Use of an indirect effect model to describe the LDL cholesterol-lowering effect by statins in hypercholesterolaemic patients (original) (raw)
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Korean Circulation Journal, 2007
Background and Objectives：Although the rate of prescribing hydroxylmethyglutaryl-CoA reductase inhibitors (statin) has recently increased, there is a large treatment gap between the guidelines and actual clinical practice. We studied the effect of high potency statin on the percentage of patients who achieve the target low density lipoprotein (LDL) cholesterol level, and we determined the changes of lipid profiles with using 10 mg of rosuvastatin and 20 mg of atorvastatin. Materials and Methods：222 consecutive patients with acute coronary syndrome or acute ischemic stroke were randomly assigned to either the group treated with rosuvastatin 10 mg (Group I) or atorvastatin 20 mg (Group II). We compared the percentage of patients who achieved the target LDL cholesterol level, and the percent change of the serum lipid profile from baseline to the 40th week between the two groups. Results：117 (52.7%) patients completed this study. When the target LDL cholesterol level was <100 mg/dL, there was no significant difference in the target attainment rate between the two groups (86.7% vs. 77.2%; respectively, p=0.182). When the target LDL cholesterol level was <70 mg/dL, 48.3% of Group I and 29.8% of Group II reached the goal (p=0.040). The LDL cholesterol level was reduced by 46.8% in Group I (p<0.001), and by 40.1% in Group II (p<0.001). However, the final level showed a trend to be lower in the rosuvastatin group (p=0.077). There were no serious side effects in both groups. The study drug was discontinued due to adverse events in 2 patients (2.6%) of Group I, and in 3 patients (3.8%) of Group II (p=0.523). Conclusion：This study showed that the reduction of LDL cholesterol was not statistically different between rosuvastatin 10 mg and atorvastatin 20 mg. However, fewer than half of the patients achieved the goal in both groups despite of high potency statin therapy. This suggests that more aggressive statin therapy is preferred for high risk patients. (Korean Circulation J 2007;37:154-160) KEY WORDS：Hydroxylmethyglutaryl-CoA reductase inhibitors；Cholesterol；Guideline.
The statin studies: from targeting hypercholesterolaemia to targeting the high-risk patient
QJM: An International Journal of Medicine, 2005
The landmark HMG-CoA reductase inhibitor (statin) studies have practical lessons for clinicans. The 4S trial established the importance of treating the hypercholesterolaemic patient with cardiovascular heart disease. Next, WOSCOPS showed the benefit of treating healthy, high-risk hypercholesterolaemic men. CARE, a secondary prevention trial, showed the benefit of treating patients with cholesterol levels within normal limits. This was confirmed by the LIPID trial, another secondary prevention study, which enrolled patients with cholesterol levels 155-271 mg/dl (4-7 mmol/l). The importance of treating patients with established ischaemic heart disease, and those at high risk of developing heart disease, regardless of cholesterol level, was being realized. In the MIRACL trial, hypocholesterolaemic therapy was useful in the setting of an acute coronary syndrome, while the AVERT study showed that aggressive statin therapy is as good as angioplasty in reducing ischaemic events in patients with stable angina. By showing the value of fluvastatin after percutaneous intervention, LIPS confirmed that benefit is a class action of the statins. The HPS randomized over 20 000 patients, and showed beyond doubt the value of statins in reducing cardiovascular events in the high-risk patient. Although PROSPER showed benefit in treating the elderly patients above 70 years, statin therapy in this trial was associated with an increase in cancer incidence. The comparative statin trials, PROVE-IT, REVERSAL, Phase Z of the A to Z, ALLIANCE and TNT, all showed that highdose statins will better reduce cardiovascular events in the high-risk patient, although the adverse effects of therapy will also be increased. ALLHAT-LLT, ASCOT-LLA and CARDS showed that for statin therapy to demonstrate a significant benefit, hypertensive or diabetic patients must be at sufficiently high risk of cardiovascular events. The emphasis is now on the risk level for developing cardiovascular events, and treatment should target the high-risk group and not the lipid level of the patient. No therapy is free of adverse effect. Treatment of those most at risk will bring the most benefit; treatment of those not at high risk of cardiovascular disease may expose patients who would not benefit much from therapy to its adverse effects.
