C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus

Over 20 large-scale prospective studies show that the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) is an independent predictor of future cardiovascular events that additionally predicts risk of incident hypertension and diabetes. In many studies, the relative impact of hsCRP is at least as large as that individually of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, blood pressure, or smoking, and knowledge of hsCRP correctly reclassifies a substantial proportion of "intermediate-risk" individuals into clinically relevant higher- or lower-risk categories. Other studies show the relative benefit of statins to be greater among those with increased hsCRP and that achieved hsCRP levels after statin therapy predict recurrent event rates as much as achieved levels of low-density lipoprotein cholesterol. Nonetheless, it remains controversial whether the time has come to modify traditional algorithms used for global risk detection. As described here, 6 areas of controversy regarding hsCRP are resolvable with a consensus position that focuses in primary prevention on selective use among individuals with 5% to 20% 10-year risk as estimated by Adult Treatment Panel III, and focuses in secondary prevention on high-risk patients being treated with statin therapy. Forthcoming trial data could expand or contract this "screen selectively" policy, and investigators should be open to the possibility that second-generation inflammatory biomarkers may be developed that supplant hsCRP altogether. In the meantime, however, this consensus position on hsCRP should be one to which both advocates and critics of the inflammatory hypothesis of atherosclerosis can adhere because it is one that can immediately improve patient care.     

The Effect of Aggressive Versus Conventional Lipid-lowering Therapy on Markers of Inflammatory and Oxidative Stress

Purpose Recent trial results are in favor of aggressive lipid lowering using high dose statins in patients needing secondary prevention. It is unclear whether these effects are solely due to more extensive lipid lowering or the result of the potentially anti-inflammatory properties of statins. We aimed to determine whether aggressive compared with conventional statin therapy is more effective in reducing systemic markers of inflammation and oxidative stress. Materials and methods This was a multi-centre, double-blind, placebo-controlled trial. Patients with previous cardiovascular disease, who did not achieve low density lipoprotein (LDL) cholesterol levels <2.6 mmol/l on conventional statin therapy (simvastatin 40 mg) were randomized to continue with simvastatin 40 mg or to receive atorvastatin 40 mg for 8 weeks and thereafter atorvastatin 80 mg for the final 8 weeks (aggressive treatment). Lipids, C-reactive protein, soluble cellular adhesion molecules, neopterin, von Willebrand Factor, and antibodies against oxidized LDL were measured at baseline and after 16 weeks. Results Lipid levels decreased significantly in the aggressive treatment group (LDL-C reduction 20.8%; P < 0.001), whereas a slight increase was observed in the conventional group (LDL-C increase 3.7%; P = 0.037). A significant reduction in antibodies against oxidized LDL was seen in the aggressive (13.4%; P < 0.001) and the conventional (26.8%; P < 0.001) group, but there was no difference between groups (P = 0.25). Furthermore, no significant differences in change in other biomarkers was observed between both groups. Conclusions This study does not support the hypothesis that a more profound reduction in inflammatory and oxidative stress contributes to the benefits of aggressive statin therapy.     

