The safety and efficacy of achieving very low LDL-cholesterol concentrations with high dose statin therapy

PURPOSE OF REVIEW: The benefits of lipid lowering with statins are established in patients with or at risk for coronary artery disease. Recent trials with high doses of potent statins have examined treating to very low levels of LDL-cholesterol. Concerns have been raised about the safety of this strategy. This review examines the safety and efficacy of treating to very low LDL-cholesterol. RECENT FINDINGS: Four clinical trials, Treating to New Targets (TNT) and Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) in stable coronary artery disease and Aggrastat to Zocor (A to Z) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT)-TIMI 22 following acute coronary syndromes, have examined intensive statin therapy compared to moderate statin therapy. These trials and a meta-analysis demonstrated that intensive statin therapy reduces cardiovascular events. Subsequent analyses from these trials suggest that very low levels of LDL-cholesterol can be achieved safely and may improve clinical outcomes. A note of caution regarding hemorrhagic events following stroke with intensive statin therapy was raised by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) trial despite impressive reductions in cardiovascular events. SUMMARY: A growing body of evidence suggests progressive benefit for lowering LDL-cholesterol aggressively with intensive statin therapy in coronary artery disease. Future trials will be needed to define whether there is a level of LDL-cholesterol beyond which further benefit is not seen or safety concerns emerge.     

Statin therapy for prevention and treatment of acute and chronic cardiovascular disease: update on recent trials and metaanalyses

PURPOSE OF REVIEW: To summarize the evidence from recent clinical trials and metaanalyses on the efficacy of statin therapy to reduce death, myocardial infarction and stroke, and to review the effects of statins in patients with low LDL cholesterol, diabetes, end-stage renal disease, and acute coronary syndrome. RECENT FINDINGS: In large metaanalyses of randomized controlled trials relative risk reductions from statins compared with placebo for patients with manifest or with risk factors for coronary artery disease were 13% for overall mortality, 26% for fatal and nonfatal myocardial infarction, and 18% for fatal and nonfatal stroke. Evidence from large trials suggests that patients with type II diabetes compared with patients without diabetes have similar risk reductions from statins for cardiovascular events, but this benefit is not seen in patients with diabetes and end-stage renal disease. In patients with acute coronary syndrome, early treatment with high-dose atorvastatin reduces cardiovascular morbidity after the first 4 months following the event, but the impact on mortality endpoints remains less clear. Results from recent trials in patients with stable coronary artery disease or type II diabetes suggest that statins provide benefit at considerable low LDL cholesterol levels. Therefore, target values for LDL cholesterol of less than 1.8 mmol/l (<70 mg/dl) should be considered for all patients with coronary artery disease or equivalent coronary risk. SUMMARY: For patients at high risk of coronary artery disease there is growing evidence for the concept of 'the lower, the better' regarding LDL cholesterol levels. Ongoing trials are further investigating the safety of lower target values in patients at various risk of coronary artery disease.     

Early initiation of statin therapy after a coronary event

PURPOSE OF REVIEW: Despite improvements in the early management of acute coronary syndromes, the risk of major cardiovascular complications remains high. Lipid-modifying treatment with statins has the potential to further improve outcomes through improved endothelial function, antithrombotic and antiinflammatory actions. Statins are of proven benefit in patients with stable coronary heart disease. There has been speculation on potential mechanisms of benefit but, until recently, little data on the efficacy and safety of statins in the acute setting. Recent observational studies and randomized trials have addressed some of the questions regarding early initiation of statins in acute coronary syndromes. RECENT FINDINGS: Recent observational and randomized trials have shown that early commencement of statins in acute coronary syndromes is safe as early as 6 hours after the event and is likely to improve longer-term compliance. The current data are not sufficient to draw conclusions about the efficacy of statins early in the course of acute coronary syndromes. SUMMARY: Current management for acute coronary syndromes should include the commencement of statin therapy during initial hospital admission. This recommendation is based on safety and compliance data. More randomized trial evidence is required to determine whether early initiation will produce better outcomes than later initiation after an acute coronary event.     