Clinical Cardiology, 2009
Numerous studies have demonstrated that treatments designed to reduce lowdensity lipoprotein cholesterol (LDL-C) can reduce the risk of coronary heart disease (CHD) events in the setting of either primary or secondary prevention. The rationale for aggressive lowering of LDL-C, supported by large obkrvational studies, is the concept that no threshold exists below' which reductions fail to provide addifional benefit. The statins are widely considered first-line therapy for preventing CHD events because these agents yield the greatest reductions in LDL-C. However, many patients do not achieve target LDL-C levels with the currently available statins. Newer, more effective statins may permit the benefits of aggressive LDL-C reduction to be extended to larger numbers of patients. A novel, highly efficacious statin, rosuvastatin (Crestor", AstraZeneca group of companies), is currently undergoing clinical investigation. Dose-ranging studies in hypercholesterolemic patients have shown that rosuvastatin produces significant, dosedependent decreases in LDL-C when compared with placebo. Reductions have ranged from 34% at a dose of 1 mg/day to 65% at 80 mg/day. This agent has been found to be well tolerated across the range of doses studied. Phase III studies indicate that rosuvastatin is more effective than atorvastatin, pravastatin, and simvastatin in improving the atherogenic lipid profiles of hypercholesterolemic patients, and more effective than atorvastatin in improving the atherogenic lipid profiles of patients with heterozygous familial hypercholesterolemia. Overall, these findings suggest that rosuvastatin is a promising new medication for the treatment of dyslipidemias.
Statin therapy--Part II: Clinical considerations for cardiovascular disease
Vascular and endovascular surgery, 2010
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly known as statins, are the medical treatment of choice for hypercholesterolemia. In addition to achieving a therapeutic decrease in serum cholesterol levels, statin therapy appears to promote pleiotropic effects that are independent of changes in serum cholesterol. These cholesterol lowering and pleiotropic effects are beneficial not only for the coronary circulation, but for the myocardium and peripheral arterial system as well. Patients receiving statin therapy must be carefully monitored, however, as statins potentially have harmful side effects and drug interactions. This article is part II of a 2-part review, and it focuses on the clinical aspects of statin therapy in cardiovascular disease.
Reducing morbidity and mortality in high risk patients with statins
Vascular Health and Risk Management, 2009
Residual coronary heart disease remains a significant problem even after adequate statin therapy for cardiovascular risk reduction as currently recommended by the Adult Treatment Panel III (ATP-III) of the National Cholesterol Education Program (NCEP). This is particularly true for the high risk patients as defined by ATP-III that includes those patients who have a greater than 20% 10-year risk of adverse cardiac events. For such patients the current goal of a low-density lipoprotein cholesterol (LDL-cholesterol) maintenance level of 100 mg/dL plasma appears to be suboptimal. Accumulating data from several recent randomized studies of more aggressive LDL-cholesterol reduction to levels below 70 mg/dL in the high risk patients favor acceptance of such a new lower target for LDL-cholesterol using more intensive statin therapy which would affect the treatment strategy for patients with coronary heart disease prepercutaneous intervention, metabolic syndrome, diabetes mellitus, congestive heart failure, cerebro-vascular disease and chronic kidney disease.
Relative safety profiles of high dose statin regimens
Vascular health and risk management, 2008
Recent clinical trials recommend achieving a low-density lipoprotein cholesterol level of <100 mg/dl in high-risk and <70 mg/dl in very high risk patients. To attain these goals, however, many patients will need statins at high doses. The most frequent side effects related to the use of statins, myopathy, rhabdomyolysis, and increased levels of transaminases, are unusual. Although low and moderate doses show a favourable profile, there is concern about the tolerability of higher doses. During recent years, numerous trials to analyze the efficacy and tolerability of high doses of statins have been published. This paper updates the published data on the safety of statins at high doses.
