New progress in lipid-lowering therapy for acute coronary syndrome


Expert introduction:
He is the deputy director of the Cardiovascular Center of Qilu Hospital (Qingdao) and the deputy director of the Department of Cardiology, the director of the Atrial Fibrillation Center, the director of the chest pain center, the chief physician, the master tutor of Shandong University, and the doctor of medicine.Engaged in clinical work for nearly 30 years, specializing in the diagnosis and treatment of coronary heart disease, hypertension, arrhythmia, cardiac insufficiency and other diseases.Engaged in the interventional diagnosis and treatment of coronary heart disease for nearly 20 years, can lead the team to complete high-quality and efficient coronary angiography, intravascular ultrasound, coronary interventional therapy including balloon expansion, stent placement, plaque rotation and other technical operations.Acute coronary syndrome (ACS) is a common serious cardiovascular disease and is a serious type of coronary heart disease. It is a rupture or erosion of coronary atherosclerotic plaque, and secondary or completeA group of clinical syndromes with incomplete occlusive thrombosis as a pathological basis, including acute ST-segment elevation myocardial infarction, acute non-ST-segment elevation myocardial infarction, and unstable angina.ACS is a serious and serious disease in cardiovascular disease, with acute onset, dangerous condition, high morbidity and mortality, and is one of the important cardiovascular diseases that threaten human health and life. Although effective reperfusion therapy can reduce mortality,The risk of re-ischemic events and death in these patients is still very high, so it is necessary to further improve the diagnosis and treatment of ACS diseases, and to improve the education and management of patients, which can further effectively reduce the risk of ACS recurrence and help improve the health of residents in China.Lipid-lowering therapy is one of the core elements of ACS treatment.1, ACS lipid-lowering drugs 1.1 statins are the cornerstone of ACS lipid-lowering therapy: statins, also known as 3-hydroxy-3-methylglutaryl-coenzyme A, HMG-CoA) reductase inhibitors, which inhibit the cholesterol synthesis rate-limiting enzyme HMG-CoA reductase, reduce cholesterol synthesis, and then upregulate cell surface LDL receptors and accelerate serum LDL catabolism.The advent of statins in the 1970s opened a new era of coronary heart disease prevention and treatment.In 1976, Japanese biochemist Akira Endo discovered a substance that reduced cholesterol synthesis by 50%, so Akira Endo is also known as the “father of statins.”Since then, statins such as lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin and rosuvastatin have been introduced and marketed for clinical use, and a series of clinical studies have been completed.The 4S clinical trial confirmed for the first time that statins can reduce coronary heart disease mortality and total patient mortality. Later, CARE, LIPID, LIPS and other studies have confirmed the important role of these drugs in secondary prevention of coronary heart disease.HPS studies have shown that statin therapy can benefit from high-risk populations with low baseline cholesterol.Clinical trials of intensive statin therapy include PROVE-IT, A to Z, TNT, MIRACL, and IDEAL. Compared with conventional doses of statins, intensive statin therapy in patients with coronary heart disease can further reduce cardiovascular events, and ASTEROID studies confirm statins.Treatment can reverse coronary atherosclerotic plaque.So many large-scale clinical studies not only provide a reliable basis for the clinical application of statins, but also strongly demonstrate the importance of actively and effectively reducing cholesterol in the prevention and treatment of cardiovascular diseases.From the pathogenesis of ACS, atherosclerotic plaque rupture is the core of ACS cardiovascular events.Most patients with ACS are unstable plaques, like “small dumplings with thin skin stuffing”. The plaque fiber cap is thin, the core of lipid and necrosis is large, very unstable, prone to rupture, and once unstable plaque rupturesThe lipid enters the vascular lumen, causing a blood clotting reaction to form a thrombus. The thrombus causes the lumen to be further narrowed or completely occluded, resulting in ACS, and severe cases may cause sudden death.On the other hand, patients with ACS often have multivessel disease of the coronary artery, not only the lesions of the offender are in a vulnerable state, but also the vulnerable vessels of the non-criminal vessels are vulnerable or ruptured.Studies have shown that after 8 to 10 months of ACS statin treatment, the necrotic core of non-culprit lesions becomes smaller, and the proportion of non-criminal lesions in ACS patients increases significantly after 12 months.In addition, inflammation after ACS lasts for 6 to 12 months.These factors together determine the increased risk of recurrence of events within one year after ACS.Therefore, statins for ACS patients require early, intensive, and long-term applications.The Efficacy of High-Intensity Atorvastatin for Asian Patients Undergoing Percutaneous Coronary Intervention, published in June 2016 for a Chinese population, showed that patients undergoing PCI