Statin use in acute coronary syndromes: cellular mechanisms and clinical evidence

PURPOSE OF REVIEW: Review the cellular mechanisms and clinical evidence for the use of statins in patients with unstable coronary syndromes. RECENT FINDINGS: Clinical trials of statin therapy in acute coronary syndromes demonstrate a rapid improvement in endothelial function, improved perfusion to ischemic myocardium, and an early reduction in cardiovascular events. The early benefit of statin therapy is related to a combination of molecular mechanisms that involve the oxidized LDL receptor (LOX-1), endothelial localized nitric oxide synthase, inflammatory cytokines, interstitial collagenases, and tissue factor expression. In human atheroma, 3 months' use of statin (pravastatin) therapy reduced the content of oxidized LDL, inflammatory cells (macrophage, T cells) infiltrates, and improved plaque stability by increasing the collagen content of the fibrous cap. SUMMARY: The antiatherothrombotic effects of statin therapy appear to have important clinical relevance to patients with impaired myocardial perfusion and acute coronary syndrome.     

Intensive statin therapy in acute coronary syndromes: clinical benefits and vascular biology

PURPOSE OF REVIEW: The results of a landmark clinical study comparing intensive statin therapy with conventional statin therapy, in patients with acute coronary syndromes (ACS), are reviewed. The mechanisms behind these results are analysed drawing data from vascular and cell biology. RECENT FINDINGS: The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction (PROVE IT-TIMI 22) study showed that intensive statin therapy with 80 mg of atorvastatin to achieve a low-density lipoprotein cholesterol of 62 mg/dl resulted in a 3.9% absolute and a 16% relative risk reduction in death or major cardiovascular events up to 2 years, compared to 40 mg of pravastatin, in patients with ACS. The results were especially significant as intensive statin therapy resulted in a very early benefit (<30 days) and occurred against a background of percutaneous coronary intervention (69%) for the index admission and high use of medications for secondary prevention. The PROVE IT and the Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering (MIRACL) C-reactive protein sub-study also showed that atorvastatin (80 mg) resulted in a significant reduction in markers of inflammation, whilst the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study showed that intensive statin therapy was associated with reduced progression of atherosclerosis compared with conventional doses of statins. SUMMARY: Intensive statin therapy results in a significant early reduction in adverse cardiac events in ACS patients which are sustained over 2 years. The early benefits seen are likely to result from modulation of inflammation, endothelial function and coagulation, i.e. the pleiotropic effects, whereas the greater reduction in low-density lipoprotein cholesterol results in reduced long-term events.     

Treating patients with low high-density lipoprotein cholesterol: choices, issues and opportunities

Three clinical trials have recently focused on the benefits of lipid-regulating therapy in populations with normocholesterolaemia and low high-density lipoprotein (HDL)-cholesterol. Two secondary prevention studies (Veterans Affairs HDL-Cholesterol Intervention Trial [VA-HIT] and Bezafibrate Infarction Prevention [BIP] trial) testified to the efficacy of fibrates in decreasing cardiovascular events, particularly in patients with coexisting risk factors, including hypertriglyceridaemia. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) demonstrated that a statin could decrease acute coronary events in patients with isolated low HDL-cholesterol in a primary prevention setting. The absolute risk reduction in coronary events in the VA-HIT study compares favourably with those reported from the statin-based Cholesterol and Recurrent Events (CARE) and Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) trials. The absolute risk reduction in AFCAPS-TexCAPS is similar to that in West of Scotland Coronary Pravastatin Study (WOSCOPS). Recommendations are given concerning lifestyle and pharmacological management of low HDL-cholesterol. Optimal management also requires review of current treatment targets for HDL-cholesterol and triglycerides levels.     

Which is the best lipid-modifying strategy in metabolic syndrome and diabetes: fibrates, statins or both?

Although less clinical intervention studies have been performed with fibrates than with statins, there are evidences indicating that fibrates may reduce risk of cardiovascular events. The potential clinical benefit of the fenofibrate will be specified by the ongoing Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, which rationale, methods and aims have been just published. Controlled clinical trials show similar or even greater cardiovascular benefits from statins-based therapy in patient subgroups with diabetes compared with overall study populations. Therefore, statins are the drug of first choice for aggressive lipid lowering actions and reducing risk of coronary artery disease in these patients. However, current therapeutic use of statins as monotherapy is still leaving many patients with mixed atherogenic dyslipidemia at high risk for coronary events. A combination statin/fibrate therapy may be often necessary to control all lipid abnormalities in patients with metabolic syndrome and diabetes adequately, since fibrates provide additional important benefits, particularly on triglyceride and HDL-cholesterol levels. Thus, this combined therapy concentrates on all the components of the mixed dyslipidemia that often occurs in persons with diabetes or metabolic syndrome, and may be expected to reduce cardiovascular morbidity and mortality. Safety concerns about some fibrates such as gemfibrozil may lead to exaggerate precautions regarding fibrate administration and therefore diminish the use of the seagents. However, other fibrates, such as bezafibrate and fenofibrate appear to be safer and better tolerated. We believe that a proper co-administration of statins and fibrates, selected on basis of their safety, could be more effective in achieving a comprehensive lipid control as compared with monotherapy.     