Interpretation of the evidence for the effi cacy and safety of statin therapy
This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes. It explains how the evidence that is available from randomised controlled trials yields reliable information about both the effi cacy and safety of statin therapy. In addition, it discusses how claims that statins commonly cause adverse eff ects refl ect a failure to recognise the limitations of other sources of evidence about the eff ects of treatment. Large-scale evidence from randomised trials shows that statin therapy reduces the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the fi rst) that it continues to be taken. The absolute benefi ts of statin therapy depend on an individual's absolute risk of occlusive vascular events and the absolute reduction in LDL cholesterol that is achieved. For example, lowering LDL cholesterol by 2 mmol/L (77 mg/dL) with an eff ective low-cost statin regimen (eg, atorvastatin 40 mg daily, costing about £2 per month) for 5 years in 10 000 patients would typically prevent major vascular events from occurring in about 1000 patients (ie, 10% absolute benefi t) with pre-existing occlusive vascular disease (secondary prevention) and in 500 patients (ie, 5% absolute benefi t) who are at increased risk but have not yet had a vascular event (primary prevention). Statin therapy has been shown to reduce vascular disease risk during each year it continues to be taken, so larger absolute benefi ts would accrue with more prolonged therapy, and these benefi ts persist long term. The only serious adverse events that have been shown to be caused by long-term statin therapy—ie, adverse eff ects of the statin—are myopathy (defi ned as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase), new-onset diabetes mellitus, and, probably, haemorrhagic stroke. Typically, treatment of 10 000 patients for 5 years with an eff ective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of myopathy (one of which might progress, if the statin therapy is not stopped, to the more severe condition of rhabdomyolysis), 50–100 new cases of diabetes, and 5–10 haemorrhagic strokes. However, any adverse impact of these side-eff ects on major vascular events has already been taken into account in the estimates of the absolute benefi ts. Statin therapy may cause symptomatic adverse events (eg, muscle pain or weakness) in up to about 50–100 patients (ie, 0·5–1·0% absolute harm) per 10 000 treated for 5 years. However, placebo-controlled randomised trials have shown defi nitively that almost all of the symptomatic adverse events that are attributed to statin therapy in routine practice are not actually caused by it (ie, they represent misattribution). The large-scale evidence available from randomised trials also indicates that it is unlikely that large absolute excesses in other serious adverse events still await discovery. Consequently, any further fi ndings that emerge about the eff ects of statin therapy would not be expected to alter materially the balance of benefi ts and harms. It is, therefore, of concern that exaggerated claims about side-eff ect rates with statin therapy may be responsible for its under-use among individuals at increased risk of cardiovascular events. For, whereas the rare cases of myopathy and any muscle-related symptoms that are attributed to statin therapy generally resolve rapidly when treatment is stopped, the heart attacks or strokes that may occur if statin therapy is stopped unnecessarily can be devastating.
Circulation Journal, 2010
Once many epidemiological studies had proven an increase in coronary deaths and cardiac events associated with elevated levels of low-density lipoprotein-cholesterol (LDL-C), 1,2 the next clinical question became whether lowering LDL-C by drugs or diet would result in a reduction in cardiac events. This assessment was facilitated by the development of potent cholesterol-lowering drugs such as the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). In particular, statin therapy was proposed as a strategy to improve clinical outcomes and accordingly, large clinical trials using statin were started. By 2000, there had been many reports of the results of such large-scale clinical trials 3-8 and there was abundant evidence of the significant beneficial effects of lipid-lowering treatment using statin in reducing mortality and cardiovascular morbidity in patients with CAD as shown in Table 1. Interestingly, all the long-term clinical trials demonstrated that the beneficial effects of statin treatment were sustained and cumulative compared with placebo group as shown in Table 1. In the meta-analysis performed by The opinions expressed in this article are not necessarily those of the editors or of the Japanese Circulation Society.