急性冠脉综合征患者冠状动脉介入治疗围术期可溶性CXC趋化因子配体16的表达规律

目的 探讨可溶性CXC趋化因子配体16 （soluble CXCL16,sol-CXCL16）在急性冠状动脉（冠脉）综合征患者经皮冠状动脉介入（percutaneous coronary intervention,PCI）治疗围术期中的表达规律及临床意义.方法 将96例成功施行PCI治疗的急性冠脉综合征患者分为常规治疗组和强化他汀治疗组,分别于PCI治疗前、PCI治疗后1d、术后2周以及术后4周测定血清sol-CXCL16和高敏C-反应蛋白（high-sensitivity C-reactive protein,hs-CRP）的浓度.结果 所有患者PCI治疗后1d血清hs-CRP浓度和sol-CXCL16浓度均较PCI治疗前有明显的升高,差异有统计学意义（P＜0.05）.PCI治疗后1d常规治疗组中血清sol-CXCL16浓度升高较强化他汀治疗组更为明显,差异有统计学意义（P＜0.05）.治疗2周后,强化他汀治疗组血清sol-CXCL16浓度较常规治疗组及PCI治疗后1d均有明显下降,差异有统计学意义（P＜0.05）.治疗4周后,强化他汀治疗组血清sol-CXCL16及hs-CRP浓度均较常规治疗组及PCI治疗后1d有明显的下降,差异有统计学意义（P＜0.05）.强化他汀治疗组PCI治疗后4周内主要心血管事件发生率显著低于常规治疗组,差异有统计学意义（P＜0.05）.结论 sol-CXCL16浓度可能与冠状动脉炎症程度相关,并可能对评估急性冠脉综合征患者PCI治疗后短期预后有一定的作用.     

Lipid-Lowering Therapy in Patients 75 Years and Older: Clinical Priority or Superfluous Therapy?

The incidence and prevalence of cardiovascular (CV)-related morbidity and mortality significantly increase with age. In the elderly, hypercholesterolemia with elevated total and low-density-lipoprotein cholesterol is a significant predictor of incident and recurrent CV disease. Multiple lines of evidence have established the benefit of statin therapy to lower cholesterol levels and reduce the risk of CV events as well as prevent progression of subclinical atherosclerotic disease. Elderly patients, particularly those older than 75 years, have not been well represented in randomized clinical trials evaluating lipid lowering therapy. The limited available data from clinical trials do support the benefit of statin therapy in the elderly population. Based upon these data, cholesterol treatment guidelines endorse statin therapy as the primary treatment of hypercholesterolemia in elderly patients, though caution is recommended given the greater number of co-morbid conditions and concern for poly-pharmacy common in the elderly. Additional research is needed to better establish the benefit of statin therapy in the elderly within the context of reducing CV risk, minimizing side effects, and improving overall quality of life.     

Circulating desialylated low density lipoprotein

Accumulation of lipids is the central event in the development of atherosclerotic lesion. Circulating low-density lipoprotein (LDL) particles are known to be the major source of cholesterol and other lipids stored in atherosclerotic plaque. However, not all LDL particles possess atherogenic properties. In order to induce lipid accumulation in arterial cells, LDL particles have to undergo modifications. Although among such modifications the oxidation remains the most studied one, other atherogenic LDL modifications have been described. According to a series of studies conducted with blood serum and LDL from atherosclerotic patients, desialylation is one of the earliest if not the first atherogenic modification of LDL. Desialylation occurs in the bloodstream and is followed by a cascade of other modifications, including the reduction of LDL particle size and increase of its density, acquisition of negative electrical charge, oxidation and formation of highly atherogenic complexes. In this mini-review we will discuss the concept of multiple atherogenic modification of LDL leading to initiation and progression of atherosclerosis.     

血清可溶性OX40配体和高敏C反应蛋白对冠状动脉事件的预测价值

目的观察冠心病患者血清可溶性OX40配体(sOX40L)和高敏C反应蛋白(hs-CRP)水平的变化,探讨sOX40L和hs-CRP与冠状动脉粥样斑块稳定性的关系。方法选择住院患者200例,依据不同疾病分为3组:急性冠状动脉综合征(ACS)组(90例),稳定性心绞痛(SAP)组(60例),对照组(50例)。采用透视免疫比浊法检测hs-CRP;酶联免疫吸附法检测sOX40L。所有患者均行冠状动脉造影,计算冠状动脉病变形态积分,并与sOX40L,hs-CRP水平进行相关分析。结果 ACS组sOX40L及hs-CRP水平显著高于SAP组和对照组(P<0.05),SAP组与对照组间差异无统计学意义(P>0.05);ACS组冠状动脉狭窄病变形态积分明显高于SAP组和对照组(P<0.05),SAP组与对照组间病变积分差异无统计学意义(P>0.05);ACS患者sOX40L和hs-CRP水平与冠状动脉造影狭窄病变形态积分有明显相关性(P<0.05);sOX40L与hs-CRP呈显著正相关(r=0.48,P<0.01)。结论冠心病患者血清sOX40L、hs-CRP水平升高可能提示斑块不稳定;血清sOX40L、hs-CRP水平可以有效判断冠状动脉病变程度,预测急性冠状动脉事件的发生。     

