Prevention of Cardiovascular Disease
In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin calcium on fatal and non-fatal coronary heart disease was assessed in 10,305 patients with hypertension, 40-80 years of age (mean of 63 years; 19% women; 95% White, 3% Black, 1% South Asian, 1% other), without a previous myocardial infarction and with total cholesterol (TC) levels ≤251 mg/dL. Additionally, all patients had at least 3 of the following cardiovascular risk factors: male gender (81%), age >55 years (85%), smoking (33%), diabetes (24%), history of CHD in a first-degree relative (26%), TC:HDL >6 (14%), peripheral vascular disease (5%), left ventricular hypertrophy (14%), prior cerebrovascular event (10%), specific ECG abnormality (14%), proteinuria/albuminuria (62%). In this double-blind, placebo-controlled trial, patients were treated with anti-hypertensive therapy (goal BP <140/90 mm Hg for patients without diabetes; <130/80 mm Hg for patients with diabetes) and allocated to either atorvastatin calcium 10 mg daily (n=5168) or placebo (n=5137), using a covariate adaptive method which took into account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of 3.3 years.
The effect of 10 mg/day of atorvastatin calcium tablets on lipid levels was similar to that seen in previous clinical trials.
Atorvastatin significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs. 40 events in the atorvastatin calcium tablets group) or non-fatal MI (108 events in the placebo group vs. 60 events in the atorvastatin calcium tablets group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for atorvastatin calcium tablets vs. 3% for placebo), p=0.0005 (see Figure 1)]. The risk reduction was consistent regardless of age, smoking status, obesity, or presence of renal dysfunction. The effect of atorvastatin was seen regardless of baseline LDL levels.
Figure 1: Effect of Atorvastatin 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA)
Atorvastatin also significantly decreased the relative risk for revascularization procedures by 42% (incidences of 1.4% for atorvastatin calcium and 2.5% for placebo). Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p=0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7% for atorvastatin calcium tablets and 2.3% for placebo). There was no significant difference between the treatment groups for death due to cardiovascular causes (p=0.51) or noncardiovascular causes (p=0.17).
In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin on cardiovascular disease (CVD) endpoints was assessed in 2,838 subjects (94% White, 2% Black, 2% South Asian, 1% other; 68% male) ages 40 to 75 with type 2 diabetes based on WHO criteria, without prior history of cardiovascular disease and with LDL ≤ 160 mg/dL and triglycerides (TG) ≤600 mg/dL. In addition to diabetes, subjects had 1 or more of the following risk factors: current smoking (23%), hypertension (80%), retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria (3%). No subjects on hemodialysis were enrolled in the trials. In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly allocated to either atorvastatin calcium tablets 10 mg daily (1,429) or placebo (1,411) in a 1:1 ratio and were followed for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint.
Baseline characteristics of subjects were: mean age of 62 years, mean HbA1c 7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL.
The effect of atorvastatin 10 mg/day on lipid levels was similar to that seen in previous clinical trials.
Atorvastatin significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the atorvastatin calcium tablets group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 0.83) (p=0.001) (see Figure 2). An effect of atorvastatin calcium tablets was seen regardless of age, sex, or baseline lipid levels.
Atorvastatin significantly reduced the risk of stroke by 48% (21 events in the atorvastatin calcium tablets group vs. 39 events in the placebo group), HR 0.52, 95% CI (0.31, 0.89) (p=0.016) and reduced the risk of MI by 42% (38 events in the atorvastatin calcium tablets group vs. 64 events in the placebo group), HR 0.58, 95.1% CI (0.39, 0.86) (p=0.007). There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death.
There were 61 deaths in the atorvastatin calcium tablets group vs. 82 deaths in the placebo group (HR 0.73, p=0.059).
Figure 2: Effect of Atorvastatin 10 mg/day on Time to Occurrence of Major Cardiovascular Event (myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke) in CARDS
In the Treating to New Targets Study (TNT), the effect of atorvastatin calcium tablets 80 mg/day vs. atorvastatin calcium tablets 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% White, 81% male, 38% ≥65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level <130 mg/dL after completing an 8-week, open-label, run-in period with atorvastatin calcium tablets 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin calcium tablets and followed for a median duration of 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL cholesterol levels at 12 weeks were 73, 145, 128, 98, and 47 mg/dL during treatment with 80 mg of atorvastatin calcium tablets and 99, 177, 152, 129, and 48 mg/dL during treatment with 10 mg of atorvastatin calcium tablets.
