Cholesterol-lowering drugs. Some drugs with demonstrated efficacy but different benefits in primary and secondary prevention

(1) In primary prevention trials, pravastatin and lovastatin prevented myocardial infarction and had a positive risk-benefit ratio in men with LDL-cholesterol values exceeding 4.5 mmol/l (1.7 g/l). Cholestyramine and gemfibrozil also prevented myocardial infarction in men with more severe hypercholesterolaemia; while clofibrate had a negative risk-benefit ratio in patients with moderate hypercholesterolaemia. These treatments have not been assessed for primary prevention in women or in patients aged over 70. (2) In trials involving patients with coronary heart disease, pravastatin and simvastatin both reduced the risk of myocardial infarction and/or mortality in patients of both sexes with LDL-cholesterol values above 3.2 mmol/l (1.2 g/l). Gemfibrozil also reduced the risk of myocardial infarction but not mortality, while clofibrate and bezafibrate had no preventive effect.     

Atorvastatin: an updated review of its pharmacological properties and use in dyslipidaemia.

Atorvastatin is a synthetic hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. In dosages of 10 to 80 mg/day, atorvastatin reduces levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride and very low-density lipoprotein (VLDL)-cholesterol and increases high-density lipoprotein (HDL)-cholesterol in patients with a wide variety of dyslipidaemias. In large long-term trials in patients with primary hypercholesterolaemia. atorvastatin produced greater reductions in total cholesterol. LDL-cholesterol and triglyceride levels than other HMG-CoA reductase inhibitors. In patients with coronary heart disease (CHD), atorvastatin was more efficacious than lovastatin, pravastatin. fluvastatin and simvastatin in achieving target LDL-cholesterol levels and, in high doses, produced very low LDL-cholesterol levels. Aggressive reduction of serum LDL-cholesterol to 1.9 mmol/L with atorvastatin 80 mg/day for 16 weeks in patients with acute coronary syndromes significantly reduced the incidence of the combined primary end-point events and the secondary end-point of recurrent ischaemic events requiring rehospitalisation in the large. well-designed MIRACL trial. In the AVERT trial, aggressive lipid-lowering therapy with atorvastatin 80 mg/ day for 18 months was at least as effective as coronary angioplasty and usual care in reducing the incidence of ischaemic events in low-risk patients with stable CHD. Long-term studies are currently investigating the effects of atorvastatin on serious cardiac events and mortality in patients with CHD. Pharmacoeconomic studies have shown lipid-lowering with atorvastatin to be cost effective in patients with CHD, men with at least one risk factor for CHD and women with multiple risk factors for CHD. In available studies atorvastatin was more cost effective than most other HMG-CoA reductase inhibitors in achieving target LDL-cholesterol levels. Atorvastatin is well tolerated and adverse events are usually mild and transient. The tolerability profile of atorvastatin is similar to that of other available HMG-CoA reductase inhibitors and to placebo. Elevations of liver transaminases and creatine phosphokinase are infrequent. There have been rare case reports of rhabdomyolysis occurring with concomitant use of atorvastatin and other drugs. CONCLUSION: Atorvastatin is an appropriate first-line lipid-lowering therapy in numerous groups of patients at low to high risk of CHD. Additionally it has a definite role in treating patients requiring greater decreases in LDL-cholesterol levels. Long-term studies are under way to determine whether achieving very low LDL-cholesterol levels with atorvastatin is likely to show additional benefits on morbidity and mortality in patients with CHD.     

Atorvastatin versus pravastatin: intensive versus moderate lipid lowering

With so many statins available for clinical use in coronary artery syndromes, there has been much discussion about which is the best. Two recent trials have compared the clinical outcomes of intensive lipid lowering with atorvastatin 80 mg/day and standard lowering with pravastatin 40 mg/day. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) trial, patients with acute coronary artery syndromes were enrolled, and pravastatin lowered the low-density lipoprotein (LDL)-cholesterol to 2.46 mmol/l, whereas atorvastatin lowered it to 1.60 mmol/l. Associated with this, there was a lower rate of clinical events (myocardial infarction, revascularisation) over 2 years with atorvastatin than pravastatin (22.4 versus 26.3%, respectively). The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial also enrolled patients requiring angiography, and pravastatin lowered the LDL-cholesterol to 2.84 mmol/l, whereas atorvastatin lowered the LDL-cholesterol to 2.04 mmol/l. In the REVERSAL trial, atheroma volume progressed with pravastatin by 2.7% whilst remaining stable in the atorvastatin group (-0.4%) over 18 months. Thus, atorvastatin 80 mg/day causes a greater reduction in LDL-cholesterol than pravastatin 40 mg/day, and this is associated with a reduced progression of atheroma and reduced clinical events. As a consequence of these findings, the National Cholesterol Education Programme and European guidelines for LDL-cholesterol levels should be lowered.     