Cardiometabolic Impact of Non-Statin Lipid Lowering Therapies

There is evidence from epidemiology, pathophysiology, and clinical trials that high LDL cholesterol levels cause atherosclerotic heart disease. Current guidelines recommend an LDL cholesterol target of 70 mg/dL for patients at high or very high risk. The risk imposed by LDL cholesterol is modulated by the presence of additional risk factors such as age, smoking, and indices of inflammation. Epidemiologic studies as well as rare congenital conditions (e.g., hypobetalipoproteinemia) have shown that very low LDL cholesterol (lower than 70 mg/dL) levels are associated with a very low risk of cardiovascular disease. Analyses of randomized clinical trials have shown a greater benefit in reducing the risk of cardiovascular disease (without an increase in adverse events) among those with very low achieved LDL (below 40 mg/dL). In one study of patients with achieved LDL cholesterol below 30 mg/dL, there was no increase in the usual adverse events compared to patients with LDL cholesterol levels above 30 mg/dL. High-intensity statin therapy is associated with a higher rate of transaminase elevations, but no hepatic failure, a very small risk of myopathy, and an increased risk of developing diabetes. However, the small increase in the risk of developing diabetes is much smaller than the marked lowering of cardiovascular risk. The duration of statin therapy may be important in studies of primary prevention and early, probably low-dose statin therapy, may achieve primordial prevention of atherosclerotic disease.     

他汀类对低低密度脂蛋白胆固醇急性冠状动脉综合征患者介入术后的心肌保护作用

目的观察合并有低LDL-C的急性冠状动脉综合征(ACS)患者行PCI后,他汀类药物对于围手术期心肌损伤的保护作用。方法合并有低LDL-C血症并同时具备PCI指征的ACS患者220例,根据治疗方法不同随机分为2组:PCI术前服用他汀类药物治疗116例(他汀组),不服用他汀类药物治疗104例(常规组),分别测量PCI术前及PCI术后6 h肌钙蛋白I(cTnI)、肌酸激酶同工酶(CK-MB)及高敏C反应蛋白(hs-CRP)水平,评估2组患者随访3个月的主要心血管事件。结果他汀组与常规组患者术前cTnI、CK MB和hs-CRP比较,差异无统计学意义。他汀组患者术后CK MB、cTnI较常规组明显降低[(14.2±5.78 U/L vs(47.3±1 6.4)U/L,P<0.05;(0.36±0.1 2)μg/L vs(1.33±0.47)μg/L,P<0.01]。2组患者的hs-CRP水平及随访3个月的主要心血管事件没有明显的差异。结论对合并有低LDL-C的ACS患者实施他汀类预处理具有心肌保护作用,其机制可能与他汀类药物改善冠状动脉微循环的作用相关。但是这种预处理对于PCI术后3个月的主要心血管事件没有明显的改善。     