Women and the management of acute coronary syndrome

Coronary heart disease (CHD) is the leading cause of morbidity and mortality in both men and women in the developed countries. Despite this fact, females are still under-represented in the majority of clinical trials. At the present time, only limited evidence is available with respect to the female-specific aspects of pathogenesis, management, and outcomes in acute coronary syndrome (ACS). Women less frequently undergo coronary intervention, and a lower proportion of women receive evidence-based pharmacotherapy, compared with men. It has been shown that women benefit from an invasive approach and coronary intervention in ACS as much as men, despite their advanced age and higher rate of bleeding complications. Also, administration of beta-blockers, ACE-inhibitors, and intensive statin therapy is associated with a comparable reduction of cardiovascular event rates in women and men. On the other hand, women may profit less than men from fibrinolytic or glycoprotein IIb/IIIa inhibitor therapy. Both sexes benefit equally from aspirin therapy, whereas contradictory data are available on the efficacy of clopidogrel in women. There is an urgent need for intensive research in the development of female-specific therapeutic strategy in ACS, even though the detailed mechanisms of sex differences are still unknown.     

Fluvastatin in the therapy of acute coronary syndrome: Rationale and design of a multicenter, randomized, double-blind, placebo-controlled trial (The FACS Trial)[ISRCTN81331696

BACKGROUND: Activation of inflammatory pathways plays an important contributory role in coronary plaque instability and subsequent rupture, which can lead to the development of acute coronary syndrome (ACS). Elevated levels of serum inflammatory markers such as C-reactive protein (CRP) represent independent risk factors for further cardiovascular events. Recent evidence indicates that in addition to lowering cholesterol levels, statins also decrease levels of inflammatory markers. Previous controlled clinical trials reporting the positive effects of statins in participants with ACS were designed for very early secondary prevention. To our knowledge, no controlled trials have evaluated the potential benefits of statin therapy, beginning immediately at the time of hospital admission. A previous pilot study performed by our group focused on early initiation of cerivastatin therapy. We demonstrated a highly significant reduction in levels of inflammatory markers (CRP and interleukin-6). Based on these preliminary findings, we are conducting a clinical trial to evaluate the efficacy of another statin, fluvastatin, as an early intervention in patients with ACS. METHODS: The FACS-trial (Fluvastatin in the therapy of Acute Coronary Syndrome) is a multicenter, randomized, double-blind, placebo-controlled study evaluating the effects of fluvastatin therapy initiated at the time of hospital admission. The study will enroll 1,000 participants admitted to hospital for ACS (both with and without ST elevation). The primary endpoint for the study is the influence of fluvastatin therapy on levels of inflammatory markers (CRP and interleukin-6) and on pregnancy associated plasma protein A (PAPP-A). A combined secondary endpoint is 30-day and one-year occurrence of death, nonfatal myocardial infarction, recurrent symptomatic ischemia, urgent revascularization, and cardiac arrest. CONCLUSION: The primary objective of the FACS trial is to demonstrate that statin therapy, when started immediately after hospital admission for ACS, results in reduction of inflammation and improvement of prognosis. This study may contribute to new knowledge regarding therapeutic strategies for patients suffering from ACS and may offer additional clinical indications for the use of statins.     

Statins: are any questions unanswered?

PURPOSE OF REVIEW: To summarize recent and ongoing randomized trials of statin therapy for the prevention of major vascular events. RECENT FINDINGS: Four large-scale randomized trials have compared high-dose vs. standard doses of statin therapy among patients with coronary heart disease, and their results suggest that higher doses are more effective for preventing major vascular events, albeit with evidence of increased toxicity. There is now clear evidence that statin therapy is effective among most patients with type 2 diabetes, although uncertainty remains about the benefits in those with advanced nephropathy. Ongoing trials will assess whether statin therapy is beneficial among patients with noncoronary vascular disease (such as congestive heart failure, cerebrovascular disease, or aortic stenosis), and among people with comorbid conditions or risk factors that increase the risk of vascular disease (including chronic kidney disease and raised C-reactive protein with below average low-density lipoprotein cholesterol). SUMMARY: Statin therapy safely reduces the risk of vascular events in a wide range of patients. Uncertainties persist about the effects of higher statin doses and the role of statins among patients with specific conditions or risk factors.     