Treatment with atorvastatin calcium tablets 80 mg/day significantly reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548 events in the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI (0.69, 0.89), p=0.0002 (see Figure 3 and Table 7). The overall risk reduction was consistent regardless of age (<65, ≥65) or sex.
Figure 3: Effect of Atorvastatin 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT)
Table 7: Overview of Efficacy Results in TNT
| Endpoint | Atorvastatin | Atorvastatin | HRa (95%CI) | ||
| 10 mg | 80 mg | ||||
| (N=5006) | (N=4995) | ||||
| PRIMARY ENDPOINT | n | (%) | n | (%) | |
| First major cardiovascular endpoint | 548 | (10.9) | 434 | (8.7) | 0.78 (0.69, 0.89) |
| Components of the Primary Endpoint | |||||
| CHD death | 127 | (2.5) | 101 | (2.0) | 0.80 (0.61, 1.03) |
| Non-fatal, non-procedure related MI | 308 | (6.2) | 243 | (4.9) | 0.78 (0.66, 0.93) |
| Resuscitated cardiac arrest | 26 | (0.5) | 25 | (0.5) | 0.96 (0.56, 1.67) |
| Stroke (fatal and non-fatal) | 155 | (3.1) | 117 | (2.3) | 0.75 (0.59, 0.96) |
| SECONDARY ENDPOINTS* | |||||
| First CHF with hospitalization | 164 | (3.3) | 122 | (2.4) | 0.74 (0.59, 0.94) |
| First PVD endpoint | 282 | (5.6) | 275 | (5.5) | 0.97 (0.83, 1.15) |
| First CABG or other coronary revascularization procedureb | 904 | (18.1) | 667 | (13.4) | 0.72 (0.65, 0.80) |
| First documented angina endpointb | 615 | (12.3) | 545 | (10.9) | 0.88 (0.79, 0.99) |
| All-cause mortality | 282 | (5.6) | 284 | (5.7) | 1.01 (0.85, 1.19) |
| Components of All-Cause Mortality | |||||
| Cardiovascular death | 155 | (3.1) | 126 | (2.5) | 0.81 (0.64, 1.03) |
| Noncardiovascular death | 127 | (2.5) | 158 | (3.2) | 1.25 (0.99, 1.57) |
| Cancer death | 75 | (1.5) | 85 | (1.7) | 1.13 (0.83, 1.55) |
| Other non-CV death | 43 | (0.9) | 58 | (1.2) | 1.35 (0.91, 2.00) |
| Suicide, homicide, and other traumatic non-CV death | 9 | (0.2) | 15 | (0.3) | 1.67 (0.73, 3.82) |
a Atorvastatin 80 mg: atorvastatin 10 mg
b Component of other secondary endpoints
* Secondary endpoints not included in primary endpoint
HR=hazard ratio; CHD=coronary heart disease; CI=confidence interval; MI=myocardial infarction; CHF=congestive heart failure; CV=cardiovascular; PVD=peripheral vascular disease; CABG=coronary artery bypass graft
Confidence intervals for the Secondary Endpoints were not adjusted for multiple comparisons
Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin calcium tablets 80 mg/day significantly reduced the rate of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD death or resuscitated cardiac arrest (Table 7). Of the predefined secondary endpoints, treatment with atorvastatin calcium tablets 80 mg/day significantly reduced the rate of coronary revascularization, angina, and hospitalization for heart failure, but not peripheral vascular disease. The reduction in the rate of CHF with hospitalization was only observed in the 8% of patients with a prior history of CHF.
There was no significant difference between the treatment groups for all-cause mortality (Table 7). The proportions of subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke, were numerically smaller in the atorvastatin calcium tablets 80 mg group than in the atorvastatin calcium tablets 10 mg treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in the atorvastatin calcium tablets 80 mg group than in the atorvastatin calcium tablets 10 mg treatment group.
Primary Hyperlipidemia in Adults
Atorvastatin reduces total-C, LDL-C, apo B, and TG, and increases HDL-C in patients with hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. Therapeutic response is seen within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during chronic therapy.