高敏C反应蛋白联合低密度脂蛋白胆固醇作为他汀治疗靶目标的临床研究

目的:探讨急性冠状动脉综合征(ACS)介入术后,以高敏C反应蛋白(hs-CRP)联合低密度脂蛋白胆固醇(LDL-C)作为他汀治疗靶目标的可行性。方法:2007-01-2009-01期间,连续纳入ACS患者400例,随机分为A、B组(每组200例),常规行介入手术,术后每组给予阿托伐他汀40mg/d,口服1个月;此后给予阿托伐他汀20mg/d,口服维持。A组治疗靶目标为LDL-C<2.07mmol/L,B组治疗靶目标为LDL-C<2.07mmol/L且hs-CRP<3mg/L,观察2组LDL-C、hs-CRP指标变化,随访6个月、12个月、18个月主要心血管不良事件(MACE:全因性死亡、非致死性心肌梗死、靶血管再次血运重建)。结果:2组患者基线特征差异无统计学意义;2组在18个月时均达到各自治疗靶目标;2组LDL-C水平差异无统计学意义;hs-CRP在12个月和18个月随访时差异有统计学意义,分别为(5.96±3.51)和(3.85±2.23)mg.L-1(P<0.05),(4.68±2.81)和(2.05±0.91)mg.L-1(P<0.05);在18个月随访时,2组靶血管再次血运重建率和MACE发生率差异有统计学意义,分别为8.6%和3.6%(P<0.05),16.8%和9.7%(P<0.05)。A组发生MACE的概率是B组的1.73倍(HR=1.73,95%CI:1.12～5.27,P=0.025)。结论:ACS介入术后,对于血脂已达标但炎症仍较为活跃患者,hs-CRP和LDL-C双重达标可进一步减少MACE发生,降低残余心血管风险。hs-CRP可能是他汀治疗的另一有效靶目标。     

Newer pharmaceutical agents to treat lipid disorders

The National Cholesterol Education Program Adult Treatment Panel III guidelines and the results of the Heart Protection Study have provided a stronger rationale to more aggressively treat high-risk patients to a low-density (LDL) cholesterol goal of less than 100 mL/dL. Two new therapies, ezetimibe and rosuvastatin, have recently been added to the lipid-lowering armamentarium to improve guideline adherence. Ezetimibe, a novel cholesterol absorption inhibitor, lowers LDL by 18% to 20% and can be used safely in combination with statins. Adding ezetimibe to a statin is comparable with the LDL-lowering efficacy of tripling the dose of the statin. Rosuvastatin is a highly efficacious statin providing 8% greater LDL reduction than equivalent doses of atorvastatin, and the starting dose of 10 mg/d provides nearly a 50% reduction in LDL cholesterol. There are several investigational drugs in development for the prevention and treatment of atherosclerosis. Of these investigational drugs, the most promising are the cholesterol ester transfer protein inhibitors, which have the potential to significantly raise high-density lipoprotein cholesterol and acetyl-coenzyme A: cholesterol acyltransferase inhibitors, which may directly inhibit the progression of atherosclerosis.     

Randomised, Double-Blind, Placebo-Controlled Trial of Ivabradine in Patients with Acute Coronary Syndrome: Effects of the If Current Inhibitor Ivabradine on Reduction of Inflammation Markers in Patients with Acute Coronary Syndrome—RIVIERA Trial Study Design and Rationale

Purpose  Elevated levels of serum inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP) represent independent risk factors for further cardiovascular events. In an atherosclerosis model, selective heart rate (HR) reduction with ivabradine has been shown to decrease markers of vascular oxidative stress, to improve endothelial function, and to reduce atherosclerotic plaque formation. We hypothesized that the addition of ivabradine to standard medical therapy has a beneficial effect on markers of inflammatory stress in acute coronary syndromes (ACS) patients. Methods  RIVIERA is a unicenter, randomized, double-blind, placebo-controlled trial involving 1,270 patients of either gender admitted to hospital with non ST elevation ACS. The primary study aim is to evaluate the effects of ivabradine therapy, initiated at the time of hospital admission, on hs-CRP levels. There is also a combined secondary endpoint i.e. to assess the effects of ivabradine on the occurrence of death, nonfatal myocardial infarction, recurrent symptomatic ischemia, urgent revascularization, and cardiac arrest at 30-days and 1-year follow up. Conclusion  We hypothesize that ivabradine therapy, when started immediately after hospital admission for ACS, will result in the reduction of hs-CRP levels and the improvement of cardiovascular outcome.     