Atorvastatin versus pravastatin: intensive versus moderate lipid lowering

With so many statins available for clinical use in coronary artery syndromes, there has been much discussion about which is the best. Two recent trials have compared the clinical outcomes of intensive lipid lowering with atorvastatin 80 mg/day and standard lowering with pravastatin 40 mg/day. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) trial, patients with acute coronary artery syndromes were enrolled, and pravastatin lowered the low-density lipoprotein (LDL)-cholesterol to 2.46 mmol/l, whereas atorvastatin lowered it to 1.60 mmol/l. Associated with this, there was a lower rate of clinical events (myocardial infarction, revascularisation) over 2 years with atorvastatin than pravastatin (22.4 versus 26.3%, respectively). The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial also enrolled patients requiring angiography, and pravastatin lowered the LDL-cholesterol to 2.84 mmol/l, whereas atorvastatin lowered the LDL-cholesterol to 2.04 mmol/l. In the REVERSAL trial, atheroma volume progressed with pravastatin by 2.7% whilst remaining stable in the atorvastatin group (-0.4%) over 18 months. Thus, atorvastatin 80 mg/day causes a greater reduction in LDL-cholesterol than pravastatin 40 mg/day, and this is associated with a reduced progression of atheroma and reduced clinical events. As a consequence of these findings, the National Cholesterol Education Programme and European guidelines for LDL-cholesterol levels should be lowered.     

Relating statin therapy to C-reactive protein levels

Inflammation is pivotal in atherosclerosis, and C-reactive protein (CRP) is an inflammatory marker that predicts cardiovascular events. The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial compared the standard lowering of low-density lipoprotein (LDL)-cholesterol with pravastatin 40 mg/day, with the intense lowering of LDL-cholesterol with atorvastatin 80 mg/day on atheroma volume in patients with coronary artery disease, and showed that the atheroma progressed by 2.7% in the pravastatin group, and remained unchanged in the atorvastatin group. At 18 months follow-up, the CRP levels were reduced from a baseline level of 2.8 mg/l to 1.8 mg/l by atorvastatin, whereas pravastatin had little effect, and there was a good correlation between both the ultrasonographic progression of disease and the reduction in CRP levels. The Pravastatin or Atorvastatin Evaluation and Infection Therapy--Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial compared the long-term effects of the standard lowering of LDL-cholesterol with pravastatin, with the intense lowering of LDL-cholesterol with atorvastatin in patients with an acute coronary syndrome. The primary end point was the first of death, myocardial infarction, unstable angina requiring hospitalisation, revascularisation or stroke, and, at the end of 2 years, was greater in the pravastatin than the atorvastatin group (26.3 versus 22.4%, respectively). Patients with CRP levels of 2 mg/l had lower rates of recurrent myocardial infarction or death from coronary causes than patients with higher levels. Further analysis should be undertaken to assess cardiovascular risk at different levels of CRP, including assessing cardiovascular risk at different levels in men and women. Definitive results about the importance of lowering CRP levels are not likely to be obtained until the results of the Justification for Use of Statins in Primary Prevention, an Intervention Trial in Evaluating Rosuvastatin (JUPITER) study are published.     

Relating statin therapy to C-reactive protein levels

Inflammation is pivotal in atherosclerosis, and C-reactive protein (CRP) is an inflammatory marker that predicts cardiovascular events. The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial compared the standard lowering of low-density lipoprotein (LDL)-cholesterol with pravastatin 40 mg/day, with the intense lowering of LDL-cholesterol with atorvastatin 80 mg/day on atheroma volume in patients with coronary artery disease, and showed that the atheroma progressed by 2.7% in the pravastatin group, and remained unchanged in the atorvastatin group. At 18 months follow-up, the CRP levels were reduced from a baseline level of 2.8 mg/l to 1.8 mg/l by atorvastatin, whereas pravastatin had little effect, and there was a good correlation between both the ultrasonographic progression of disease and the reduction in CRP levels. The Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial compared the long-term effects of the standard lowering of LDL-cholesterol with pravastatin, with the intense lowering of LDL-cholesterol with atorvastatin in patients with an acute coronary syndrome. The primary end point was the first of death, myocardial infarction, unstable angina requiring hospitalisation, revascularisation or stroke, and, at the end of 2 years, was greater in the pravastatin than the atorvastatin group (26.3 versus 22.4%, respectively). Patients with CRP levels of 2 mg/l had lower rates of recurrent myocardial infarction or death from coronary causes than patients with higher levels. Further analysis should be undertaken to assess cardiovascular risk at different levels of CRP, including assessing cardiovascular risk at different levels in men and women. Definitive results about the importance of lowering CRP levels are not likely to be obtained until the results of the Justification for Use of Statins in Primary Prevention, an Intervention Trial in Evaluating Rosuvastatin (JUPITER) study are published.     

