Prescribing high-dose lipid-lowering therapy early to avoid subsequent cardiovascular events: is this a cost-effective strategy?

BACKGROUND: While evidence shows high-dose statins reduce cardiovascular events compared with moderate doses in individuals with acute coronary syndrome (ACS), many primary care trusts (PCT) advocate the use of generic simvastatin 40 mg/day for these patients. METHODS AND RESULTS: Data from 28 RCTs were synthesized using a mixed treatment comparison model. A Markov model was used to evaluate the cost-effectiveness of treatments taking into account adherence and the likely reduction in cost for atorvastatin when the patent expires. There is a clear dose-response: rosuvastatin 40 mg/day produces the greatest reduction in low-density lipoprotein cholesterol (56%) followed by atorvastatin 80 mg/day (52%), and simvastatin 40 mg/day (37%). Using a threshold of £20,000 per QALY, if adherence levels in general practice are similar to those observed in RCTs, all three higher dose statins would be considered cost-effective compared to simvastatin 40 mg/day. Using the net benefits of the treatments, rosuvastatin 40 mg/day is estimated to be the most cost-effective alternative. If the cost of atorvastatin reduces in line with that observed for simvastatin, atorvastatin 80 mg/day is estimated to be the most cost-effective alternative. CONCLUSION: Our analyses show that current PCT policies intended to minimize primary care drug acquisition costs result in suboptimal care.

Protection Against Nephropathy in Diabetes with Atorvastatin (PANDA): a randomized double-blind placebo-controlled trial of high- vs. low-dose atorvastatin(1).

AIMS: To compare the renal effects of low- vs. high-dose atorvastatin in patients with Type 2 diabetes mellitus and optimally managed early renal disease. METHODS: We compared the 2-year progression of nephropathy in a double-blind randomized controlled trial of atorvastatin 80 mg/day (n = 60) vs. 10 mg/day (n = 59) in patients with Type 2 diabetes with microalbuminuria or proteinuria [mean (sd): age 64 years (10 years); HbA(1c) 7.7% (1.3%), 61 mmol/mol (10 mmol/mol); blood pressure 131/73 mmHg; renin-angiotensin system blocker use > 80%; dual blockade > 67%] recruited from diabetes clinics in Greater Manchester. RESULTS: Over (mean) 2.1 years of follow-up, the Modification of Diet in Renal Disease estimated glomerular filtration rate declined by 3 ml min(-1) 1.73 m(-2) in the combined group. The mean (95% CI) between-group difference during follow-up was not significant [2.2 ml min(-1) 1.73 m(-2) (-1.1 to 5.4 ml min(-1) 1.73: m(-2) ), P = 0.20] after adjusting for baseline differences in renal function; positive difference favours 80 mg dose. Similarly, there was no significant difference in creatinine clearance by Cockcroft and Gault [2.5 ml/min (-2.4 to 7.3 ml/min), P = 0.32]; serum creatinine/24-h urine collections [4.0 ml/min (-4.8 to 12.7 ml/min), P = 0.38]; cystatin C (P = 0.69); or 24-h urine protein or albumin excretion (P = 0.92; P = 0.93). We recorded no significant between-group differences in deaths or adverse events. CONCLUSIONS: In patients with Type 2 diabetes with early renal disease, we found no statistical difference in renal function between those taking high- or low-dose atorvastatin over 2 years. We cannot exclude a beneficial effect of < 1.6 ml min(-1) 1.73 m(-2) year(-1) on Modification of Diet in Renal Disease estimated glomerular filtration rate, or if blood pressure management or if renin-angiotensin system blocker use had not been optimized.

Omega 3 fatty acids for prevention and treatment of cardiovascular disease.

