1. Section II: Lipid management
C. Update on clinical trials of aggressive lipid management
Randomized intervention trials: Relationship between LDL-C reduction
and major coronary events
Content points:
The major statin intervention trials demonstrate that cholesterol lowering reduces the risk of coronary events and total mortality in patients with coronary disease. This slide summarizes the relation between LDL-C levels and event rates in primary and secondary-prevention trials of cholesterol lowering. The lines join the placebo result to the active treatment result for each trial.16
The primary prevention trials include LRC-CPPT (Lipid Research Clinics Coronary Primary Prevention Study), WOSCOPS (West of Scotland Coronary Prevention Study), and AFCAPS/TexCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study).
The secondary prevention trials include 4S (Scandinavian Simvastatin Survival Study), LIPID (Long-term Intervention with Pravastatin in Ischemic Disease), CARE (Cholesterol and Recurrent Events), Post-CABG (Post Coronary Artery Bypass Graft Study), HPS (Heart Protection Study),17 and MIRACL (Myocardial Ischemia Reduction with Acute Cholesterol Lowering).18
The degree of event reduction appears to be in proportion to the degree of LDL-C reduction across the range of LDL-C levels studied, from 200 mg/dL to well below 100 mg/dL.
For all the baseline LDL-C levels studied, reductions in LDL-C with treatment are associated with lower event rates.

2. Statins reduce CV risk in women Content points:
Statins have proven to be effective in reducing the risk of morbidity and mortality for both primary and secondary prevention of CHD. This slide summarizes the outcomes of treatment in women in one primary and three secondary prevention trials.19 The proportion of women in these major statin trials ranged from 14% to 19%.
In the secondary prevention trials, Scandinavian Simvastatin Survival Study (4S), Cholesterol And Recurrent Events study (CARE), and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID), statins reduced the risk of coronary events in women. The overall evidence shows that women derive at least as much benefit from statin therapy for secondary prevention as do men.
Data from the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) seem to indicate that women benefit from statins as primary prevention therapy. However, the number of women in the trial was small and the 95% confidence interval was wide.
The favorable results achieved with statin therapy in major intervention trials led to current ATP III recommendations advising the use of statins in postmenopausal women to reduce cardiovascular risk.20 Because the benefit of hormone replacement therapy for reducing cardiovascular risk is not supported by clinical trials, ATP III advises against the use of hormone replacement therapy as an alternative to cholesterol-lowering drugs to reduce cardiovascular risk in women.

3. Statins: Adverse events since US launch to 12/2000
Content points:
Statins have been studied in people for almost 20 years and have been perceived as one of the safest classes of drugs developed.21 However, the recent withdrawal of cerivastatin has placed the class under unwarranted suspicion.21,22 Cerivastatin was withdrawn from the market in August 2001 following reports of sometimes fatal rhabdomyolysis.22
As seen in this summary from the FDA database of all reports of adverse events with statins since their introduction up to the end the year 2000, the largest proportion of rhabdomyolysis, as well as other side effects, have been associated with cerivastatin.23 Of 31 US deaths due to rhabdomyolysis with cerivastatin, 12 involved concomitant gemfibrozil use.22
The data show that statins are a safe class of drugs and probably offer a risk-benefit profile superior to all other widely used drugs, given their ability to reduce morbidity and mortality in a broad range of patients.21,22
The five other statins now available in the US may be considered as alternatives.21,22 Although any drug should be administered with caution, the benefit of statin therapy far exceeds the risk.21

4. Heart Protection Study (HPS): Design
Content Points:
The Medical Research Council/British Heart Foundation Heart Protection Study (HPS) was designed to determine whether statins offer benefit to individuals with average-to-low LDL-C levels who are nevertheless at high risk for coronary artery disease.17
HPS recruited patients in 69 UK hospitals, aged 40 to 80 years.
Eligibility included a history of coronary artery disease (CAD) and low-to-average total or LDL-C levels, people at risk for CAD due to a history of peripheral vascular disease, stroke, or diabetes.
HPS enrolled people that had been inadequately studied, including women (25%) and people aged >70 years (28%).
Two regimens were investigated: simvastatin (40 mg daily) and a cocktail of antioxidant vitamins (vitamin E [600 mg], vitamin C [250 mg], and β-carotene [20 mg daily]).
Patients were randomized to 4 groups of ~5000 each for treatment with simvastatin alone, simvastatin plus vitamins, vitamins alone, or placebo.
Average follow-up was 5.5 years.