Atorvastatin efficacy in the prevention of cardiovascular events in patients with diabetes mellitus and/or metabolic syndrome

Several large-scale clinical trials have assessed the efficacy of atorvastatin in the primary and secondary prevention of cardiovascular events in patients with diabetes mellitus and/or metabolic syndrome. In primary prevention, CARDS (Collaborative Atorvastatin Diabetes Study) showed that atorvastatin 10 mg/day (vs placebo) reduced relative risk of the composite primary endpoint (acute coronary heart disease [CHD] events, coronary revascularisation, or stroke) by 37% (p = 0.001). This decrease was similar to decreases in major cardiovascular events in the ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm) trial and HPS (Heart Protection Study). However, in CARDS, atorvastatin efficacy was evident as early as 6 months after starting treatment, whereas in HPS, simvastatin efficacy was noticeable only from about 15-18 months after starting treatment. In the ASCOT-LLA trial, in 2226 hypertensive diabetic patients without previous cardiovascular disease, atorvastatin (vs placebo) reduced the relative risk of all cardiovascular events and procedures by 25% (p = 0.038). In secondary prevention, substudies of the GREACE (GREek Atorvastatin and Coronary-heart-disease Evaluation), TNT (Treating to New Targets) and PROVE-IT (PRavastatin Or atorVastatin Evaluation and Infection Therapy) trials reported results for the approximately 15-25% of study participants who had diabetes. In the GREACE substudy, atorvastatin (vs physicians' standard care) significantly reduced the relative risk of total mortality by 52% (p = 0.049), coronary mortality by 62% (p = 0.042), coronary morbidity by 59% (p < 0.002) and stroke by 68% (p = 0.046). In the TNT substudy, incidence of the primary endpoint was significantly lower in diabetic patients treated with atorvastatin 80 mg/day rather than 10 mg/day (13.8% vs 17.9%; relative risk 0.75; p = 0.026). In the PROVE-IT substudy, a significantly lower incidence of acute cardiac events was reported for atorvastatin versus pravastatin recipients (21.1% vs 26.6%; p = 0.03) and, therefore, an absolute risk reduction of 5.5% was associated with atorvastatin therapy. ASPEN (Atorvastatin Study for Prevention of coronary heart disease Endpoints in Non-insulin-dependent diabetes mellitus) - a mixed primary and secondary prevention trial in diabetic patients - found that a 29% lower low-density lipoprotein-cholesterol level was seen with atorvastatin than placebo at endpoint (p < 0.0001); however, the reduction in composite primary endpoint of major cardiovascular events (cardiovascular mortality, nonfatal major cardiovascular event or stroke, and unstable angina requiring hospitalisation) with atorvastatin (13.7% vs 15.0% with placebo), and reduction in acute myocardial infarction relative risk of 27% with atorvastatin were not statistically significant. In CHD patients with metabolic syndrome (n = 5584) in a sub-analysis of the TNT trial, intensive versus lower-dosage atorvastatin therapy reduced the relative risk of major cardiovascular and cerebrovascular events by 29% (p < 0.0001). The analysis also revealed that CHD patients with, rather than those without, metabolic syndrome had a 44% greater level of absolute cardiovascular risk, thus clearly underscoring the clinical feasibility of administering intensive lipid-lowering therapy to CHD patients with metabolic syndrome. In summary, several patient populations, from definitive, large-scale studies, are now available to corroborate the integral place of atorvastatin--in line with various regional and internationally accepted disease management guidelines--in the primary and secondary prevention of cardiovascular events in patients with diabetes and/or metabolic syndrome.     