were preoperatively andHigh-intensity atorvastatin treatment within 1 year after surgery significantly reduced the incidence of MACE (including cardiac death, spontaneous myocardial infarction, and unintended revascularization), especially in patients with ACS receiving high-intensityAtorvastatin treatment will result in better short-term and long-term clinical benefit, and in terms of safety, 40 mg/d atorvastatin is similar to 20 mg/d atorvastatin.1.2 Combination of non-statin drugs reduces the residual risk of cardiovascular events: Despite the high-intensity statin therapy, patients with coronary heart disease still have a considerable residual risk.International data on dyslipidemia China data show that the rate of LDL-C compliance in China’s extremely high-risk patients is still at a low level of only 39.7%.The effect of relying solely on statin doses to double cholesterol lowering is very limited. The statin monotherapy lipid-lowering treatment can reduce the dose by 6%, while at the same time there is a risk of side effects and adverse reactions.According to the theory of cholesterol and the current situation of lipid-lowering therapy in China, it is necessary to rethink how to strengthen lipid-lowering drugs. The lipid-lowering drugs with different combined mechanisms can make patients’ blood lipids more effective and safe.1.2.1 ezetimibe: ezetimibe is a specific intestinal cholesterol absorption inhibitor, which can selectively bind to NPC1L1 protein, so that the latter loses the ability to transport cholesterol, thus specifically inhibiting intestinal cholesterol absorption..Since ezetimibe inhibits exogenous cholesterol absorption, it has a synergistic effect with statins that inhibit endogenous cholesterol synthesis, and the combination of the two can significantly lower cholesterol.The IMPROVE-IT study aims to explore whether ezetimibe and statins reduce LDL-C below 70 mg/dl to further reduce cardiovascular events.A total of 18,144 patients with stable acute coronary syndrome were enrolled and randomized into two groups. One group was treated with ezetimibe/simvastatin (10 mg/40 mg), and the other group was only treated with simvastatin.Statin (40mg) treatment.The results showed that moderate-intensity statin + ezetimibe synergistically reduced LDL-C levels by 24% (P < 0.001) on the basis of statins, and the endpoint event decreased by 6% compared with simvastatin alone.This study confirms that in patients with ACS, a combination of moderate-intensity statin doses plus ezetimibe can further reduce major cardiovascular events.However, intensive statin therapy is usually used for patients with ACS. Is reinforced statin or moderate-intensity statin + ezetimibe for ACS patients?The conclusions from different studies are not completely consistent.According to the 2016 HIJ-PROPE study, in patients with ACS with dyslipidemia, statin combined with second-line cholesterol-lowering drugs for intensive lipid-lowering therapy did not significantly reduce the incidence of major composite endpoints compared with statin monotherapy.The results of an acute myocardial infarction registration study in Korea showed that the "medium-intensity statin + ezetimibe" clinical benefit is not as good as strengthening statins.1.2.2 PCSK9 inhibitors: PCSK9 belongs to the family of proprotein convertases. The main biological function is the degradation of low density lipoprotein receptor (LDLR) at the protein level, which affects the balance of cholesterol metabolism in the body.When PCSK9 inhibits the action of LDLR, blood LDL-C levels increase.Therefore, blocking the binding of PCSK9 to LDLR has become a new therapeutic target for hypercholesterolemia.The 2017 FOURIER study included 27,564 patients with previous myocardial infarction, ischemic stroke, or symptomatic peripheral arterial disease, and patients with LDL-C ≥70 mg/dL or non-HDL-C≥100 mg/dL based on optimized statin therapy.The results showed that the primary end point of the combination of PCSK9 inhibitor Evolocumab decreased by 15%, and the incidence of cardiovascular death, MI and stroke decreased by 20%.There are continuing benefits in patients with high-intensity statin therapy and low LDL-C.The group's cardiovascular death, MI and stroke rate decreased by 25% a year later, and safety and tolerance were good.The study once again confirmed that a strong cholesterol lowering level can bring significant clinical benefits.The EVOPACS study was the first to study the acute phase (1-3 days) of PCSK9 inhibitors in patients with ACS, and to evaluate the effectiveness of ilyuximab compared with placebo in the acute phase of LDL-C reduction in ACS after 8 weeks.Sex and safety.The results suggest that ilujuximab significantly increased the rate of LDL-C compliance: more than 95% of patients in the Yiluo's monoclonal antibody group met the standard after 8 weeks, compared with 38% of the control group.Ellozumab reduced LDL-C by 77% relative to baseline and was safe and did not differ significantly from the control group.Although this study did not endemic events, the researchers believe that PCSK9 inhibitors such as ilujuxab may be a new paradigm for ultra-early lipid-lowering in the acute phase of ACS patients, and further cardiovascular events are necessary in the future.A related study for the end point.2, ACS