5. HPS: Primary outcome
Content Points:
The primary outcome of HPS was the effect of simvastatin on all-cause mortality and deaths from heart disease and related blood vessel disease.17
All-cause mortality was recorded in 1328 people in the simvastatin group vs 1503 in the placebo group (12.9% vs 14.6%, P < 0.001).
Deaths from heart disease and related blood vessel disease occurred in 791 patients taking simvastatin vs 943 taking placebo (7.7% vs 9.2%, P < 0.002).
Vitamin E: In the vitamin E part of the study, the results were entirely negative. There was no harm or benefit from treatment.

6. HPS: Reduction in major vascular events with statin therapy
Content Points:
Treatment with 40 mg daily of simvastatin produced a 24% reduction in the risk of the individual outcomes including total CHD, fatal and nonfatal stroke, and the need for revascularization procedures.17
When allowance is made for noncompliance and treatment changes during the trial, simvastatin is concluded to reduce these major vascular events by about one third.

7. HPS: Vascular events according to prior disease
Content Points:
Results of the 5-year study show benefits among people with different diseases at baseline.17
Risk reductions were evident among people with previous MI, but also among those with other CHD, including those who had undergone coronary angioplasty or bypass grafting.
Benefits were also observed in people without diagnosed CHD at baseline, including people with prior stroke, peripheral vascular disease (eg, intermittent claudication), and among patients with diabetes.
Risk was reduced by about one quarter in each of the categories of prior disease. Allowing for noncompliance, the risk reduction was estimated to be at least one third in the patients who actually took the statin regimen.

8. HPS: Vascular events according to age and sex
Content Points:
The HPS trial enrolled 6000 patients aged ≥70 years, including 1200 aged ≥75 years.17 As seen on the slide, there was a definite reduction in the risk of major vascular events among the older patients. The risk reduction was similar to that seen in younger patients.
Women enrolled in the study had a similar risk reduction with simvastatin as men. The study included about 5000 women with previous disease that put them at risk for future major vascular events.
Overall, the risk reduction in this group was 24%, again estimated to be about one third after allowing for noncompliance and changes in treatment.

9. HPS: Reduction in vascular events regardless of baseline lipid levels
Content Points:
Results showed that treatment with a statin among patients who are currently considered to have low cholesterol levels produces a substantial decrease in the risk of major vascular events.17
Baseline LDL-C was <116 mg/dL in 33% of the participants; between 116 and 135 mg/dL in 25%, and ≥135 mg/dL in the remaining 42%. There was a 24% reduction in major vascular events that included patients with all baseline LDL-C and total cholesterol levels.

10. HPS: Main conclusions
Content Points:
After allowance for noncompliance, 40 mg/day of simvastatin safely reduces the risk of heart attack, stroke, and revascularization procedures by at least one third, regardless of baseline cholesterol or LDL-C levels.17
Benefits were seen in a wide range of high-risk patients for whom the indication for cholesterol-lowering therapy had been uncertain:
– Women – >70 years of age – LDL-C <120 mg/dL
Five years of statin therapy typically will prevent major vascular events in every 1000 patients as follows:
– 100 with previous MI – 80 with other coronary artery disease – 70 with diabetes (age 40+) – 70 with other peripheral vascular disease – 70 with previous stroke

11. HDL-Atherosclerosis Treatment Study (HATS): Design
Content Points:
The HDL-Atherosclerosis Treatment Study (HATS) investigated the independent and additive effect of lipid-altering and antioxidant therapy in 160 patients with coronary artery disease and low high-density lipoprotein-C (HDL-C) levels (≤40 mg/dL) and normal LDL-C levels (<145 mg/dL).24
Patients were randomly assigned to one of four regimens: simvastatin, simvastatin and niacin plus antioxidant vitamins, antioxidants, or placebo.
Simvastatin was initiated at 10 mg/day for patients with an LDL-C level of ≤110 mg/dL and at 20 mg/day for LDL-C >110 mg/dL and adjusted according to treatment response.
Slow-release niacin was increased linearly from 250 mg twice daily to 1000 mg twice daily at 4 weeks; the mean dose was 2.4 g/day.
Antioxidants (800 IU vitamin E, 1000 mg vitamin C, 25 mg beta carotene, and 10 µg selenium) were given twice daily
The primary outcomes were arteriographic evidence of a change in coronary stenosis and the occurrence of a first cardiovascular event (death, MI, stroke, or revascularization).
Follow-up was 3 years.