Cardiovascular disease with diabetes or the metabolic syndrome: should statins or fibrates be first line lipid therapy?

PURPOSE OF REVIEW: Subgroups with diabetes or with features of the metabolic syndrome have been increasingly highlighted in large clinical endpoint trials with lipid therapy. This review will focus on the results of trials with statins or fibrates and examine the strength of the evidence for major cardiovascular event reduction with each kind of therapy in these high-risk subgroups that typically have low-to-moderate levels of LDL cholesterol. RECENT FINDINGS: Of six statin trials in populations with moderately increased LDL cholesterol only one, the Heart Protection Study, has shown that statin therapy will significantly reduce the major coronary heart disease events of non-fatal myocardial infarction or coronary heart disease death in diabetes. None of these trials has shown that statins have a particular predilection for reducing cardiovascular events in individuals with higher levels of body weight or other features of the metabolic syndrome. There are far fewer trial data with fibrates than with statins. However, the Veterans Affairs High Density Lipoprotein Intervention Trial has shown that a fibrate can significantly reduce major cardiovascular events, most particularly coronary heart disease death, in those with diabetes as well as those without diabetes who have insulin resistance. Indeed, all fibrate trials show that this therapy appears to selectively benefit the individual with obesity and features of the metabolic syndrome. SUMMARY: Based principally on evidence from the Veterans Affairs High Density Lipoprotein Intervention Trial and the cumulative experience with statins, trial data would thus far suggest that the patient with a modest increase in LDL cholesterol who has diabetes or features of the metabolic syndrome might be likely to achieve more substantial cardiovascular benefit from fibrate than from statin therapy.     

The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials

Background

Recent lipid guidelines recommend aggressive low-density lipoprotein (LDL) cholesterol lowering in patients with coronary artery disease. To clarify the evidence for this recommendation, we conducted a meta-analysis of randomized controlled trials that compared different intensities of statin therapy.

Methods

We searched electronic databases (MEDLINE, EMBASE, Cochrane Central Registery of Controlled Trials, Web of Science) for randomized controlled trials published up to July 19, 2007, that compared statin regimens of different intensities in adults with coronary artery disease and that reported cardiovascular events or mortality. Data were pooled using random-effects models to calculate odds ratios (OR).

Results

A total of 7 trials (29 395 patients) were included. Compared with less intensive statin regimens, more intensive regimens further reduced LDL levels (0.72 mmol/L reduction, 95% confidence interval [CI] 0.60–0.84 mmol/L), and reduced the risk of myocardial infarction (OR 0.83, 95% CI 0.77–0.91) and stroke (OR 0.82, 95% CI 0.71–0.95). Although there was no effect on mortality among patients with chronic coronary artery disease (OR 0.96, 95% CI 0.80–1.14), all-cause mortality was reduced among patients with acute coronary syndromes treated with more intensive statin regimens (OR 0.75, 95% CI 0.61–0.93). Compared with lower intensity regimens, more intensive regimens were associated with small absolute increases in rates of drug discontinuation (2.5%), elevated levels of aminotransferases (1%) and myopathy (0.5%), and there was no difference in noncardiovascular mortality. All 7 trials reported events by randomization arm rather than by LDL level achieved. About half of the patients treated with more intensive statin therapy did not achieve an LDL level of less than 2.0 mmol/L, and none of the trials tested combination therapies.