BACKGROUND: It has been suggested that omega 3 (W3, n-3 or omega-3) fats from oily fish and plants are beneficial to health. OBJECTIVES: To assess whether dietary or supplemental omega 3 fatty acids alter total mortality, cardiovascular events or cancers using both RCT and cohort studies. SEARCH STRATEGY: Five databases including CENTRAL, MEDLINE and EMBASE were searched to February 2002. No language restrictions were applied. Bibliographies were checked and authors contacted. SELECTION CRITERIA: RCTs were included where omega 3 intake or advice was randomly allocated and unconfounded, and study duration was at least six months. Cohorts were included where a cohort was followed up for at least six months and omega 3 intake estimated. DATA COLLECTION AND ANALYSIS: Studies were assessed for inclusion, data extracted and quality assessed independently in duplicate. Random effects meta-analysis was performed separately for RCT and cohort data. MAIN RESULTS: Forty eight randomised controlled trials (36,913 participants) and 41 cohort analyses were included. Pooled trial results did not show a reduction in the risk of total mortality or combined cardiovascular events in those taking additional omega 3 fats (with significant statistical heterogeneity). Sensitivity analysis, retaining only studies at low risk of bias, reduced heterogeneity and again suggested no significant effect of omega 3 fats. Restricting analysis to trials increasing fish-based omega 3 fats, or those increasing short chain omega 3s, did not suggest significant effects on mortality or cardiovascular events in either group. Subgroup analysis by dietary advice or supplementation, baseline risk of CVD or omega 3 dose suggested no clear effects of these factors on primary outcomes. Neither RCTs nor cohorts suggested increased relative risk of cancers with higher omega 3 intake but estimates were imprecise so a clinically important effect could not be excluded. REVIEWERS' CONCLUSIONS: It is not clear that dietary or supplemental omega 3 fats alter total mortality, combined cardiovascular events or cancers in people with, or at high risk of, cardiovascular disease or in the general population. There is no evidence we should advise people to stop taking rich sources of omega 3 fats, but further high quality trials are needed to confirm suggestions of a protective effect of omega 3 fats on cardiovascular health. There is no clear evidence that omega 3 fats differ in effectiveness according to fish or plant sources, dietary or supplemental sources, dose or presence of placebo.

Omega-3 fatty acids: their role in the prevention and treatment of atherosclerosis related risk factors and complications.

Fatty acids are an important source of energy which can have an influence on serum lipids. Omega-3 and omega-6 fatty acids, both polyunsaturated fatty acids, have been advocated as replacement for saturated fat. Omega-3 fatty acids, derived from fish and certain green plants, lower serum triglycerides, but they have also been shown to have a direct effect on myocardial contractility, blood pressure, platelet function, coagulation factors, cell-mediated immunity and markers of inflammation. Recently available clinical trial data, including those using the concentrated omega-3 fatty acid preparation Omacor, indicate that omega-3 fatty acids are valuable in preventing sudden death following myocardial infarction. Studies indicate that omega-3 fatty acids are just as effective as, or have a benefit superior to, statins in secondary prevention. Omacor is also useful in the treatment of hypertriglyceridaemia, both as monotherapy and in combination with statins.

Preventing cardiovascular disease in hypertension: effects of lowering blood pressure and cholesterol.