12. HATS: Changes in lipid levels with treatment
Content Points:
Patients treated with the simvastatin-niacin combination had a 31% reduction in total cholesterol, a 42% reduction in mean LDL-C, and a 26% increase in HDL-C. There was a 60% increase in HDL2, which is considered to be the most protective component of HDL-C.24
Antioxidants interacted adversely with simvastatin-niacin. The addition of antioxidants blunted the effects of simvastatin-niacin on lipid levels, including total cholesterol, LDL-C, and HDL-C. Importantly, concurrent antioxidant therapy blunted the protective increase in HDL2.
The antioxidant and placebo groups had no significant changes in mean lipid levels. However, the antioxidants reduced HDL2 by 15% (P = 0.05 vs placebo).

13. HATS: Rate of clinical events according to treatment
Content Points:
Simvastatin-niacin was associated with a 3% rate of clinical events, compared with a 14% rate in patients receiving simvastatin-niacin plus antioxidants, 21% in the group taking antioxidants, and 24% in the placebo group.24
This indicates that when antioxidants are combined with simvastatin-niacin, clinical benefits diminish compared with simvastatin-niacin alone. The adverse interactions between the two therapeutic strategies did not have a significant effect on clinical outcomes (P = 0.13).
This negative interaction between the statin-niacin combination and the antioxidant vitamins appears to result from substantial and specific blunting by the vitamins of the expected increase in HDL2. A similar effect has been found with the potent nonvitamin antioxidant probucol.25

14. HATS: Statin-niacin combination lowers the risk of coronary events
Content Points:
The composite primary outcome of the study included death from coronary causes, confirmed MI, stroke, or revascularization for worsening ischemia.24
The risk of the primary composite outcome was 90% lower in the simvastatin-niacin group than in the groups given all placebos (P = 0.03, 95% confidence interval ). When all patients given simvastatin and niacin were compared with those patients who were not given simvastatin and niacin there was a 60% reduction in the risk of a primary event.
The clinical and angiographically measurable benefits of simvastatin plus niacin were greater than would be expected from statins alone. Findings in this small study require confirmation.

15. HATS: Simvastatin-niacin combination causes angiographic regression of coronary lesions
Content Points:
The study evaluated arteriographic changes in the severity of proximal stenosis as a primary outcome in nine proximal lesions.24 On average, after 3 years of therapy, the mean percent stenosis in the placebo group increased by 3.9%. By comparison, the change in the other groups included a 0.4% decrease with simvastatin-niacin (P < 0.001), a 0.7% increase with simvastatin-niacin plus antioxidants (P = 0.004), and a 1.8% increase with antioxidants (P = 0.16).
An analysis of secondary stenosis outcomes showed that in general, the changes were consistent for all degrees of stenotic lesions measured.
Thus simvastatin and niacin combined was associated with a regression of stenosis, rather than slowed progression. This benefit was attenuated when antioxidants were added.

16. HATS: Adverse effects and study limitations
Content Points:
Adverse effects: Simvastatin plus niacin therapy caused small but consistent increases in aspartate aminotransferase (AST), creatinine kinase, uric acid, homocysteine, and insulin, but not in the level of glucose. Compliance with treatment was similar in the simvastatin-niacin group as in patients taking placebo.24
Reports of flushing in patients taking niacin were similar to placebo (30% vs 23%, P = 0.35). Of the 80 patients who were taking niacin, 2 withdrew from the study because of flushing and 2 remained in the study but stopped taking niacin.
Study limitation: A limitation of the study, which is due to its small size, is the relatively wide 95% confidence interval for the substantial clinical benefits of combined therapy. The relative risk of an event was 0.10, but the 95% confidence interval was 0.01 to The authors suggest that the credibility of the clinical results gain support from the parallel and compelling effects of the combined treatment on the progression of stenosis.