The Clinical Relevance of Low-Density-Lipoproteins Size Modulation by Statins

The predominance of small, dense low density lipoproteins (LDL) has been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III; in fact, LDL size seems to be an important predictor of cardiovascular events and progression of coronary heart disease. Several studies have also shown that the therapeutical modulation of LDL size is of great benefit in reducing the risk of cardiovascular events. Hypolipidemic treatment is able to alter LDL subclass distribution and statins are currently the most widely used lipid-lowering agents. Statins are potent inhibitors of hydroxy-methyl-glutaryl-coenzyme A reductase, the rate-limiting enzyme in hepatic cholesterol synthesis and are the main drugs of choice for the treatment of elevated plasma LDL cholesterol concentrations. Statins potentially lower all LDL subclasses (e.g., large, medium and small particles); thus, their net effect on LDL subclasses or size is often only moderate. However, a strong variation has been noticed among the different agents: analyses of all published studies suggest a very limited role of pravastatin and simvastatin in modifying LDL size and their subclasses, while fluvastatin and atorvastatin seem to be much more effective agents. Finally, rosuvastatin, the latest statin molecule introduced in the market, seems to be promising in altering LDL subclasses towards less atherogenic particles.     

Antibodies to malondialdehyde oxidized low-density lipoproteins predict long term cardiovascular mortality in high risk patients

Aims

Antibodies to oxidized low-density lipoproteins (oxLDLAbs) are detectable in the serum of patients with and without atherosclerosis, but it is unclear if they play a pathogenic or a protective role in atherogenesis or if they are simply a marker of atherosclerosis. Therefore, in a prospective cohort study we investigated if oxLDLAbs titer predicts cardiovascular (CV) events in high-risk coronary artery disease patients.

Methods and results

The titer of IgG antibodies to malondialdehyde modified oxidized low-density lipoproteins was measured in 748 randomly selected patients of the GENICA study who underwent coronary angiography and assessment of incident CV events at follow-up. Patients were classified by oxLDLAbs into a low and a high titer group, corresponding to the first three and the last quartile, respectively. Cardiovascular event-free survival was compared between oxLDLAbs groups by Kaplan–Meier and multivariate technique including propensity score matching analysis. During long-term follow-up (median 7.2 years) CV deaths were observed in 65 patients (11.6%), more commonly in the high than in the low oxLDLAbs group (patients free from CV death 83.1% vs. 89% respectively, p = 0.025). The incidence of CV events was also higher in the former than in latter (event-free survival 69.2% vs. 77.7% respectively, p = 0.030).

Conclusions

An oxLDLAbs titer above the 75th percentile is a marker of LDL oxidation which predicts a worse CV prognosis at long term follow-up in high-risk Caucasian patients referred for coronary angiography.     

The Use of Fibric Acid Derivatives in Cardiovascular Prevention

Clinical trials have demonstrated the benefit of reduction of low-density lipoprotein (LDL) cholesterol levels in the prevention of atherosclerotic cardiovascular disease. Evidence is less robust for the effect of reduction of triglyceride levels and increase of high-density lipoprotein (HDL) cholesterol levels. In spite of the decrease of cardiovascular events in trials of LDL cholesterol–lowering medications, considerable residual risk remains, even with the use of high-dose statins. The fibric acid derivatives or fibrates reduce triglyceride and increase HDL cholesterol levels, effects that would be expected to affect cardiovascular events. However, clinical outcomes trials with fibrates have shown mixed results. Post-hoc analyses of fibrate trials as well as several meta-analyses suggest an overall decrease in primarily non-fatal coronary events without decrease in total mortality. The effects are most apparent in patients with elevated triglycerides and low HDL cholesterol levels. Statin therapy is the treatment of choice for most patients with dyslipidemia. The addition of a fibrate appears to be most beneficial in high-risk patients who continue to have significant dyslipidemia on statin therapy, most notably patients with diabetes mellitus or the metabolic syndrome. Thus, fibrates are not first-line drugs, but they do have a place in the management of the atherogenic lipid profile.     