BACKGROUND: In guidelines for the primary prevention of cardiovascular disease, systolic blood pressure (SBP) or diastolic blood pressure (DBP) is treated with medication at lower levels of risk than those at which statin treatment is recommended for cholesterol lowering. AIM: To compare the potential benefits of antihypertensive medication and statin therapy in hypertensive patients, and examine whether this policy is rational. DESIGN: Retrospective cross-sectional survey. METHODS: We studied 146 men and 150 women aged 56 (54-58) (mean (95% CI)) years and 60 (58-62) years, respectively, who had commenced drug therapy for hypertension within 10 years in five general practices in Greater Manchester. Coronary heart disease (CHD) and stroke risk were calculated, and the potential benefit of blood pressure lowering treatment and statin therapy estimated using the results of published meta-analyses of clinical trials. RESULTS: Blood pressure before treatment was initiated was 176 (173-179)/102 (100-104) mmHg in men and 176 (172-179)/98 (96-100) mmHg in women. Serum cholesterol was 5.7 (5.5-5.9) mmol/l and high density lipoprotein (HDL) cholesterol 1.3 (1.2-1.4) mmol/l in men. The corresponding values in women were 6.3 (6.1-6.5) mmol/l and 1.5 (1.4-1.6) mmol/l. Of the men, 44% (36-52%) smoked and 23% (17-31%) had diabetes mellitus, whereas 27% (20-35%) of the women smoked and 26% (19-34%) had diabetes. These risk factors gave the combined group of men and women a CHD risk of 19.7% (12.0-28.0%) (median (IQR)) and a stroke risk of 8.8% (3.8-13.9%) over the next 10 years. All patients were prescribed antihypertensive medication and 15% subsequently received statin treatment. The 10-year CHD risk would be expected to decrease to 16.5% (10.1-23.5%) on anti-hypertensive therapy. Had statin treatment been given instead, it would have been reduced to 13.2% (8.05-18.7%). For stroke, the 10-year risk on antihypertensive therapy was calculated as 5.5% (2.4-8.6%) and on statin 6.2% (2.7-9.9%). This meant that combined CHD and stroke risk would be reduced from 29.4% (17.5-41.5%) to 22.4% (17.5-41.5%) on antihypertensive therapy and to 20.1% (11.9-28.2%) on statins. The difference between statin and antihypertensive therapy was statistically significant (p<0.0001). DISCUSSION: Because the object of drug treatment in mild-moderate hypertension is to reduce cardiovascular disease risk and not simply to decrease blood pressure, current recommendations and practice should be revised so that more patients can benefit from evidence-based therapy favouring a more holistic approach, including cholesterol-lowering therapy.

An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia.

BACKGROUND: Omega-3 fatty acids, such as those present in fish oil, have been reported to prolong life in myocardial infarction survivors. These fatty acids can decrease serum triglyceride concentrations, but so far the doses used in trials examining their effects on coronary end points have had only minimal triglyceride lowering effects. OBJECTIVE: To examine the triglyceride lowering effectiveness, safety, and tolerability of Omacor, a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil (84% of the total as opposed to an average of 35% in fish oil) over one year in patients with established coronary heart disease (CHD) and persisting hypertriglyceridaemia, despite receiving simvastatin in doses similar to those employed in the Scandinavian simvastatin survival study. SUBJECTS AND METHODS: 59 patients with CHD, receiving simvastatin 10-40 mg daily with serum triglycerides > 2.3 mmol/l, were randomised to receive Omacor 2 g twice a day or placebo for 24 weeks in a double blind trial. Forty six patients accepted the offer of active treatment for a further 24 weeks in an open phase of the trial. RESULTS: There was a sustained significant decrease in serum triglycerides by 20-30% (p < 0.005) and in very low density lipoprotein (VLDL) cholesterol by 30-40% (p < 0.005) in patients receiving active Omacor at three, six, and 12 months compared either to baseline or placebo. Omacor did not have any deleterious effect on low density or high density lipoprotein cholesterol or on biochemical and haematological safety tests. There was no adverse effect on glycaemic control in patients with diabetes, who showed a decrease in serum triglyceride, which was at least as great as in non-diabetic patients. One patient receiving placebo died of acute myocardial infarction. Three patients withdrew from the trial (two on placebo and one on active treatment). Omacor was generally well tolerated. CONCLUSION: Omacor was found to be a safe and effective means of lowering serum triglycerides over one year in patients with CHD and combined hyperlipidaemia, whose triglycerides remained elevated despite simvastatin treatment.

Vitamin E supplementation increases the resistance of both LDL and HDL to oxidation and increases cholesteryl ester transfer activity.