Rosuvastatin: new preparation. Opt for statins with evidence of efficacy on clinical outcome

(1) Simvastatin and pravastatin are the two reference statins for type IIA and type IIB hypercholesterolaemia because they have the best-documented protective effect against cardiovascular events. Simvastatin and pravastatin are also the reference statins for familial heterozygous hypercholesterolaemia, though there is no evidence that they prevent cardiovascular events in this group. Statins are not very effective in familial homozygous hypercholesterolaemia. (2) Rosuvastatin is the sixth statin to arrive on the French market. The fifth, cerivastatin, was withdrawn from the market in 2001 because of serious adverse effects. (3) Rosuvastatin has not been assessed in terms of morbidity or mortality. The results of comparative trials in type IIA and type IIB hypercholesterolaemia suggest that rosuvastatin is slightly more active than simvastatin, pravastatin and atorvastatin on some lipid parameters after a few weeks of treatment. (4) Rosuvastatin has not been compared with simvastatin or pravastatin in familial heterozygous hypercholesterolaemia. One trial showed it to be slightly more effective than atorvastatin on cholesterol levels. According to one trial, rosuvastatin does not appear to be more effective than atorvastatin in homozygous forms. (5) In clinical trials the adverse effects of rosuvastatin were similar to those of other statins, with the exception of renal adverse effects. We don't know whether rosuvastatin is more or less likely than other statins to cause rhabdomyolysis. (6) Clinical trials reported some cases of proteinuria and renal failure suggesting there is a need for more thorough assessment in long-term trials. (7) In practice, statins with the best-documented benefits (simvastatin and pravastatin) should be used first for cardiovascular prevention in patients with hypercholesterolaemia.     

Atorvastatin: a review of its use in the primary prevention of cardiovascular events in patients with type 2 diabetes mellitus

Atorvastatin (Lipitor) is an HMG-CoA reductase inhibitor with well documented lipid-lowering effects. It has recently been evaluated for the primary prevention of major cardiovascular events in patients with type 2 diabetes mellitus without elevated serum low-density lipoprotein (LDL)-cholesterol levels. Atorvastatin 10mg daily for 4 years was effective at reducing the risk of a first major cardiovascular event, including stroke, in a large, placebo-controlled, multicentre trial in patients with type 2 diabetes and at least one other coronary heart disease (CHD) risk factor, but without markedly elevated LDL-cholesterol levels. In this trial, known as CARDS (the Collaborative AtoRvastatin Diabetes Study), atorvastatin had a similar tolerability profile to that of placebo. Thus, atorvastatin has a potential role in the primary prevention of cardiovascular events in diabetic patients at risk of CHD, irrespective of pre-treatment LDL-cholesterol levels.     

Statins in the 21st century: end of the simple story?

The development of the HMG-CoA reductase inhibitors (the statins) has lead to important advances in the management of cardiovascular disease. There have several landmark mortality and morbidity clinical trials with the statins. The 4S (Scandinavian Simvastatin Survival Study) was the first large-scale randomised cholesterol-lowering trial to show a decrease in mortality. In patients with coronary heart disease and relatively high cholesterol, simvastatin decreased mortality, hospital stays, the risk of undergoing myocardial re-vascularisation, stroke and transient ischaemic attack. The CARE (Cholesterol and Recurrent Events) trial showed that lowering average cholesterol levels after myocardial infarction with pravastatin reduced a composite primary end point of coronary mortality and myocardial infarction, coronary bypass surgery, angioplasty and strokes. The LIPID (Long-term Intervention with Pravastatin in Ischaaemic Disease) study showed that lowering average cholesterol levels after previous myocardial infarction or unstable angina reduced mortality. WOSCOPS (The West of Scotland Coronary Prevention Study) was the first trial to demonstrate the benefit of pravastatin, as primary prevention for cardiovascular disease, in men with high cholesterol levels. AFCAPS/Tex CAPS (The Air Force/Texas Coronary Atherosclerosis Prevention Study) showed that the benefits of lowering cholesterol levels were also evident in healthy men and women who initially had average cholesterol levels. Rather surprisingly the reductions in mortality and morbidity with statins are only associated with small improvements in coronary angiographic findings. A preliminary study indicated than lovastatin prevented restenosis, but larger and better-controlled studies indicate that the statins do not have beneficial effects in restenosis. Effects other than lipid-lowering or as a consequence of their lipid-lowering may contribute to the beneficial effects of statins. These effects include improvement in vascular endothelial function, cardiac remodelling, changes in blood rheology, anti-oxidant, anti-inflammatory and anti-hypertensive actions.     

