 Division of Cardiology, Istituti Clinici Scientifici Maugeri, IRCCS, Via Revislate 13, 28013 Gattico-Veruno, Italy 2 Department of Translational and Precision Medicine, Sapienza University of Rome, Viale dell’Università 37, 00161 Roma, Italy; [email protected] (M.A.); [email protected] (L.D.) 3 Chair of Cardiology, Cardiovascular Division, Pisa University Hospital, University of Pisa, Via Paradisa 2, 56126 Pisa, Italy; [email protected] 4 Fondazione Villa Serena per la Ricerca, 65013 Città Sant’Angelo, Italy * Correspondence: [email protected]; Tel.: +39-0322-884711 Abstract: Hyperlipidemia is a powerful risk factor for coronary heart disease (CHD). It has been known for a long time that lipid-lowering drugs significantly reduce morbidity from CHD, thus proving a causal role for cholesterol in coronary events. Conversely, the relationship between low- density lipoprotein cholesterol (LDL-C) levels and stroke has been less clear and debated for many years. Recent data conclusively demonstrate not only the inverse epidemiological relationship of blood LDL-C with stroke, but also the efficacy of different strategies to attain cholesterol-lowering on stroke. They also dissipate lingering doubts about the possibility that lipid-lowering is linked to an increase in hemorrhagic stroke. However, despite current international lipid guidelines now strongly recommend aggressive lipid-lowering therapy in patients with atherosclerotic cardiovascular disease, including CHD and cerebrovascular disease (CeVD), secondary prevention patients are often undertreated with lipid-lowering therapies in routine clinical practice. This review highlights that Citation: Temporelli, P.L.; Arca, M.; D’Erasmo, L.; De Caterina, R. patients with CHD and concomitant CeVD do not receive aggressive lipid-lowering therapy despite Lipid-Lowering Therapy in Patients being at very high risk and with clear evidence of benefit from lowering LDL-C levels below current with Coronary Heart Disease and targets. Prior Stroke: Mission Impossible? J. Clin. Med. 2021, 10, 886. https:// Keywords: coronary heart disease; stroke; lipid-lowering therapy; cholesterol; triglycerides doi.org/10.3390/jcm10040886 Academic Editor: Leonardo De Luca 1. Introduction Received: 5 January 2021 Atherosclerotic cardiovascular disease currently accounts for the majority of deaths Accepted: 18 February 2021 in most parts of the world [1]. Within the realm of cardiovascular disease, coronary heart Published: 22 February 2021 disease (CHD) and stroke are the number 1 and number 3 causes of death, respectively. Hyperlipidemia is a powerful risk factor for CHD [2]. It has been known for a long Publisher’s Note: MDPI stays neutral time that nonpharmacological as well as pharmacological cholesterol-lowering treatments with regard to jurisdictional claims in significantly reduce morbidity from CHD, thus proving a causal role for cholesterol in published maps and institutional affil- iations. coronary events. Conversely, the relationship between cholesterol levels and stroke has been less clear and debated for many years [3]. Anyhow, current international lipid guidelines now strongly recommend lipid-lowering therapy for secondary prevention in patients with atherosclerotic cardiovascular disease (ASCVD), including CHD and cerebrovascular disease (CeVD) [4,5]. Copyright: © 2021 by the authors. Despite the overwhelming evidence that reducing low-density lipoprotein cholesterol Licensee MDPI, Basel, Switzerland. (LDL-C) levels is highly beneficial in preventing recurrent ischemic events, secondary This article is an open access article prevention patients are often undertreated with lipid-lowering therapies in community distributed under the terms and conditions of the Creative Commons practice [6–9]. While appropriate statin therapy is an important goal in patients with Attribution (CC BY) license (https:// CHD, it is still unclear whether CeVD patients are treated differently [7]. Furthermore, creativecommons.org/licenses/by/ patients with CHD may have multisite artery disease involving additional vascular beds, 4.0/). including CeVD and/or peripheral artery disease (PAD), and a direct correlation exists J. Clin. Med. 2021, 10, 886. https://doi.org/10.3390/jcm10040886 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 886 2 of 14 between the number of arterial territories affected by atherosclerosis and the risk for future cardiovascular events [10,11]. Indeed, the presence of CeVD in patients with CHD has been found to be associated with increased long-term major adverse cardiovascular events (MACE). These are highest when the two conditions