17. VA-HIT: Secondary prevention of CHD in men with low HDL-C and normal LDL-C
Content Points:
The VA-High-density Lipoprotein Intervention Trial (VA-HIT) studied the effect of raising HDL-C concentrations on major coronary events in a high-risk group of men with low HDL-C and low LDL-C levels.26
The trial involved 2531 men with CHD and a mean HDL-C level of 32 mg/dL; their mean LDL-C level was 111 mg/dL. Patients were randomly treated with either gemfibrozil 1200 mg/day or placebo.
Results showed that among men with CHD and low HDL-C, but without high-risk LDL-C levels, gemfibrozil reduced the risk of death from CHD or MI by 22%.
The change in lipid levels included a 6% increase in HDL-C, a 31% decrease in triglycerides, a 4% decrease in total cholesterol, and no change in LDL-C levels.

18. Post-CABG: Long-term follow-up demonstrates clinical benefit of aggressive lipid lowering
Content Points:
The Post-Coronary Artery Bypass Graft (CABG) Trial demonstrated that aggressive lipid lowering therapy decreased obstruction of saphenous vein grafts by 31%.27 Using lovastatin (and cholestyramine when necessary), mean LDL-C level ranged from 93 to 97 mg/dL in aggressively treated patients; LDL-C levels ranged from 132 to 136 mg/dL in the others. At a 4 to 5 year follow-up, clinical outcomes with the two treatment strategies did not differ significantly.
On extended follow-up, at 7.5 years, the differences in clinical outcomes between the groups had widened substantially.28 The group that received aggressive treatment had a 24% lower rate of clinical events (P = 0.001) and a 30% lower rate of revascularization (P = ).
The late findings in patients assigned to aggressive treatment are consistent with the angiographic findings in the trial and demonstrate that the angiographic outcome had clinical relevance.
The Post-CABG Trial did not provide clear evidence of a threshold effect, but it did support the NCEP recommendation that LDL-C levels should be reduced to <100 mg/dL in patients who have coronary artery disease.28

19. Post-CABG long-term follow-up: Reduction in mortality with low-dose warfarin
Content Points:
During the Post-CABG Trial, low-dose anticoagulation with warfarin (average international normalized ratio 1:4) had no visible effect on the progression of vein graft disease and no statistically significant effect on clinical events.27
By 7.5 years, however, total mortality was reduced by 35% (P = 0.008) in the warfarin group. Death or MI was reduced by 31% (P = ), but the benefit in MI was significant for reductions in fatal rather than nonfatal MI.28
The finding that warfarin reduced mortality from all causes emerged after treatment was discontinued and was unexpected. Only 11% of patients were taking anticoagulation on extended follow-up, and therefore, the benefit could not be attributed to continued anticoagulation.
Post-CABG Trial long-term results are consistent with the low-intensity anticoagulation trial reported by the Medical Research Council’s General Practice Research Framework.29 In this primary prevention trial in men at risk for ischemic heart disease, warfarin reduced all events, primarily fatal events, by 34%.
So far, the evidence is not strong enough to treat post by-pass patients routinely with low-dose warfarin.30 The apparent late clinical benefit of low-dose warfarin in patients after bypass surgery was unexpected, unexplained, and requires confirmation.

20. Aggressive lipid-lowering (LDL-C <100 mg/dL) slows plaque growth and improves plaque stability
Content Points:
In this study, the German Atorvastatin Intravascular Ultrasound Study investigators compared the effects of aggressive and moderate lipid-lowering strategies on plaque volume and composition in patients with coronary artery disease using intravascular ultrasound.31
The study was a 12-month open-label, randomized multicenter trial in which 65 patients were randomized to atorvastatin and 66 to usual care. The aggressive treatment strategy used atorvastatin 20 to 80 mg/dL to reach the target LDL-C of <100 mg/dL. The moderate treatment was targeted at an LDL-C of 140 mg/dL. In this group, treatment was determined by the patient’s physician but did not use atorvastatin.
After 12 months, LDL-C was reduced 42% (from 155 mg/dL to 86 mg/dL) in the atorvastatin group and 18% (from 166 to 140 mg/dL) with usual care.
Aggressive lipid lowering produced a smaller increase in plaque volume than usual care (1.2 mm3 vs 9.6 mm3), although the difference was not statistically significant.
Aggressive treatment led to a significant 42.5% increase in the hyperechogenicity index of the plaque vs a 10.1% increase with usual care (P = 0.021). The larger increase in plaque hyperechogenicity most likely is due to a change in plaque composition.
Acoustic characterization of coronary plaque composition has been shown to be a good indicator of morphologic findings.31Hyperechogenic plaque is assumed to indicate a larger fraction of dense fibrous or elastic tissue, which is characteristic of more clinically stable plaque. More hypoechogenic plaque is associated with a greater fraction of loose fibrous tissue, lipid deposits, or necrotic tissue.