Interpretation

Our analysis supports the use of more intensive statin regimens in patients with established coronary artery disease. There is insufficient evidence to advocate treating to particular LDL targets, using combination lipid-lowering therapy to achieve these targets or for using more intensive regimens in patients without established coronary artery disease.Dyslipidemia is the most important modifiable risk factor for myocardial infarction worldwide,¹ and serum cholesterol levels are directly related to mortality from coronary artery disease in all populations studied.^2–4 Over the past decade, randomized controlled trials enrolling a wide variety of patients have confirmed that for every 1-mmol/L reduction in serum low-density lipoprotein (LDL) cholesterol achieved by statin therapy, the relative risks of cardiovascular events and mortality are reduced (by 21% and 12% respectively).⁵Statins exert their beneficial effects primarily by reducing the level of LDL cholesterol,⁶ and the reductions in the relative risk of cardiovascular events achieved by statin therapy appears to be similar regardless of baseline cholesterol levels.⁵ As a result, attention has increasingly focused on defining optimal target LDL levels, particularly in patients at highest risk (i.e., those with coronary artery disease). Based on the observational studies mentioned above,^2,3 the apparent lack of a lower threshold for statin benefit in the randomized controlled trials, and recent trials reporting greater benefits with more intensive statin regimens (compared with less intensive regimens), Canadian⁷ and American⁸ guidelines for secondary prevention now recommend target LDL levels below 2.0 mmol/L in patients with coronary artery disease. On the other hand, European guidelines specify a target LDL of 2.5 mmol/L in these patients.⁹ Questions have been raised about the safety and incremental benefits of more intensive statin regimens.^10–12We performed a systematic review and meta-analysis to critically examine the evidence for the safety, efficacy (LDL lowering) and clinical effectiveness from trials comparing more intensive statin therapy with less intensive statin therapy in patients with coronary artery disease.     

Are statins anti-inflammatory?

Large scale clinical trials demonstrate significant reductions in cardiovascular event rates with statin therapy. The observed benefit of statin therapy, however, may be larger in these trials than that expected on the basis of lipid lowering alone. Emerging evidence from both clinical trials and basic science studies suggest that statins have anti-inflammatory properties, which may additionally lead to clinical efficacy. Measurement of markers of inflammation such as high sensitivity C-reactive protein in addition to lipid parameters may help identify those patients who will benefit most from statin therapy.     

Efficacy of Short-Term High-Dose Statin Pretreatment in Prevention of Contrast-Induced Acute Kidney Injury: Updated Study-Level Meta-Analysis of 13 Randomized Controlled Trials

Background

There have been conflicting results across the trials that evaluated prophylactic efficacy of short-term high-dose statin pre-treatment for prevention of contrast-induced acute kidney injury (CIAKI) in patients undergoing coronary angiography (CAG). The aim of the study was to perform an up-to-date meta-analysis regarding the efficacy of high-dose statin pre-treatment in preventing CIAKI.

Methods and Results

Randomized-controlled trials comparing high-dose statin versus low-dose statin or placebo pre-treatment for prevention of CIAKI in patients undergoing CAG were included. The primary endpoint was the incidence of CIAKI within 2–5days after CAG. The relative risk (RR) with 95% CI was the effect measure. This analysis included 13 RCTs with 5,825 total patients; about half of them (n = 2,889) were pre-treated with high-dose statin (at least 40 mg of atorvastatin) before CAG, and the remainders (n = 2,936) pretreated with low-dose statin or placebo. In random-effects model, high-dose statin pre-treatment significantly reduced the incidence of CIAKI (RR 0.45, 95% CI 0.35–0.57, p<0.001, I² = 8.2%, NNT 16), compared with low-dose statin or placebo. The benefit of high-dose statin was consistent in both comparisons with low-dose statin (RR 0.47, 95% CI 0.34–0.65, p<0.001, I² = 28.4%, NNT 19) or placebo (RR 0.34, 95% CI 0.21–0.58, p<0.001, I² = 0.0%, NNT 16). In addition, high-dose statin showed significant reduction of CIAKI across various subgroups of chronic kidney disease, acute coronary syndrome, and old age (≥60years), regardless of osmolality of contrast or administration of N-acetylcystein.

Conclusions

High-dose statin pre-treatment significantly reduced overall incidence of CIAKI in patients undergoing CAG, and emerges as an effective prophylactic measure to prevent CIAKI.     

High-Dose Statin Pretreatment Decreases Periprocedural Myocardial Infarction and Cardiovascular Events in Patients Undergoing Elective Percutaneous Coronary Intervention: A Meta-Analysis of Twenty-Four Randomized Controlled Trials

Background

Evidence suggests that high-dose statin pretreatment may reduce the risk of periprocedural myocardial infarction (PMI) and major adverse cardiac events (MACE) for certain patients; however, previous analyses have not considered patients with a history of statin maintenance treatment. In this meta-analysis of randomized controlled trials (RCTs), we reevaluated the efficacy of short-term high-dose statin pretreatment to prevent PMI and MACE in an expanded set of patients undergoing elective percutaneous coronary intervention.