Atorvastatin efficacy in the primary and secondary prevention of cardiovascular events

Atorvastatin has been extensively studied in the primary and secondary prevention of cardiovascular events, and may have some clinical advantages over various other statins in these respects. The principal primary prevention study of atorvastatin, ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm), revealed that atorvastatin reduced the relative risk of primary coronary heart disease (CHD) events by 36% (p = 0.0005) compared with placebo in patients with hypertension. Much published data confirm the secondary preventive benefits of atorvastatin in various clinical settings. The IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) and TNT (Treating to New Targets) trials demonstrate the preventive efficacy of atorvastatin in patients with stable CHD. Relative to simvastatin (in the IDEAL trial) and low-dosage atorvastatin (in the TNT trial), intensive atorvastatin therapy (80 mg/day) reduced the risk of nonfatal myocardial infarction (MI) by 17-22% (p < or = 0.02). Furthermore, the ALLIANCE (Aggressive Lipid-Lowering Initiation Abates New Cardiac Events) and GREACE (GREek Atorvastatin and Coronary-heart-disease Evaluation) trials highlight the benefits of atorvastatin in the 'real world' setting in patients with stable CHD. Compared with 'usual' care, atorvastatin reduced the risk of nonfatal MI by 47-59% (p < or = 0.0002).Moreover, the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering), PROVE-IT (PRavastatin Or atorVastatin Evaluation and Infection Therapy) and IDEAL-ACS (Acute Coronary Syndromes) studies outline the benefits of high-dosage atorvastatin therapy started within 24-96 hours, 10 days or 2 months, respectively, of an acute coronary syndrome. Relative to placebo, pravastatin and simvastatin, atorvastatin reduced the risk of death or major cardiovascular events by 16-18% (p < or = 0.048). In patients undergoing revascularisation procedures, the AVERT (Atorvastatin VErsus Revascularisation Treatment) study revealed that 18 months' administration of atorvastatin 80 mg/day was at least as effective as angioplasty plus usual care in reducing the risk of ischaemic events in low-risk patients with stable coronary artery disease. Furthermore, the ARMYDA (Atorvastatin for Reduction in MYocardial DAmage during angioplasty) and ARMYDA-3 trials showed that 7 days' administration of atorvastatin 40 mg/day before coronary intervention significantly reduced the risks of periprocedural myocardial damage (ARMYDA), postprocedural MI (p = 0.025; ARMYDA) and atrial fibrillation (p = 0.003; ARMYDA-3) versus placebo. In addition, it has been reported that C-reactive protein levels and the combined incidence of cardiovascular events (death, MI and target segment revascularisation during the 6-month follow-up) were significantly higher in coronaropathic patients undergoing non-surgical revascularisation procedures (stent implantation) not receiving statin therapy compared with those treated with atorvastatin (80mg). Overall, therefore, the marked efficacy of atorvastatin in the primary and secondary prevention of cardiovascular events underscores the pivotal place that this statin has in general cardiovascular disease management, and suggests even greater potential clinical utility for the drug in some clinical settings.     

Comparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin, and pravastatin in achieving lipid goals: results from the STELLAR trial

In the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial, the efficacy of rosuvastatin calcium (Crestor) was compared with that of atorvastatin (Lipitor), simvastatin (Zocor), and pravastatin (Pravachol) for lowering plasma low-density lipoprotein cholesterol (LDL-C) after 6 weeks of treatment. In this multicenter, parallel-group, open-label trial, adults with hypercholesterolemia were randomized to treatments with rosuvastatin 10, 20, 40, or 80 mg, atorvastatin 10, 20, 40, or 80 mg, simvastatin 10, 20, 40, or 80 mg, or pravastatin 10, 20, or 40 mg. Efficacy and safety results from this trial have been previously published. The additional analyses included in this report show that 53% (83/156) to 80% (125/157) of patients in the rosuvastatin 10- to 40-mg groups achieved LDL-C levels < 100 mg/dl (< 2.6 mmol/l), compared with 18% (28/158) to 70% (115/165) of patients who received atorvastatin, 8% (13/165) to 53% (86/163) of patients who received simvastatin, and 1% (1/160) to 8% (13/161) of patients who received pravastatin. Other additional analyses showed that more patients in the rosuvastatin 10- to 40-mg groups than in the comparator groups who were at high risk of coronary heart disease according to National Cholesterol Education Program Adult Treatment Panel (ATP) III, Joint European Societies, or Canadian guidelines achieved the LDL-C goals of < 100 mg/dl (< 2.6 mmol/l) (55% to 77% compared with 0 to 64%), < 3.0 mmol/l (< 116 mg/dl) (76% to 94% compared with 6% to 81%), and < 2.5 mmol/l (< 97 mg/dl) (47% to 69% compared with 0 to 53%), respectively. Results favoring rosuvastatin versus the comparators were also reported for patients: (a) who had triglycerides > or = 200mg/dl (> or = 2.3 mmol/l), and achieved both ATP III LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) goals (80% to 84% versus 15% to 84%); (b) overall who achieved the Canadian LDL-C goals of < 2.5 (< 97 mg/dl) to < 5.0 mmol/l (< 193 mg/dl) (85% to 91% versus 44% to 86%); and (c) who achieved all 3 Canadian goals for LDL-C, triglycerides (< 3.0 mmol/l [< 266 mg/dl] to < 2.0 mmol/l [< 177 mg/dl]), and the total cholesterol/high-density lipoproteincholesterol ratio (< 4 to < 7) (70% to 83% versus 35% to 79%).     