In two multicenter, placebo-controlled, dose-response trials in patients with hyperlipidemia, atorvastatin calcium tablets given as a single dose over 6 weeks, significantly reduced total-C, LDL-C, apo B, and TG. (Pooled results are provided in Table 8.)
Table 8: Dose Response in Patients with Primary Hyperlipidemia (Adjusted Mean % Change From Baseline)a
| Dose | N | TC | LDL-C | Apo B | TG | HDL-C |
| Placebo | 21 | 4 | 4 | 3 | 10 | -3 |
| 10 | 22 | -29 | -39 | -32 | -19 | 6 |
| 20 | 20 | -33 | -43 | -35 | -26 | 9 |
| 40 | 21 | -37 | -50 | -42 | -29 | 6 |
| 80 | 23 | -45 | -60 | -50 | -37 | 5 |
a Results are pooled from 2 dose-response trials.
In three multicenter, double-blind trials in patients with hyperlipidemia, atorvastatin was compared to other statins. After randomization, patients were treated for 16 weeks with either atorvastatin calcium tablets 10 mg per day or a fixed dose of the comparative agent (Table 9).
Table 9: Mean Percentage Change From Baseline at Endpoint (Double-Blind, Randomized, Active-Controlled Trials)
| Treatment(Daily Dose) | N | Total-C | LDL-C | Apo B | TG | HDL-C |
| Trial 1 | ||||||
| Atorvastatin 10 mg | 707 | -27a | -36a | -28a | -17a | +7 |
| Lovastatin 20 mg | 191 | -19 | -27 | -20 | -6 | +7 |
| 95% CI for Diff1 | -9.2, -6.5 | -10.7, -7.1 | -10.0, -6.5 | -15.2, -7.1 | -1.7, 2.0 | |
| Trial 2 | ||||||
| Atorvastatin 10 mg | 222 | -25b | -35b | -27b | -17b | +6 |
| Pravastatin 20 mg | 77 | -17 | -23 | -17 | -9 | +8 |
| 95% CI for Diff1 | -10.8, -6.1 | -14.5, -8.2 | -13.4, -7.4 | -14.1, -0.7 | -4.9, 1.6 | |
| Trial 3 | ||||||
| Atorvastatin 10 mg | 132 | -29c | -37c | -34c | -23c | +7 |
| Simvastatin 10 mg | 45 | -24 | -30 | -30 | -15 | +7 |
| 95% CI for Diff1 | -8.7, -2.7 | -10.1, -2.6 | -8.0, -1.1 | -15.1, -0.7 | -4.3, 3.9 |
1 A negative value for the 95% CI for the difference between treatments favors atorvastatin for all except HDL-C, for which a positive value favors atorvastatin . If the range does not include 0, this indicates a statistically significant difference.
a Significantly different from lovastatin, ANCOVA, p ≤0.05
b Significantly different from pravastatin, ANCOVA, p ≤0.05
c Significantly different from simvastatin, ANCOVA, p ≤0.05
Table 9 does not contain data comparing the effects of atorvastatin 10 mg and higher doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the trials summarized in the table are not necessarily interchangeable.
Hypertriglyceridemia in Adults
The response to atorvastatin in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table below (Table 10). For the atorvastatin calcium tablets-treated patients, median (min, max) baseline TG level was 565 (267 to 1,502).
Table 10: Combined Patients with Isolated Elevated TG: Median (min, max) Percentage Change From Baseline
| Placebo | Atorvastatin 10 mg | Atorvastatin 20 mg | Atorvastatin 80 mg | |
| (N=12) | (N=37) | (N=13) | (N=14) | |
| Triglycerides | -12.4 (-36.6, 82.7) | -41.0 (-76.2, 49.4) | -38.7 (-62.7, 29.5) | -51.8 (-82.8, 41.3) |
| Total-C | -2.3 (-15.5, 24.4) | -28.2 (-44.9, -6.8) | -34.9 (-49.6, -15.2) | -44.4 (-63.5, -3.8) |
| LDL-C | 3.6 (-31.3, 31.6) | -26.5 (-57.7, 9.8) | -30.4 (-53.9, 0.3) | -40.5 (-60.6, -13.8) |
| HDL-C | 3.8 (-18.6, 13.4) | 13.8 (-9.7, 61.5) | 11.0 (-3.2, 25.2) | 7.5 (-10.8, 37.2) |
| non-HDL-C | -2.8 (-17.6, 30.0) | -33.0 (-52.1, -13.3) | -42.7 (-53.7, -17.4) | -51.5 (-72.9, -4.3) |
Dysbetalipoproteinemia in Adults
The results of an open-label crossover trail of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia are shown in the table below (Table 11).