patients with lipid-lowering goals and guidelines recommended in Europe and the United States and China's blood lipids guidelines, ACS are listed in very high-risk groups, usually in the guidelines for very high-risk groups of LDL-C target LDL-C <1.8 mmol / L (70 mg/dl) or a reduction of ≥50%, but based on new clinical research evidence, the latest European and American guidelines have updated ASCVD risk stratification and target recommendations.In 2019, ESC "Guidelines for the Management of Dyslipidemia: Actively Strengthening Lipid-lowering and Reducing Cardiovascular Risk" pointed out that in the case of secondary prevention in very high-risk patients, it is recommended that LDL-C be reduced by ≥50% from baseline and LDL target value is <1.4Mmmol/L (<55mg/dL) (recommended in category IA); for primary prevention in patients with very high risk of familial hypercholesterolemia, it is recommended that LDL-C be reduced by ≥50% from baseline and LDL target value is <1.4Mmmol/L (<55mg/dL) (IC recommended); in the case of taking the maximum tolerated dose of statin, if the ASCVD patient still has a second cardiovascular adverse event within 2 years (may be different from the first1 time), the target value of LDL-C can be considered to be 1.0 mmol/L (40 mg/dL) (IIb Class B recommendation).For all patients with ACS, regardless of LDL-C levels, high-dose statins should be initiated or continued as early as possible if not contraindicated (IA recommended); if 4-6 weeks later, the patient is receiving the maximum tolerated dose of statin therapyOn the LDL-C, LDL-C is still not up to standard. It is recommended to use ezetimibe (IB recommended). If 4-6 weeks later, the patient is treated with the maximum tolerated dose of statin combined with ezetimibe, LDL-C is still not up to standard, it is recommended to add PCSK9 inhibitor (class IB recommended); for patients with clear statin intolerance or the use of statin contraindications, consider using ezetimibe (IIa C recommended); ACS patientsLDL-C did not reach the target value after treatment with the maximum tolerated dose of statin plus ezetimibe, and PCSK9 inhibitors (IIa Class C recommendation) were considered for early (even during hospitalization).Based on the latest clinical research results and the update of European and American guidelines, the concept of “super high-risk population” was proposed in China's “2019 CCEP lipid-lowering therapy to reduce cardiovascular events”, including recurrent ASCVD events and coronary multivessel disease., recent ACS and more.The target of ultra-high-risk LDL-C is <1.4 mmol/L (55 mg/dl) or the reduction range is ≥50%. If the combination therapy of LT-TLD-C is still ≥1.4 mmol/L (55 mg/dl), it is recommended to add PCSK9.Inhibitor.If it is predicted that statin and other combination therapy can not achieve the patient's LDL-C standard, it can also directly initiate the combination of statin and PCSK9 inhibitor.. 3, lifestyle interventions Lipid abnormalities are significantly affected by diet and lifestyle, diet therapy and lifestyle improvement are the basic measures for the treatment of dyslipidemia.Lifestyle intervention is a treatment of the best cost/benefit ratio and risk/benefit ratio.Lifestyle interventions include the use of unsaturated fatty acids when the total amount of saturated and trans fatty acids ingest exceeds the prescribed upper limit, based on the daily essential nutrient and total energy requirements.It is recommended that the daily intake of cholesterol is less than 300 mg, especially in high-risk patients such as ASCVD. The intake of fat should not exceed 20% to 30% of total energy, and the intake of saturated fatty acids in hypercholesterolemia should be less than 7% of total energy.Trans fatty acid intake should be less than 1% of total energy.Fat intake should be preferred for foods rich in n-3 polyunsaturated fatty acids (such as deep-sea fish, fish oil, vegetable oil).It is recommended that daily intake of carbohydrates be 50%-65% of total energy.Choose to replace saturated fatty acids with carbohydrates rich in dietary fiber and low glycemic index. The intake of carbohydrates is mainly cereals, potatoes and whole grains, and the added sugar intake should not exceed 10% of the total energy.Controlling body weight and maintaining a healthy weight (BMI: 20.0-23.9 kg/m2) is beneficial for blood lipid control.For post-recovery of patients with ACS, it is recommended that moderate-intensity metabolic exercise be performed every 5-7 days per week for 30 minutes, but exercise stress test should be performed first, and the safety should be fully evaluated before physical activity.Strictly quit smoking and limit drinking.After more than 100 years of continuous exploration, cholesterol theory has been deeply rooted in people's minds. The lipid-lowering therapy for patients with ACS to reduce LDL-C is still an important core of ACS treatment. Strengthening statin is still the first choice for blood lipid management in patients with ACS.-C is reduced to 50% or more. Intensive statin treatment of blood lipids is not up to standard, and can be further combined with ezetimibe, PCSK9 inhibitors and other drugs. In the future, more new drugs and new clinical research are expected to promote the development of ACS lipid-lowering therapy.


The author ouyangshaoxia