Cholesterol, C-reactive protein, and cerebrovascular events following intensive and moderate statin therapy

Background: While statins have been shown to reduce cerebrovascular events (CVE), the relationship between cholesterol, C-reactive protein (CRP), and CVE in patients treated with different statin strategies is still being explored. Methods: PROVE IT-TIMI 22 was a randomized trial of intensive (atorvastatin 80 mg/day) and moderate (pravastatin 40 mg/day) statin therapy in 4,162 patients with acute coronary syndromes followed for an average of 24 months; serial biomarkers allowed for an assessment of the lipid and non-lipid effects of statins as they relate to CVE. Results: In this study, 45 patients on intensive statin therapy and 40 patients on moderate statin therapy had a CVE during the study period (2.1% v. 1.9%, P = 0.62). While the lipid profiles of patients with and without CVE were similar, those with CVE had higher CRP levels at 30 days and 4 months (2.7 v. 1.9, 2.4 v. 1.7 mg/L; P = 0.012, P = 0.005). Day 30 CRP remained an independent predictor of CVE after adjusting for age, development of atrial fibrillation, diabetes, and prior CVE. Patients with low density lipoprotein (LDL) levels < 70 mg/dL and ≥ 70 mg/dL had similar rates of CVE, while patients with CRP < 2 mg/L tended to have lower event rates when compared to those with higher levels. The lowest rates of CVE were seen in patients who had LDL < 70 mg/dL and CRP < 2 mg/L. Conclusion: In PROVE IT - TIMI 22, achieved LDL levels did not appear to independently impact the rate of CVE. In contrast, patients with elevated CRP levels were at higher risk of stroke or transient ischemic attack, reinforcing the link between inflammation and CVE. Condensed abstract The goal of this PROVE IT-TIMI 22 sub-study was to examine the relationship between cholesterol, CRP, and CVE in patients on intensive and moderate statin therapy. The achieved lipid levels were similar in patients with and without a CVE; however, the achieved levels of CRP were higher in patients who subsequently developed a stroke or TIA. These findings further support the relationship between inflammation and CVE.     

Effects of Withdrawal of Xuezhikang, an Extract of Cholestin, on Lipid Profile and C-reactive Protein: A Short-Term Time Course Study in Patients with Coronary Artery Disease