Methods

We searched the PubMed/Medline database for RCTs that compared high-dose statin pretreatment with no statin or low-dose statin pretreatment as a prevention of PMI and MACE. We evaluated the incidence of PMI and MACE, including death, spontaneous myocardial infarction, and target vessel revascularization at the longest follow-up for each study for subgroups stratified by disease classification and prior low-dose statin treatment.

Results

Twenty-four RCTs with a total of 5,526 patients were identified. High-dose statin pretreatment was associated with 59% relative reduction in PMI (odds ratio [OR]: 0.41; 95% confidence interval [CI]: 0.34–0.49; P<0.00001) and 39% relative reduction in MACE (OR: 0.61; 95% CI: 0.45–0.83; P = 0.002). The benefit of high-dose statin pretreatment on MACE was significant for statin-naive patients (OR: 0.69; 95% CI: 0.50–0.95; P = 0.02) and prior low dose statin-treated patients (OR: 0.28; 95% CI: 0.12–0.65; P = 0.003); and for patients with acute coronary syndrome (OR: 0.52; 95% CI: 0.34–0.79; P = 0.003), but not for patients with stable angina (OR: 0.71; 95% CI 0.45–1.10; P = 0.12). Long-term effects on survival were less obvious.

Conclusions

High-dose statin pretreatment can result in a significant reduction in PMI and MACE for patients undergoing elective PCI. The positive effect of high-dose statin pretreatment on PMI and MACE is significant for statin-naïve patients and patients with prior treatment. The positive effect of high-dose statin pretreatment on MACE is significant for patients with acute coronary syndrome.     

National Assessment of Statin Therapy in Patients Hospitalized with Acute Myocardial Infarction: Insight from China PEACE-Retrospective AMI Study, 2001, 2006, 2011

BackgroundStatin therapy is among the most effective treatments to improve short- and long-term mortality after acute myocardial infarction. The use of statin, and the intensity of their use, has not been described in acute myocardial infarction patients in China, a country with a rapidly growing burden of cardiovascular disease.ConclusionsThe use of statin therapy has dramatically increased over the past decade in Chinese patients with acute myocardial infarction. However, half of patients still did not receive intensive statin therapy in 2011.Given that guidelines strongly endorse intensive statin therapy for acute myocardial infarction patients, initiatives promoting the use of statin therapy, with attention to treatment intensity, would support further improvements in practice.     

Atorvastatin modifies the protein profile of circulating human monocytes after an acute coronary syndrome

Aggressive treatment with high‐dose atorvastatin reduces more effectively the incidence of cardiovascular events than moderate statin therapy. The mechanism of this benefit has not been fully elucidated. In order to know the potential effects of statin treatment on the protein expression of circulating monocytes in acute coronary syndrome (ACS) patients, a proteomic analysis of these cells was carried out by 2‐DE and MS. Twenty‐five patients with non‐ST‐elevation acute coronary syndrome (NSTEACS) were randomized, the fourth day after admission, to receive ATV 80 mg/dL (n = 14) or conventional treatment (CT) (n = 11), for two months. Blood was withdrawn at the end of the treatment, and monocytes were extracted for proteomic analysis and their protein expression patterns determined. Age, sex, total cholesterol, LDL, HDL, triglycerides, body mass index, presence of hypertension, diabetes, and smoking status were not significantly different between the two groups of patients. The expression of 20 proteins was modified by intensive ATV. Among the most relevant results stand out the normalization by intensive ATV treatment of the expression of proteins that modulate inflammation and thrombosis such as protein disulfide isomerase ER60 (PDI), Annexin I, and prohibitin, or that have other protective effects as HSP‐70. Thus, this approach shed light at the molecular level of the beneficial mechanisms of anti‐atherothrombotic drugs.     

HDL-raising strategies in the treatment of coronary artery disease: perspectives from the Armed Forces Regression Study