Simvastatin therapy for hypercholesterolaemia in patients with coronary heart disease

The efficacy of simvastatin therapy for hypercholesterolaemia was evaluated in 26 patients with coronary heart disease, 20 of whom had undergone coronary artery bypass grafting. Simvastatin reduced total- and low-density lipoprotein (LDL) cholesterol from 8.3 to 5.1 (38%) and 6.3 to 3.3 mmol/L (48%) respectively, p less than 0.001; high-density lipoprotein (HDL) cholesterol increased from 1.19 to 1.24 mmol/L, p = NS. The changes in apoproteins A1 and B paralleled those of HDL- and LDL-cholesterol. There were no clinically important adverse effects. We conclude that simvastatin is effective lipid lowering therapy and can be used safely, in the short term, in patients with coronary heart disease.     

Atorvastatin in prevention of stroke and transient ischaemic attack

Besides blood pressure-lowering drugs and, in certain circumstances, antithrombotic agents, statins are among the most effective drugs in reducing the risk of stroke in populations of patients at high vascular risk, as well as the risk of major coronary events. In secondary prevention of stroke, statins clearly reduced the risk of major coronary events. In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, compared with placebo, the patients with a recent stroke or transient ischaemic attack without coronary heart disease randomised to atorvastatin 80 mg/day had a significant 16% relative risk reduction of stroke and a 35% reduction in the risk of major coronary events. This was obtained despite the fact that 25% of patients allocated to the placebo arm were prescribed a commercially available statin outside the trial. A post-hoc analysis used blinded low-density lipoprotein cholesterol (LDL-C) measurements (taken at study visits during the trial) as a marker of adherence to lipid-lowering therapy. Compared with the group with no change or an increase in LDL-C (the group adherent to placebo or not taking a statin), the group with >or= 50% reduction in LDL-C had a significant 31% reduction in the risk of stroke. The next step is to define whether or not achieving a LDL-C of < 70 mg/dl is better than a standard dose of statin (LDL approximately 100 - 110 mg/dl) in the secondary prevention of stroke. Statins are effective in reducing both first-ever and recurrent stroke, and this effect seems driven by the extent of LDL-C lowering.     

Atorvastatin in prevention of stroke and transient ischaemic attack

Besides blood pressure-lowering drugs and, in certain circumstances, antithrombotic agents, statins are among the most effective drugs in reducing the risk of stroke in populations of patients at high vascular risk, as well as the risk of major coronary events. In secondary prevention of stroke, statins clearly reduced the risk of major coronary events. In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, compared with placebo, the patients with a recent stroke or transient ischaemic attack without coronary heart disease randomised to atorvastatin 80 mg/day had a significant 16% relative risk reduction of stroke and a 35% reduction in the risk of major coronary events. This was obtained despite the fact that 25% of patients allocated to the placebo arm were prescribed a commercially available statin outside the trial. A post-hoc analysis used blinded low-density lipoprotein cholesterol (LDL-C) measurements (taken at study visits during the trial) as a marker of adherence to lipid-lowering therapy. Compared with the group with no change or an increase in LDL-C (the group adherent to placebo or not taking a statin), the group with ≥ 50% reduction in LDL-C had a significant 31% reduction in the risk of stroke. The next step is to define whether or not achieving a LDL-C of < 70 mg/dl is better than a standard dose of statin (LDL ～ 100 – 110 mg/dl) in the secondary prevention of stroke. Statins are effective in reducing both first-ever and recurrent stroke, and this effect seems driven by the extent of LDL-C lowering.     