There is increasing evidence that lipid peroxidation and oxidative modification of low density lipoprotein (LDL) is important in atherogenesis. Evidence that antioxidant therapy decreases mortality is, however, inconclusive. We have examined the effects of vitamin E on the susceptibility of LDL and high density lipoprotein (HDL) to oxidation, and on cholesteryl ester heteroexchange in an in vitro system using autologous serum lipoproteins. Vitamin E in doses of 200 and 400 mg/day were administered orally to 21 healthy volunteers (12 females and nine males) aged between 23 and 50 years, and to 16 healthy volunteers (eight females and eight males) aged between 22 and 51 years for 50 days, respectively. Fasting serum lipoproteins, susceptibility of lipoproteins to oxidation and cholesteryl ester transfer activity (CETA) were measured before and after vitamin E supplementation. Serum lipoprotein and lipid concentrations did not change significantly in either group. The LDL-conjugated diene (CD) lag phase during incubation with Cu(2+) was increased by 157% (110-232%) (median (interquartile range)) (P<0.05) on vitamin E (200 mg/day) and by 235% (185-259%) (P<0.0001) on 400 mg/day. The lag phases for LDL-lipid peroxide (LPO) generation were also significantly increased by 146% (122-192%) (P<0.005) and 177% (101-267%) (P<0.005), respectively. The HDL-CD lag phase also increased on both doses 140% (115-169%) (P<0.005) and 171% (122-192%) (P<0.005), as did the HDL-LPO lag phase by 123% (104-153%) (P<0.05) on 200 mg/day and 240% (97-360%) (P<0.005) on 400 mg daily. Cholesteryl ester transfer activity from HDL to very low and low density lipoproteins significantly increased from 12. 7+/-2.6 (mean+/-SEM) to 16+/-3.4 nmol/ml/h (P<0.05) on 200 mg/daily and 10.4+/-2.0 to 19.2+/-3.3 nmol/ml/h (P<0.005) on vitamin E, 400mg day. Thus, vitamin E (200 and 400mg daily) significantly decreased the susceptibility of LDL and HDL to oxidation in vitro. However, the increase in CETA resembled that reported with another antioxidant, probucol. Some evidence has suggested that increased CETA is potentially deleterious and it might therefore counteract beneficial effects of vitamin E or probucol on the susceptibility of lipoproteins to oxidation.

Effects of a new fish oil concentrate on plasma lipids and lipoproteins in patients with hypertriglyceridaemia.

OBJECTIVES: The effect of a fish oil preparation, K-85, in which the omega-3 fatty acid content was concentrated to 92% of total fat, on serum lipid and lipoprotein concentrations was investigated in patients with primary hypertriglyceridaemia. DESIGN: The study was a randomized, double-blind, placebo-controlled study. SETTING: Seven centres participated in the study, five secondary referral centres and two general practices. SUBJECTS: Men and women aged 18-70 years with fasting serum triglyceride concentrations between 2 and 10 mmol/l and fasting serum cholesterol concentrations > 5.2 mmol/l were studied. Patients with diabetes mellitus, hypothyroidism, serious illness in the previous 3 months or severe concurrent illness were excluded from the study, as were drug or alcohol abusers and pregnant and lactating women. Ninety-five subjects entered the study, 79 completed the study. INTERVENTIONS: Patients were randomized to receive K-85 2 g twice daily or corn oil 2 g twice daily for 14 weeks. MAIN OUTCOME MEASUREMENTS: The serum concentrations of triglycerides and cholesterol, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and lipoprotein (a). Fasting blood glucose and blood pressure. RESULTS: Serum triglycerides and VLDL-cholesterol were significantly lower in the group treated with K-85 than in the placebo group after 6, 10 and 14 weeks (all P < 0.01) and there was a decrease in the serum triglyceride concentration from 3.99 (2.94-9.47) to 2.87 (1.2-9.93) mmol/l (P < 0.001) and in VLDL-cholesterol from 1.47 (0.77-3.63) to 1.12 (0.21-3.67) mmol/l (P < 0.01) in patients receiving K-85. Serum HDL-cholesterol increased from 0.98 (0.95-1.01) to 1.11 (1.07-1.15) mmol/l (P < 0.01) in the patients with type IV hyperlipoproteinaemia but did not change in those with type IIb. Serum LDL-cholesterol, lipoprotein (a) and fasting blood glucose were unaffected by K-85. Diastolic blood pressure decreased from 86 +/- 11 to 80 +/- 12 mmHg (P < 0.02) and was also lower than in the placebo group (P < 0.05). The corn oil placebo did not affect any of the parameters. CONCLUSION: K-85 is effective in lowering serum triglycerides and VLDL in patients with primary hypertriglyceridaemia and may have utility as a triglyceride-lowering agent.