PURPOSE OF REVIEW: Even with the aggressive reduction of LDL-cholesterol, the risk of cardiovascular events in patients with coronary artery disease remains substantial. The Armed Forces Regression Study was a randomized, double-blind, placebo-controlled trial of combination drug therapy aimed at raising HDL-cholesterol in patients with angiographically evident coronary artery disease. Drug therapy ultimately resulted in regression of the angiographic lesions and a reduction in cardiovascular events. This review places the Armed Forces Regression Study within the context of other recent studies. RECENT FINDINGS: In the past few years a number of other important papers have further defined the important role HDL-cholesterol plays in the pathobiology of atherosclerosis. These studies have focused on three general areas: HDL-cholesterol metabolism and the reverse cholesterol transport pathway; novel therapeutic interventions and their effects on coronary artery disease as assessed through non-invasive imaging modalities; and finally a re-analysis of previous outcomes trials with established HDL-cholesterol modifying agents. SUMMARY: The results of the Armed Forces Regression Study fit nicely within the evolving paradigm of targeting HDL-cholesterol in patients at risk of cardiovascular events. The use of niacin and well-tolerated fibrates as an adjunct to statins or as primary therapy in patients intolerant of statins appears reasonable in patients with low levels of HDL-cholesterol and at high risk of cardiovascular events. The further development of novel therapeutic approaches, in addition to broadening our pharmacological armamentarium, should further advance our understanding of HDL-cholesterol.     

Role for fibrate therapy in diabetes: evidence before FIELD

PURPOSE OF REVIEW: Diabetic dyslipidaemia, among the main factors contributing to vascular risk in type 2 diabetes, is characterized by hypertriglyceridaemia, low HDL-cholesterol and increased prevalence of small dense LDL particles. Because fibrates have positive effects on triglycerides, HDL-cholesterol and LDL particle size, they may be an appropriate treatment for diabetic dyslipidaemia. Statins have been shown to diminish significantly the risk for coronary disease in patients with type 2 diabetes, and so what are the real effects of fibrates on cardiovascular risk in type 2 diabetes? RECENT FINDINGS: Although statins reduce the incidence of coronary disease in type 2 diabetes, data from clinical trials demonstrate 'residual' cardiovascular risk in these patients treated with statins. Clinical trials with fibrates show that they are particularly effective in reducing cardiovascular risk in patients with type 2 diabetes/metabolic syndrome and in those exhibiting the lipid abnormalities typical of diabetic dyslipidaemia (elevated triglycerides, low HDL-cholesterol). SUMMARY: Data on the effects of fibrates on cardiovascular risk in diabetes were obtained from subgroup analyses. Thus far, the only study performed specifically in patients with type 2 diabetes is the angiographic Diabetes Atherosclerosis Intervention Study which demonstrated a significant reduction in progression of atherosclerosis in patients receiving fenofibrate, but it was not powered to analyse the effects of fibrates on clinical outcomes. This is why the Fenofibrate Intervention and Event Lowering in Diabetes study is needed; it will provide robust data on the ability of fibrates to reduce cardiovascular risk in patients with type 2 diabetes.     

Role of lipid-modifying therapy in the prevention of initial and recurrent stroke

PURPOSE OF REVIEW: To establish the role of cholesterol-modifying therapy in stroke prevention. RECENT FINDINGS: Population-based observational cohort studies show a variable weak positive relationship between increasing plasma total cholesterol concentrations and an increasing risk of ischaemic stroke, which is partly offset by a weaker negative association between decreasing total cholesterol concentrations and an increasing risk of with haemorrhagic stroke. However, randomized controlled trials show unequivocally that lowering plasma total cholesterol by approximately 1.2 mmol/l (and LDL-cholesterol by 1.0 mmol/l) is associated with a reduced relative risk of stroke and other serious vascular events by at least a quarter, and probably a third, without any increase in haemorrhagic stroke, in a wide range of men and women (including individuals with previous stroke). The proportional reduction in stroke risk is consistent, irrespective of the patient's age, baseline plasma cholesterol concentration, and absolute risk of stroke (although perhaps less in very low-risk individuals), but is increased with greater degrees of cholesterol lowering (15% or more), and thus with statin medications, which are more potent than non-statin interventions in lowering cholesterol levels. The absolute reduction in stroke risk achieved by statins is greatest among individuals at highest risk of stroke. Preliminary evidence suggests that lowering total cholesterol levels by diet may be an effective adjunctive therapy to statins, and raising plasma HDL-cholesterol concentrations among patients with coronary heart disease and low HDL-cholesterol levels ( 1 mmol/l) by means of gemfibrozil may also effectively prevent stroke. SUMMARY: Statin drugs are effective and safe in preventing initial and recurrent stroke. However, because they are costly, they should probably be restricted to individuals with an annual risk of stroke and other serious vascular events of 3% or greater, and possibly as low as 1.5%, because routine monitoring of plasma cholesterol, and liver and muscle enzyme concentrations is probably no longer necessary.