Objective C-reactive protein (CRP) is considered a risk factor for coronary artery disease. In addition to its lipid-lowering properties, statin decreases the level of CRP. Abrupt cessation of statin therapy during treatment could increase CRP level independently of the elevation of serum lipids and the incidence of cardiac events in patients with atherosclerotic heart disease. Xuezhikang (XZK), an extract of cholestin, has a marked modulating effect on lipid and CRP concentrations in different study time course. However, no attention has been paid to the changes of lipid profile and CRP concentrations after withdrawal of XZK treatment. This study was designed to explore short-term time course effects on lipid profile and CRP concentrations after withdrawal of XZK treatment in coronary heart disease patients. Materials and methods Seventy-five consecutive patients with documented coronary heart disease were randomly divided into three groups: 1. Pretreatment with XZK 1,200 mg daily for 6 weeks and then replaced by placebo (XZK discontinued group; n = 25); 2. Treatment with XZK 1,200 mg daily throughout the study (XZK continued group; n = 25); or 3. Placebo (no XZK group; n = 25). Lipid levels (total cholesterol, HDL-C, LDL-C and triglycerides) and CRP were assessed before receiving the XZK therapy, 1 day before discontinuation of XZK, and on days 1, 2, 3, 7 and 14 after discontinuation of XZK, respectively. Results After 6-week XZK treatment, the fasting total cholesterol, LDL-C, triglyceride and median hs-CRP concentrations decreased, whereas HDL-C concentration increased significantly (p < 0.001, respectively). At day 14 after discontinuation of XZK therapy, total cholesterol (15%), LDL-C (17%) and triglyceride (20%) significantly increased (p < 0.001, respectively), whereas HDL-C level (15%) significantly decreased (p < 0.05). The median level of CRP increased by 11, 65, 128, 103 and 101% on the first, second, third, seventh, and fourteenth day after withdrawal of XZK therapy (p > 0.05, <0.05, <0.001, <0.001, <0.001, compared with 1 day before withdrawal of XZK therapy, respectively). There was a prominent rebound of CRP concentration 3 days after discontinuation of XZK therapy. At this time point, hs-CRP concentration was higher than in the placebo group (p < 0.05). Seven to 14 days after discontinuation of XZK therapy, the hs-CRP concentration declined to a similar level as in the placebo group. No significant correlation was seen between the changes in hs-CRP and lipid profile at all time points. Conclusions The level of hs-CRP increases on the second day after withdrawal of XZK and there is a prominent rebound 3 days after discontinuation of XZK therapy. The increase of CRP ends within 7 days, where lipids increase at 14 days after discontinuation of XZK therapy. The results may be clinically important for patients with coronary artery disease.     

Relation of markers of inflammation (C-reactive protein, fibrinogen, von Willebrand factor, and leukocyte count) and statin therapy to long-term mortality in patients with angiographically proven coronary artery disease

We evaluated a possible interaction between statins and inflammation in 1,246 patients with angiographically diagnosed coronary artery disease. Four different inflammatory markers were determined: high, sensitive C-reactive protein (hs-CRP) (p = 0.001), fibrinogen (p = 0.006), von Willebrand factor (p = 0.006), and leukocyte count (p = 0.03); these levels were significantly higher among the 88 patients who died of cardiac causes during follow-up (median 2.9 years) than among survivors. In a multivariate backward stepwise Cox regression mode, only hs-CRP was evaluated to be a significant predictor of death from coronary artery disease. This prediction was lost in statin-treated patients. Compared with patients receiving statin medication, patients without statins did not have increased cardiac mortality (even when low-density lipoprotein [LDL] levels were >125 mg/dl) when hs-CRP levels were not elevated. In contrast, patients without statins and elevated hs-CRP (top quartile) had a 2.3-fold increase in risk for fatal coronary events, independent of LDL levels. In conclusion, only elevated hs-CRP was selected as an independent predictor of death. Statin therapy is associated with elevated hs-CRP, with a risk reduction for fatal coronary events, independent of LDL levels; this, in part, may be explained by the anti-inflammatory effects on atherosclerosis.     

Small dense low‐density lipoprotein cholesterol is a promising biomarker for secondary prevention in older men with stable coronary artery disease

Aim

The study objective was to investigate whether small dense low‐density lipoprotein cholesterol (sdLDL‐C) is superior to low‐density lipoprotein cholesterol (LDL‐C) and other biomarkers to predict future cardiovascular events (CE) in secondary prevention.

Methods

sdLDL‐C measured by a homogeneous assay, remnant lipoprotein cholesterol, LDL particle diameter and other biomarkers were compared in 345 men aged ≥65 years with stable coronary artery disease. Baseline LDL‐C was 100.5 ± 30.1 mg/dL. CE including cardiovascular death, onset of acute coronary syndrome, need for arterial revascularization, hospitalization for heart failure, surgery procedure for cardiovascular disease and hospitalization for stroke were monitored for 5 years.