The role of high-density lipoprotein and lipid-soluble antioxidant vitamins in inhibiting low-density lipoprotein oxidation.

1. The oxidation of low-density lipoprotein (LDL) is believed to play a central role in atherogenesis. We have compared the effect of antioxidant vitamins and high-density lipoprotein (HDL) on the Cu(2+)-catalysed oxidation of LDL. 2. Antioxidant vitamin supplementation significantly reduced conjugated diene formation but did not affect the formation of lipid peroxides. 3. Conversely, HDL did not affect conjugated diene formation but inhibited the formation of lipid peroxides by up to 90%. 4. The inhibition by HDL of lipid peroxide formation in oxidized LDL was dependent on the concentration of HDL and was not due to HDL chelating Cu2+. 5. Large interindividual variations in the inhibition of lipid peroxide formation by autologous HDL were evident, which were related to the rate of lipid peroxide generation in the LDL. 6. We conclude that HDL is a powerful antioxidant or more probably inhibitor of LDL oxidation in vitro and may play an important role in vivo in preventing atherosclerosis by inhibiting LDL oxidation in the artery wall.

Management of hyperlipidaemia: guidelines of the British Hyperlipidaemia Association.

There is considerable evidence to suggest that the identification and treatment of dyslipidaemia will reduce the risk of premature CHD, i.e. before the age of 65. Diagnosis of the cause of raised plasma lipid levels will enable appropriate decisions to be taken with regard to management. The cornerstone of treatment is nutritional counselling and attention to other major risk factors for CHD, particularly smoking and hypertension. For a small percentage of patients with severe hyperlipidaemia drug therapy is indicated. Appropriate drug choices need to be made based on the particular lipid abnormality to be treated. In general those patients with clinical vascular disease are treated more aggressively than those where the aim is primary prevention. More research is needed to determine individual risk more precisely and to allow proper targeting of therapy. Genetic factors, qualitative changes in lipoproteins, lipoprotein (a), fibrinogen, and other coagulation and thrombotic factors are likely to be important in individual risk assessment. There is no doubt that more information is needed from prospective studies of lipid-lowering therapy in terms of risk benefit for affected individuals. Hopefully the major studies currently underway will fill some of the gaps in our knowledge. Until then aggressive therapy with drugs should be reserved for those at highest risk where the benefit is likely to be greatest.

Effect of pectin on serum lipids and lipoproteins, whole-gut transit-time, and stool weight.

Pectin (12g daily with meals) was taken by twelve healthy men aged 22-45 (mean 25 yr) for 3 weeks. This produced a statistically significant mean decrease in total serum-cholesterol of 0.48 +/- 0.18 mmol/1 (+/- S.E.M.)--i.e., 7.9 +/- 2.6%. The decrease was largely due to a reduction in serum-low-density-lipoprotein-cholesterol of 0.45 +/- 0.19 mmol/1 accompanied by a fall in serum-apolipoprotein-B of 0.11 +/- 0.04 g/1. During pectin administration wet stool weight increased from 150 +/- 10 to 186 +/- 15 g/24 h. There was no clear change in total serum-triglycerides, serum very low density lipoproteins, or in whole-gut transit-time.