21. Prolonged intensive lipid-lowering therapy (10 years) reduces lipid content of carotid plaques
Content Points:
This study documents a reduction in lipid content in carotid artery plaque with long-term intensive cholesterol-lowering therapy. Zhao and coworkers used high resolution MRI to monitor the effects of intensive drug treatment on the dimensions and composition of atherosclerotic plaques in human coronary arteries.32
In this small case-control study, 8 patients with familial atherosclerosis who had been treated for 10 years with intensive triple lipid-lowering therapy (niacin 2.5 mg/day, lovastatin 40 mg/day, and colestipol 20 mg/day) were compared with 8 patients with coronary artery disease who had never been treated with lipid-lowering therapy.
From the MR image slice that showed the largest plaque area in each carotid, the authors measured the dimensions and composition of plaque, including the area occupied by lipid deposits, fibrous tissue, and calcification.
The only substantial difference between the treated and untreated groups was a significant difference in plaque lipid core area (0.2 mm2 vs 10.2 mm2, respectively, P = 0.01). Lipid composition in plaque was 1% in treated patients vs 17% in untreated patients. Calcium composition tended to be higher in the treated patients, but the difference was not significant.
Clinical implications: Prolonged intensive lipid-lowering therapy is associated with a marked decrease in plaque lipid content, which is a characteristic of clinically stable plaque. The effect of prolonged treatment on plaque lipid content would predict greater plaque stability and a reduction in clinical ischemic events.

22. 10-Year risk of CHD by LDL-C quintile
Content Points:
Despite consensus on the need for blood cholesterol reductions to prevent CHD, available evidence on optimal cholesterol levels is relatively sparse.
The Atherosclerosis Risk in Communities (ARIC) study followed-up middle-aged participants who were free of CHD at the beginning of the study.33 Over the course of 10 years, 725 CHD events occurred. Correlation of lipid levels with CHD events showed that the lowest incidence of events was in people in the lowest LDL-C quintile.
Median LDL-C in the lowest quintile was 88 mg/dL in women and 95 mg/dL in men. Compared with the lowest LDL-C quintile, the relative risk for a CHD event in the highest quintile was 2.7 in women and 2.5 in men.
The data show that for both men and women, maintaining an LDL-C level of <100 mg/dL significantly reduces the risk of a cardiovascular event.

23. Changes in LDL-C levels with five statins at weeks 6 and 54 of treatment
Content Points:
This study compared five statins and their ability to reduce LDL-C to the National Cholesterol Education Program (NCEP) target level.34 The study involved 3900 hypercholesterolemic patients who were randomly assigned to one of the five statins beginning at the lowest recommended dose: atorvastastin, pravastatin, and simvastatin 10 mg/day; fluvastatin and lovastatin 20 mg/day. Patients who achieved the LDL-C target on the initial dose stayed at that dose for 54 weeks.
The doses were titrated to their maximum recommended dose. The total treatment duration was 54 weeks.
Atorvastatin achieved the greatest mean reduction in LDL-C at both 6 weeks (36%) and 54 weeks (42%) compared with all other treatments (P < 0.01). Simvastatin reduced LDL-C significantly more than lovastatin at 6 weeks, and significantly more than fluvastatin or pravastatin at weeks 6 and 54 (P < 0.01 for all comparisons).
The next slide shows the impact of treatment on NCEP target levels.

24. Patients at NCEP target for LDL-C with five statins
Content Points:
This slide shows the percentage of patients who were at their NCEP goal for LDL-C at week The proportion of patients at NCEP goal for LDL-C at week 54 was significantly greater in the atorvastatin group (76%) than in the groups on simvastatin (58%), pravastatin (49%), lovastatin (34%), and fluvastatin (37%).
There was a strong correlation between the percent reduction in LDL-C achieved with the five different agents at their initial dose (week 6) and the proportion of patients who maintained their NCEP target LDL-C at week 54. This suggests that by achieving a greater percent reduction in LDL-C at the initial statin dose, the patient’s chances of maintaining NCEP LDL-C goal levels over the long term are increased.