TABLE 1
Intensive LDL-C lowering in high-risk patients: What the research tells us
| Trial Name | Daily statin treatment; patient population | Mean baseline LDL-C level | Mean achieved LDL-C level,* % reduction | Major findings |
|---|---|---|---|---|
| Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial—Lipid-Lowering Trial (ALLHAT-LLT)15 | Pravastatin 40 mg vs usual care; ≥55 y, moderately hypertensive and hypercholesterolemic | 146 mg/dL | 104 mg/dL, 29% (pravastatin); 121 mg/dL, 17% (usual care) | CHD event rates not significantly reduced, except in blacks (27%, P=.03) |
| Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA)14 | Atorvastatin 10 mg vs placebo; hypertensive, multiple risk factors | 132 mg/dL | 90 mg/dL, 32% (atorvastatin); 126 mg/dL (placebo) | Atorvastatin 10 mg added to an antihypertensive regimen reduced major CV events by 36% (P=.0005) |
| Heart Protection Study (HPS)13 | Simvastatin 40 mg vs placebo; high-risk coronary or other occlusive arterial disease, or diabetes | 132 mg/dL | 89 mg/dL, 33% (simvastatin); 128 mg/dL (placebo) | Significant 18% decrease in coronary deaths, even in individuals with baseline LDL-C <116 mg/dL |
| Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL)11 | Atorvastatin 80 mg vs simvastatin 20 mg; history of MI | 122 mg/dL | 80 mg/dL, 34% (atorvastatin); 100 mg/dL, 17% (simvastatin) | Nonsignificant reduction in primary outcome, but significant reductions in selected secondary outcomes: 13% (P<.02) for major CV events, 16% (P<.001) for any CHD event, 16% (P<.001) for any CV event |
| Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)16 | Pravastatin 40 mg vs placebo; 70-82 y with CVD or at high risk | 147 mg/dL | 97 mg/dL, 34% (pravastatin) | 15% (P=.014) reduction in composite incidence of coronary death, nonfatal MI, and stroke vs placebo |
| Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22)12 | Atorvastatin 80 mg vs pravastatin 40 mg; hospitalized for ACS | 106 mg/dL | 62 mg/dL, 42% (atorvastatin, 80 mg); 95 mg/dL, 10% (pravastatin, 40 mg) | Intensive therapy reduced risk of death and major CV events early in treatment vs standard therapy |
| Treating to New Targets (TNT)10 | Atorvastatin 80 mg vs atorvastatin 10 mg; stable CHD | 98 mg/dL | 77 mg/dL, 21% (80 mg); 101 mg/dL, (10 mg) | Intensive therapy reduced rate of major CV events by 22% vs moderate therapy |
| ACS, acute coronary syndromes; CHD, coronary heart disease; CV, cardiovascular; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction. | ||||
| *PROVE IT values reflect the median. | ||||
Treating to New Targets (TNT)
After an 8-week run-in period with atorvastatin 10 mg/d, the TNT researchers randomized 10,000 patients with stable CHD and mean baseline LDL-cholesterol levels of 98 mg/dL to atorvastatin 80 mg/d or continued with atorvastatin 10 mg/d.10 Patients in the high-dose group achieved a mean LDL-cholesterol level of 77 mg/dL, which was associated with a 22% relative reduction in risk of a major cardiovascular event (P<.001) and significant reductions in stroke (25%) and cerebrovascular events (23%).10,17
PROVE IT
The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial enrolled 4162 patients who had been hospitalized for acute coronary syndrome within the previous 10 days.12 Patients were randomly assigned to intensive (atorvastatin 80 mg/d) or moderate (pravastatin 40 mg/d) therapy for 24 months—in addition to therapeutic lifestyle interventions. Median LDL-cholesterol levels fell from 106 mg/dL at baseline to 62 mg/dL in the intensive-therapy group and to 95 mg/dL in the standard-therapy group. At 2 years, the primary end point—a composite of cardiovascular events—was 16% lower (P=.005) in patients on intensive therapy than in patients on moderate therapy, with the greatest apparent benefit in those with baseline LDL-cholesterol levels of at least 125 mg/dL.12 Favorable outcomes were more closely related to the on-treatment levels of LDL-cholesterol and C-reactive protein than to the specific agent used.18
Taken together, the TNT and PROVE IT trials show that in high-risk patients with CHD, achieving LDL-cholesterol levels of 60 to 80 mg/dL results in better outcomes than regimens that achieve LDL-cholesterol levels of approximately 100 mg/dL.
Moving the goal posts
The 2002 NCEP Adult Treatment Panel III (ATP III) guidelines recommend LDL-cholesterol goals depending on the patient’s level of risk, with <100 mg/dL as the goal for those in the highest risk category.2 Statin-treated patients in the Heart Protection Study (HPS) achieved a mean LDL-cholesterol level of 89 mg/dL, and investigators reported a “highly significant” 18% reduction in coronary deaths (P=.0005), even in individuals who entered the study with baseline LDL-cholesterol level of <116 mg/dL.13 No indication of a threshold effect was found. For that reason, the HPS investigators suggested that reducing LDL-cholesterol still further with dietary and statin therapy might produce even greater reductions in cardiovascular events.13
In 2004, <70 was a “therapeutic option”
The 2004 update of the NCEP guidelines took into account the findings of the HPS and several other statin trials—most of them secondary prevention studies—that provided further evidence for the benefit of lowering LDL-cholesterol to levels well below 100 mg/dL.12-16,19 The mean achieved LDL-cholesterol levels in these trials and the impact on CHD events are summarized in TABLE 1. The more intensive vs less intensive LDL-cholesterol lowering trials discussed earlier provided evidence that reducing LDL-cholesterol levels to <70 mg/dL is a “therapeutic option” for people at very high CHD risk. The “very-high-risk” category includes those with established cardiovascular disease and additional risk factors such as diabetes mellitus, continued cigarette smoking, metabolic syndrome, and acute coronary syndrome.19 TABLE 2 summarizes the 2004 NCEP goals.