Section 7: Aggressive vs moderate approach to lipid lowering Benefits of aggressive LDL-C lowering Content Points: As shown earlier, aggressive LDL-C lowering improves endothelial function and reduces reflex vasoconstriction.25 Specific clinical benefits in patients with atherosclerotic disease include: Decreased incidence of angina and ischemia39,40 Reduced need for revascularization through angioplasty or surgery46-48 Improved clinical outcomes, specifically reduced morbidity and mortality from stroke or MI39,46-48 Reductions in hospitalization in response to a CV event

Post-CABG: Aggressive vs moderate LDL-C reduction Content Points: This slide describes the trial design of a study to determine whether an aggressive rather than a moderate approach to reducing LDL-C is more effective in blunting the progression of atherosclerotic lesions in saphenous vein grafts (SVGs).49 A 2x2 factorial design was used to assign patients to aggressive or moderate lipid lowering therapy, warfarin or placebo. Warfarin was started at 1 mg/day, with titration up to a total of 4 mg/day. The goal was to achieve an international normalized ratio of 1.8. The study sample included 1351 participants who were 1 to 11 years post-CABG. Each of the men in the study had at least 2 patent SVGs, and each woman participant had at least 1. The LDL-C levels were 130 to 175 mg/dL after being on a diet. Participants were randomized and blinded to the intensity of treatment which consisted of lovastatin at 40 to 80 mg/day plus or minus cholestyramine (2.5 to 5 g/day). The goal was to reach an aggressive target LDL-C of less than 85 mg/dL, and a moderate target LDL-C of 130 to 140 mg/dL.

Post-CABG: Aggressive vs moderate LDL-C reduction Content Points: The study outcomes were a mean per-patient percent of grafts with significant progression in SVG greater than a 0.6 mm change.49 The secondary end point was the occurrence of new occlusions and lesions plus lumen narrowing.

Post-CABG: Aggressive vs moderate LDL-C reduction Content Points: This slide examines the LDL-C reductions achieved with moderate and aggressive treatment strategies.49 The mean daily dose of lovastatin was 76 mg in the aggressively treated group, and 30% were prescribed 8 g of cholestyramine. The mean LDL-C during the study ranged from 93 to 96 mg/dL for the lovastatin and warfarin groups. In the moderately treated group the mean daily dose of lovastatin was 40 mg, and 5% of the patients were prescribed cholestyramine. The mean LDL-C was considerably higher, and ranged from 134 to 135 mg/dL during the study for the lovastatin and warfarin groups. Note that target LDL-C reductions (to a mean of < 140 mg/dL and < 85 mg/dL in the moderate and aggressive groups, respectively) were not achieved in any group.

Post-CABG: Angiographic vein graft outcomes Content Points: In all study parameters, there was consistently greater benefit in the group of patients who were treated aggressively.49 Note the statistically significant reductions in the primary end point of substantial progression and in the secondary end points of new occlusions, new lesions and changes in minimum and mean lumen diameter (P < 0.001 for all comparisons).

Post-CABG: Event rates by cholesterol group Content Points: This slide plots the event rates by cholesterol group.49 There was a 29% reduction in revascularization, PTCA or CABG in the aggressively treated group. Note that there was no significant difference in the first 2.5 years, but that the curves progressively diverged in the last 2 years of the study.

Post-CABG: Study summary Content Points: The overall study conclusions are shown here.49 Aggressive treatment resulted in decreased rates of progression, new occlusions, new lesions and decreases in mean lumen narrowing. In addition, as seen on the previous slide, revascularization rates were decreased by 29%. The primary conclusion is that by achieving a mean LDL-C of 95 mg/dL, there is greater benefit than if the patient carries a mean LDL-C of 135 mg/dL. This also supports the NCEP recommendations of a target LDL-C of less than 100 mg/dL in patients with CHD.

Post-CABG: Aggressive LDL-C reduction benefits patients with other CV risk factors Content Points: In this substudy of the Post-CABG trial the influence of risk factors on benefit from LDL-C reduction was investigated.50 Risk factors included in this analysis were smoking, diabetes, hypertension, HDL-C < 40 mg/dL, triglycerides < 145 mg/dL and number of risk factors. As shown in the slide, aggressive lowering of LDL-C resulted in superior reduction in progression of atherosclerosis regardless of the number of risk factors.

CURVES: Study design Content Points: The CURVES study is the first to compare the lipid-lowering efficacy of all available HMG-CoA reductase inhibitors across their dose ranges.50 It was a multicenter, open-label, randomized, parallel group study conducted over 8 weeks. It compared the dose efficacy and safety of once-daily atorvastatin with simvastatin, pravastatin, lovastatin and fluvastatin. The study consisted of 534 patients with LDL-C greater than 160 mg/dL and triglycerides less than 400 mg/dL.

CURVES: Study methodology Content Points: This slide provides the CURVES trial methodology.51 There was a 6-week dietary baseline, followed by an 8-week active treatment period. Patients who qualified were randomized to 1 of 15 treatment groups at the doses shown here.

CURVES: Clinical characteristics Content Points: The study included men and women greater than 18 and less than 80 years of age.51 Eligibility for inclusion included 2 consecutive visits where there was an LDL-C greater than 160 mg/dL, and triglycerides less than 400 mg/dL. Inclusions also pertained to those with a body mass index (BMI) less than 32 kg/m2. Mean age of the patients was 55.2 years, and 59% were males and 41% were females. Thirty-seven percent had a family history of CHD. Thirteen percent were smokers, and the average BMI was 26.7 kg/m2.

CURVES: Comparative LDL-C reductions across dose ranges Content Points: This slide shows the lipid-lowering effects from the available dosing strengths of fluvastatin, pravastatin, simvastatin, lovastatin and atorvastatin.51 Over the 10- to 40-mg dose range, atorvastatin demonstrated significantly greater LDL-C reductions than milligram-equivalent doses of comparative agents.

CURVES: Comparative efficacy of statins Content Points: Also from the CURVES trial, this slide compares the LDL-C reductions observed at the usual starting doses of the available statins.51

Patients reaching the NCEP-recommended LDL-C concentrations with statin treatment Content Points: Hunninghake et al evaluated the ability of atorvastatin, fluvastatin, lovastatin, and simvastatin to achieve NCEP-recommended LDL-C concentrations.52 The study included 344 patients (53% women and 47% men) ranging between 18 and 80 years of age; 82 had < 2 risk factors, 262 had > 2 risk factors and the mean LDL-C level at baseline was 205 mg/dL. The study consisted of an optional 8-week screening/dietary assessment phase, a 4-week lead-in phase, and a 54-week open-label treatment phase. Study subjects were randomized to initial daily doses of atorvastatin 10 mg, fluvastatin 20 mg, lovastatin 20 mg or simvastatin 10 mg and titrated if necessary at 12-week intervals to maximum doses. If the NCEP goal was not achieved at maximum dose, colestipol 5 g/day was titrated to a maximum of 20 mg/day. The slide shows cumulative response over time. At all study intervals, significantly more patients taking atorvastatin had reached their NCEP goal (P < 0.05). At week 12, the percentages of patients reaching their goal were atorvastatin (71%), fluvastatin (16%), lovastatin (34%) and simvastatin (41%). At study end, the corresponding figures were atorvastatin (95%), fluvastatin (60%), lovastatin (77%) and simvastatin (83%). All atorvastatin patients who reached goal were on monotherapy and required fewer titration and office visits than patients in the other groups; consequently, mean total cost of care was lowest with atorvastatin. The study investigators concluded that atorvastatin was a highly effective treatment in a population at risk for CHD.