Table 11. Open-Label Crossover Trial of 16 Patients with Dysbetalipoproteinemia (Fredrickson Type III)
| Median % Change (min, max) | |||
| Median (min, max) at | Atorvastatin | Atorvastatin | |
| Baseline (mg/dL) | 10 mg | 80 mg | |
| Total-C | 442 (225, 1320) | -37 (-85, 17) | -58 (-90, -31) |
| Triglycerides | 678 (273, 5990) | -39 (-92, -8) | -53 (-95, -30) |
| IDL-C + VLDL-C | 215 (111, 613) | -32 (-76, 9) | -63 (-90, -8) |
| non-HDL-C | 411 (218, 1272) | -43 (-87, -19) | -64 (-92, -36) |
HoFH in Adults and Pediatric Patients
In a trial without a concurrent control group, 29 patients (mean age of 22 years, median age of 24 years, 31% <18 years) withHoFH received maximum daily doses of 20 to 80 mg of atorvastatin calcium tablets. The mean LDL-C reduction in this trial was 18%. Twenty-five patients with a reduction in LDL-C had a mean response of 20% (range of 7% to 53%, median of 24%); the remaining 4 patients had 7% to 24% increases in LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, 2 patients also had a portacaval shunt and had no significant reduction in LDL-C. The remaining 3 receptor-negative patients had a mean LDL-C reduction of 22%.
HeFH in Pediatric Patients
In a double-blind, placebo-controlled trial followed by an open-label phase, 187 boys and post-menarchal girls 10 years to 17 years of age (mean age 14.1 years; 31% female; 92% White, 1.6% Blacks, 1.6% Asians, 4.8% other) with heterozygous familial hypercholesterolemia (HeFH) or severe hypercholesterolemia, were randomized to atorvastatin calcium tablets (n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin calcium tablets for 26 weeks. Inclusion in the trial required 1) a baseline LDL-C level ≥ 190 mg/dL or 2) a baseline LDL-C level ≥ 160 mg/dL and positive family history of FH or documented premature cardiovascular disease in a first or second-degree relative. The mean baseline LDL-C value was 219 mg/dL (range: 139 to 385 mg/dL) in the atorvastatin calcium tablets group compared to 230 mg/dL (range: 160 to 325 mg/dL) in the placebo group. The dosage of atorvastatin calcium tablets (once daily) was 10 mg for the first 4 weeks and uptitrated to 20 mg if the LDL-C level was > 130 mg/dL. The number of atorvastatin calcium tablets-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 78 (56%).
Atorvastatin significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week double-blind phase (see Table 12).
Table 12: Lipid-altering Effects of Atorvastatin in Adolescent Boys and Girls with Heterozygous Familial Hypercholesterolemia or Severe Hypercholesterolemia (Mean Percentage Change From Baseline at Endpoint in Intention-to-Treat Population)
| DOSAGE | N | Total-C | LDL-C | HDL-C | TG | Apolipoprotein B |
| Placebo | 47 | -1.5 | -0.4 | -1.9 | 1.0 | 0.7 |
| Atorvastatin | 140 | -31.4 | -39.6 | 2.8 | -12.0 | -34.0 |
The mean achieved LDL-C value was 130.7 mg/dL (range: 70 to 242 mg/dL) in the atorvastatin group compared to 228.5 mg/dL (range: 152 to 385 mg/dL) in the placebo group during the 26-week double-blind phase.
Atorvastatin was also studied in a three year open-label, uncontrolled trial that included 163 patients with HeFH who were 10 years to 15 years old (82 boys and 81 girls). All patients had a clinical diagnosis of HeFH confirmed by genetic analysis (if not already confirmed by family history). Approximately 98% were White, and less than 1% were Black or Asian. Mean LDL-C at baseline was 232 mg/dL. The starting atorvastatin dosage was 10 mg once daily and doses were adjusted to achieve a target of < 130 mg/dL LDL-C. The reductions in LDL-C from baseline were generally consistent across age groups within the trial as well as with previous clinical trials in both adult and pediatric placebo-controlled trials.