Atorvastatin: a pharmacoeconomic review of its use in the primary and secondary prevention of cardiovascular events

Atorvastatin is a lipid-lowering agent that has been evaluated in a number of primary and secondary intervention studies. In the primary prevention trials ASCOT-LLA and CARDS, atorvastatin 10 mg/day significantly reduced cardiovascular events compared with placebo. A prospectively conducted economic analysis of the 3.3-year ASCOT-LLA trial showed that atorvastatin was associated with incremental cost-effectiveness ratios (ICERs) of euro11,693 (UK) and euro12,673 (Sweden) per event avoided (2002 values). Longer-term modelled analyses using data from CARDS showed ICERs of euro8046 (Spain) and 6471pound (UK) per QALY gained (2003/2004 values), and a US analysis showed atorvastatin was dominant versus no statin when modelled over the lifetime of a representative US diabetic primary prevention population. In a modelled analysis based on results of the IDEAL trial, which showed significant reductions in cardiovascular endpoints with high-dose atorvastatin (80 mg/day) compared with conventional-dose simvastatin in patients with stable coronary heart disease, ICER values were below the commonly used cost-effectiveness threshold of euro50,000 per QALY gained in Norway, Sweden and Denmark, but were above this threshold in Finland (2005 values). A modelled US analysis that also included data from IDEAL and other sources showed an ICER of $US33,400 per QALY gained, assuming the incremental difference in acquisition cost between high-dose atorvastatin and conventional-dose simvastatin was $US1.40/day (2005 value). Most cost-effectiveness analyses with atorvastatin in patients with acute coronary syndrome used data from the 16-week MIRACL study, which showed a significant reduction in cardiovascular events with high-dose atorvastatin compared with placebo. Analyses were conducted in North America and Europe and showed that 31-86% of the acquisition cost of high-dose atorvastatin was offset by reductions in costs associated with cardiovascular events. Across five countries, ICER values ranged from approximate $US850 to $US4100 per event avoided (2000/2001 values). Another analysis conducted in the US used longer-term data and showed that high-dose atorvastatin versus conventional-dose statin was associated with an ICER of $US12,900 per QALY gained, assuming the daily difference in acquisition cost was $US1.40 (2005 value). In conclusion, atorvastatin has demonstrated beneficial effects on various cardiovascular endpoints in large, well designed primary and secondary intervention trials. These benefits in moderate- to high-risk patients were achieved at a relatively low incremental cost and, across the economic analyses, a substantial proportion of atorvastatin acquisition costs was offset by reductions in healthcare resource use associated with cardiovascular events. Cost-effectiveness analyses based on major clinical trials comparing atorvastatin with placebo, usual medical care, simvastatin or pravastatin have generally shown that atorvastatin is associated with favourable ICER values, often well below commonly used cost-effectiveness thresholds. These modelled analyses have the inherent limitation that projecting long-term outcomes beyond the time period of a clinical trial imparts a degree of uncertainty to the results. Nevertheless, while some findings were sensitive to changes in model assumptions, such as the long-term benefits of statin therapy, most sensitivity analyses showed that results of the base-case analyses were robust to plausible changes in key parameters. Although a clear pattern is not evident from available data, intuitively, the value of atorvastatin would be expected to increase with the patient's risk for serious cardiovascular events.     

Effects of policosanol and pravastatin on lipid profile, platelet aggregation and endothelemia in older hypercholesterolemic patients