co-existed. Attainment of LDL-C treatment goals was related to lower risk for adverse events. Nevertheless, a large proportion of CHD patients with CeVD does not achieve lipid goals [7]. Recent guideline updates [4,5] specifically identified the presence of high-risk co- morbidities as scenarios in which the addition of new lipid-lowering therapies should be considered if LDL-C levels remain high despite maximally tolerated statin therapy. Recent randomized controlled trials provide support for these recommendations by showing that, within a relatively short-time frame, these very high-risk patient groups have a lower risk of MACE with lower achieved LDL-C [12–14]. The present narrative review is aimed at updating the available evidence and the dif- ferences in cholesterol-lowering therapy in patients with isolated CHD vs. those with stroke and those with concomitant CHD and stroke, to stimulate a more aggressive approach in reducing LDL-C in all these very high-risk patients. 2. Lipid Lowering Therapy in Patients with Coronary Heart Disease Treatment of derangements in lipid parameters is an essential objective for controlling the risk of cardiovascular complications in patients with established CHD. Numerous components of the lipid profile (LDL-C, triglyceride-rich lipoproteins (TGL), apolipoprotein B (apoB), lipoprotein (Lp) (a) and high-density lipoproteins (HDL)) have been identified as targets for therapy. Here, however, we will focus only on those with the largest body of evidence and with the widest acceptance in daily clinical practice. 2.1. Lowering LDL-Cholesterol: The Cornerstone of Lipid-Lowering Therapy Since the pivotal Scandinavian Simvastatin Survival Study (4S) study in 1994 [15], many randomized controlled trials have tested the impact of LDL-C lowering interventions on the re-occurrence of ischemic events in patients with history of atherosclerotic CHD. A first summary of these results was reported in 2005 by the Cholesterol Treatment Trialists’ (CTT) Collaborators meta-analysis, where in patients with previous CHD a reduction of 1 mmol/L (38.7 mg/dL) of LDL-C was associated with a 21% relative risk (RR) reduction of recurrent events (RR: 0.79, 95% CI 0.76–0.81) [16]. The role of LDL-C reduction as the main driver of cardiovascular risk reduction in CHD patients has been further reinforced by the demonstration that a more pronounced decrease in LDL-C generates an incremental cardiovascular protection. A comprehen- sive quantification of the benefit of a more intensive vs. less intensive LDL-C lowering has been offered by a further meta-analysis of the CCT Collaborators [17] that included 170,000 patients participating into 26 randomized trials with statins. When in CHD pa- tients less intensive were compared with more intensive regimens, a highly significant 21% further decline in the recurrence of major cardiovascular events was found per 1 mmol/dL (38.7 mg/dL) LDL-C difference at 1-year follow-up. These consistent results represented the basis for recommending the use of high- intensity, high-dose statins in patients with previous CHD [5]. However, this pragmatic approach has been challenged by the observation that these patients even if treated with intense statin regimen remain at high risk if they do not achieve adequate levels of LDL- C[18]. This has opened the way to studies aimed at identifying the level of LDL-C (and the LDL-C lowering strategy) that is associated with the lowest risk of recurrence of ischemic events. In the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE- IT) [12], 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and showing baseline LDL-C of 94 mg/dL were randomized to re- ceive simvastatin (40 mg) or simvastatin (40 mg) plus ezetimibe (10 mg). The average LDL-C during the study was 53.7 mg/dL in the simvastatin plus ezetimibe group as compared with J. Clin. Med. 2021, 10, 886 3 of 14 69.5 mg/dL in the simvastatin-monotherapy group (p < 0.001). This difference translates into a 2% absolute risk reduction for a composite of cardiovascular death, nonfatal myocar- dial infarction, unstable angina requiring rehospitalization, coronary revascularization, or non-fatal stroke (RR: 0.936; 95% CI, 0.89–0.99; p = 0.016). More recent trials with proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), have further evaluated whether cardiovascular protection in CHD patients extends down to very low levels of LDL-C. In the FOURIER study [19], involving 27,564 patients with atherosclerotic cardiovascular disease and LDL-C levels above 70 mg per deciliter when receiving
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