Results

CE occurred in 96 patients during the study period. LDL‐C, sdLDL‐C non‐high‐density lipoprotein cholesterol, apolipoprotein B, remnant lipoprotein cholesterol, glucose, glycated hemoglobin and brain natriuretic peptide were significantly higher; LDL particle diameter and apolipoprotein A‐1 were significantly lower in patients with than in those without CE. Age‐adjusted Cox regression analysis showed that sdLDL‐C per 10 mg/dL, but not LDL‐C, was significantly associated with CE (HR 1.206, 95% CI 1.006–1.446). A significant association of sdLDL‐C and incident CE was observed in statin users (HR 1.252, 95% CI 1.017–1.540), diabetes patients (HR 1.219, 95% CI 1.018–1.460), patients without diabetes (HR 1.257, 95% CI 1.019–1.551) and patients with hypertriglyceridemia (HR 1. 376, 95% CI 1.070–1.770).

Conclusions

sdLDL‐C was the most effective predictor of residual risk of future CE in stable coronary artery disease patients using statins and in high‐risk coronary artery disease patients with diabetes or hypertriglyceridemia. Geriatr Gerontol Int 2018; 18: 965–972 .     

Key questions resulting from the JUPITER trial assessing cardiovascular disease intervention with rosuvastatin

THIS PAPER PRESENTS AN ANALYSIS OF THE RECENTLY PUBLISHED JUSTIFICATION FOR THE USE OF STATINS IN PREVENTION (JUPITER: an intervention trial evaluating rosuvastatin) trial, which tested the statin rosuvastatin in apparently healthy individuals with no prior cardiovascular (CVD) disease and with normal plasma low density lipoprotein (LDL) cholesterol concentrations but with raised plasma high sensitivity C-reactive protein (hsCRP) levels. The rate of the combined primary CVD endpoint was significantly reduced in the treatment arm after a median of under 2 years. The JUPITER trial is distinct from previous studies examining statin use in primary prevention groups because the target group for drug therapy was apparently healthy men and women at low or intermediate risk for developing CVD. On the basis of JUPITER's findings, there are key questions that should be assessed on the therapeutic intervention of CVD regarding: the primary prevention groups that should be targeted for statin therapy, the utility of targets in addition to plasma LDL cholesterol levels, and the need to consider the metabolic state of individuals targeted for therapy (including the presence of obesity and inflammation). The conclusion from the current analysis is that the JUPITER results warrant further LDL cholesterol lowering than is currently targeted in primary prevention groups that have a pre-existing condition or lifestyle that elevates CVD risk but still do not have a high global CVD risk (as assessed with current algorithms). This group is not captured in current widely used CVD risk calculations, however, with the identification of useful biomarkers, such as hsCRP, this group can be better identified and targeted for intervention.     

Safety of aggressive lipid management

Data from recent clinical trials of high- versus moderate-dose statin therapy support the recommendation to achieve a low-density lipoprotein (LDL) <100 mg/dl in high-risk patients and reveal that many patients will require a high-dose statin to achieve this goal. Overall, low rates of serious musculoskeletal (<0.6%) and hepatic (<1.3%) toxicity have been observed with high-dose statin therapy. In the long-term trials, atorvastatin 80 mg had higher rates of persistent transaminase elevations but rates of myopathy and rhabdomyolysis similar to lower doses of statins. The rate of myopathy and rhabdomyolysis for simvastatin 80 mg, although still low, was about 4x higher than for atorvastatin 80 mg and lower doses of statin. A similar margin of safety would be expected in properly selected patients with characteristics similar to those who participated in the clinical trials. High-dose statin therapy or combination therapy will be required for the large majority of very high-risk patients to achieve the optional LDL goal of <70 mg/dl. While the combination of ezetimibe, bile-acid sequestering agents, niacin, and fenofibrate with moderate dose statins appears to be reasonably safe, the long-term safety of combination with high-dose statins remains to be established. In order to optimize patient outcomes, clinicians should be aware of specific patient characteristics, such as advancing age, gender, body mass index, or glomerular filtration rate, which predict muscle and hepatic statin toxicity.