This randomized, double-blind study was undertaken to compare the effects of policosanol and pravastatin administered at 10 mg/day on lipid profile, platelet aggregation and endothelemia in older patients with type II hypercholesterolemia and high coronary risk. After 6 weeks on a lipid-lowering diet, patients with low-density lipoprotein (LDL) cholesterol levels > 3.4 mmol/l were randomized to receive, under double-blind conditions, policosanol or pravastatin 10 mg tablets that were taken with the evening meal for 8 weeks. Policosanol significantly (p < 0.00001) lowered LDL-cholesterol (19.3%), total cholesterol (13.9%) and the ratios of LDL-cholesterol/high-density lipoprotein (HDL)-cholesterol (28.3%) and total cholesterol/HDL-cholesterol (24.4%). Pravastatin significantly (p < 0.00001) lowered LDL-cholesterol (15.6%), total cholesterol (11.8%) and the ratios (p < 0.0001) of LDL-cholesterol/HDL-cholesterol (18.9%) and total cholesterol/HDL-cholesterol (15.7%). Policosanol, but not pravastatin, significantly increased (p < 0.001) levels of HDL-cholesterol (18.4%) and reduced (p < 0.01) triglycerides (14.1%). Policosanol was more effective (p < 0.05) than pravastatin in inhibiting platelet aggregation induced by all agonists and it significantly reduced (p < 0.0001) platelet aggregation induced by arachidonic acid at 1.5 and 3 mmol/l by 42.2% and 69.5%, respectively, platelet aggregation induced by collagen 0.5 microgram/ml (p < 0.05) (16.6%) and that induced by adenosine diphosphate 1 mumol/l (p < 0.01) (20.3%). Pravastatin significantly reduced (p < 0.001) (27%) only platelet aggregation induced by arachidonic acid 3 mmol/l. Both drugs significantly decreased (p < 0.00001) endothelemia levels but final values were significantly lower (p < 0.001) in the policosanol than in the pravastatin group. Both treatments were safe and well tolerated. Pravastatin significantly (p < 0.01) increased serum levels of alanine amine transferase but individual values remained within normal. Two patients on pravastatin discontinued the study because of adverse experiences (myocardial infarction and jaundice, respectively). In conclusion, the effects of policosanol (10 mg/day) on lipid profile, platelet aggregation and endothelemia in older patients with type II hypercholesterolemia and high coronary risk are more favorable than those induced by the same doses of pravastatin.     

A comparison of the effects of simvastatin and pravastatin monotherapy on muscle histology and permeability in hypercholesterolaemic patients.

1. In this double-blind, placebo controlled, prospective study, it was assessed whether simvastatin or pravastatin monotherapy have adverse effects on muscle histology and muscle membrane permeability in hypercholesterolaemic patients. 2. Twenty-four patients, seven females and 17 males, with primary hypercholesterolaemia (LDL cholesterol levels > or = 4.14 mmol l-1) were selected from the outpatient lipid clinic of a 650 bed academic medical centre. 3. After a 6-week lipid lowering diet and placebo period, patients were randomized into two groups of 12 subjects with similar characteristics, to receive either simvastatin or pravastatin in dosages of 10-40 mg day-1 for three periods of 6 weeks. After each 3-week period the dose was adjusted to LDL cholesterol to aim for equipotent dosage. 4. All subjects performed a 45 min, lean body mass standardized bicycle ergometer test, before and after 18 weeks of treatment. As parameter for muscle damage, the exercise-induced rise of the muscle proteins, creatine kinase (CK) and myoglobin (Mb), relative to pre-exercise levels, were determined 1 and 8 h after the test. Forty-eight hours after each test a biopsy was taken from the quadriceps muscle and histology was judged by three independent observers. 5. Eighteen weeks of monotherapy with simvastatin and pravastatin did not affect the exercise induced release of CK and Mb, neither were any differences observed in muscle histology before and after treatment with either of the drugs. 6. Although simvastatin doses were lower than pravastatin, reductions in total- and LDL-cholesterol were greater in the simvastatin treated patients than in the pravastatin treated group.(ABSTRACT TRUNCATED AT 250 WORDS)     

LDL-C goal attainment with the addition of ezetimibe to ongoing simvastatin treatment in coronary heart disease patients with hypercholesterolemia

OBJECTIVE: To evaluate the addition of ezetimibe or placebo to on-going simvastatin treatment on attaining the LDL-C treatment target of 2.60 mmol/L and 100 mg/dL and 相似文献   

Antihypertensive drugs: diuretics and betablockers are the best assessed

(1) In trials involving hypertensive non diabetic patients under 65, some diuretics and betablockers have prevented strokes, without conferring protection from coronary events or death. In one trial captopril had an effect comparable to that of diuretics or betablockers in terms of overall cardiovascular prevention, but was a little less effective in preventing strokes. (2) In trials involving hypertensive subjects over 65, some diuretics and betablockers have reduced the risk of stroke, coronary events, heart failure, and death. In one trial a diuretic was superior to a betablocker in terms of preventive efficacy and adverse effects. Nitrendipine, in combination with other antihypertensive drugs, prevented strokes in one trial. (3) In a trial involving hypertensive diabetic patients, captopril and atenolol reduced the risk of stroke, heart failure and worsening of retinal disease, without preventing coronary events or death. In two trials coronary events were more frequent on dihydropyridine than on an angiotensin-coverting-enzyme (ACE) inhibitor. (4) In one trial a diuretic reduced the risk of relapse after stroke, even in patients without severe hypertension.