Overview

The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP) unveiled its third evidence-based set of guidelines on cholesterol management in 2001. These guidelines were based on the results of several large, randomized clinical trials of cholesterol-lowering statin therapy published over the previous decade. These primary and secondary prevention trials demonstrated benefits across a wide spectrum of cholesterol levels using varying doses of statins to achieve a 25-35% reduction in lipid levels.

The current guidelines recommend a goal LDL-C level of less than 100 mg/dL for persons with manifest heart disease, diabetes mellitus, or coronary disease equivalents; however, new data from 5 major statin trials conducted since the 2001 ATP III update suggest that, while the earlier approach does reduce the risk of cardiac events, a more aggressive approach reduces the risk even further for high-risk patients (Singh, 2005), thus necessitating the update published in July 2004 (Grundy, 2004).

MAJOR TRIALS PUBLISHED SINCE ATP III

The HPS

The Heart Protection Study (HPS) randomized 20,536 adults aged 40-80 years (5963 individuals with diabetes mellitus; 14,573 without diabetes mellitus) to either 40 mg/d of simvastatin or a placebo. All subjects exhibited a highly significant reduction (25%) in the first event rate for major coronary events, strokes, and revascularizations. Furthermore, a reduction of 27% (95% CI, 12-40; P = .0007) occurred among the 2426 participants with diabetes mellitus whose pretreatment LDL-C level was lower than 116 mg/dL. This study provided direct evidence that cholesterol-lowering therapy is beneficial for people with diabetes mellitus, even if they do not already have overt coronary disease or high cholesterol. Statin therapy should therefore be used routinely for all patients with diabetes mellitus regardless of their initial cholesterol levels (HPS Collaborative Group, 2002).

The PROSPER trial

The PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial was designed to examine the efficacy and safety of statins in men and women aged 70 years or older with or at high risk of developing cardiovascular disease and stroke. In this study, 5804 subjects (2804 men; 3000 women) aged 70-82 years were randomized to 40 mg/d of pravastatin (n = 2891) or a placebo (n = 2913). Pravastatin lowered LDL-C levels by 34% and significantly reduced the incidence of coronary death, nonfatal myocardial infarction (MI), and fatal or nonfatal stroke to 408 events compared to 473 events for patients on the placebo (hazard rate [HR], 0.85; 95% CI, 0.74-0.97; P = .014). The effect on stroke reduction was not significant, however. The mortality rate from coronary disease fell by 24% (P = .043) in the pravastatin group. The authors concluded that pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals. The PROSPER trial therefore extends to older individuals the treatment strategy currently used for middle-aged people (Shepherd, 2002).

The lipid-lowering arm of the ALLHAT

The lipid-lowering arm of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT-LLT) trial examined the effects of lipid-lowering therapy in individuals older than 55 years with moderate hypercholesterolemia, hypertension, and at least 1 additional risk factor and who had fasting LDL-C levels of 120-189 mg/dL (or 100-129 mg/dL if known coronary heart disease [CHD]). Subjects were randomized to 40 mg/d of pravastatin (n = 5170) or usual care (n = 5185). At year 4, subjects taking pravastatin had reduced LDL-C levels of 28% versus reduced levels of 11% in patients with usual care. However, neither all-cause mortality nor CHD event rates differed significantly. The authors speculated that this may be because of smaller differences in total cholesterol and LDL-C levels between the pravastatin and usual-care groups compared with other statin-therapy trials (ALLHAT Collaborative Research Group, 2002).

The ASCOT-LLA Trial

The Anglo-Scandinavian Cardiac Outcomes Trial–lipid-lowering arm (ASCOT-LLA) studied the benefits of cholesterol lowering with 10 mg/d of atorvastatin versus a placebo in the primary prevention of coronary artery disease (CAD) in 10,305 hypertensive patients, who are not conventionally deemed dyslipidemic. The study was stopped prematurely because of a significant reduction (36%) in the primary end points, such as nonfatal MI and fatal CHD (P <.0005). In hypertensive patients who achieved good blood pressure control, LDL-C lowering produced clinically significant additional reductions in the risk of CAD. In addition, a 27% stroke reduction rate was observed in subjects with good blood pressure control and average LDL-C levels (Sever, 2003).

The PROVE-IT-TIMI 22 trial

The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial examined whether statins are effective in reducing cardiovascular events in patients with acute coronary syndromes (ACS) and whether intensive LDL-C lowering to an average of 65 mg/dL achieves a greater reduction in clinical events than the standard LDL-C–lowering goal of 95 mg/dL. In the trial, 4162 patients within 10 days of presentation with ACS were randomized to 40 mg/d of pravastatin or 80 mg/d of atorvastatin. The results demonstrated that intensive LDL-C lowering (median LDL-C level of 62 mg/dL) using high-dose statin therapy (atorvastatin 80 mg/d) compared with moderate lipid-lowering therapy (median LDL-C level of 95 mg/dL) using moderate-dose statin therapy (pravastatin 40 mg/d) reduced the risk of all-cause mortality or major cardiac events by an additional 16% (pravastatin group, 26.3% vs atorvastatin group, 22.4%; P = .005). These benefits emerged within 30 days post-ACS, with continued benefit observed throughout the 2.5 years of follow-up. Additionally, the benefits were consistent across all cardiovascular end points except stroke and most clinical subgroups. In summary, patients recently hospitalized for an ACS benefit from early and continued lowering of LDL-C to levels substantially below current target levels (Cannon, 2004).

SUBSEQUENT LIPID TRIALS SINCE THE 2004 UPDATE

The CARDS

Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes mellitus was the focus of the Collaborative Atorvastatin Diabetes Study (CARDS). The CARDS examined the effectiveness of atorvastatin at 10 mg/d in individuals with diabetes mellitus who did not have overt CHD or high baseline LDL-C levels but had 1 of the following: retinopathy, albuminuria, a current smoking habit, or hypertension. In the study, 2838 subjects aged 40-75 years were randomized to atorvastatin at 10 mg/d (n = 1428) or a placebo (n = 1410). Coronary events were reduced by 37%, coronary revascularizations by 31% (-59 to 16), and strokes by 48% (-69 to -11); however, the trial was terminated 2 years early on ethical grounds because the benefit shown may have been greater since a proportion of subjects on the placebo received statin therapy as well. Nevertheless, results still showed that atorvastatin at 10 mg/d is effective in helping decrease the risk of first cardiovascular disease events, including stroke, in patients with type 2 diabetes mellitus who do not have high baseline LDL-C levels (Colhoun, 2004).

The ALLIANCE trial

The Aggressive Lipid Lowering Initiation Abates New Cardiac Events (ALLIANCE) trial randomized 2442 subjects with CHD (within 6 mo of MI or after an ACS) to either atorvastatin (n = 1217) or usual care (n = 1225) with 52 months of follow-up. The baseline LDL-C level was reduced from 147 mg/dL to 95 mg/dL (a 56% reduction) in the atorvastatin group and to 111 mg/dL (a 36% reduction) in the usual-care group. Atorvastatin therapy was associated with a 47% decrease in nonfatal MI versus usual care. These results clearly show the important cardiovascular benefits of intensive lipid lowering in patients at high risk for recurrent coronary events (Koren and Hunninghake, 2004).

The REVERSAL trial

The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial used intravascular ultrasonography to measure progression of atherosclerosis in 654 subjects randomized to receive a moderate lipid-lowering regimen consisting of 40 mg/d of pravastatin or an intensive lipid-lowering regimen consisting of 80 mg/d of atorvastatin. The baseline LDL-C level of 150.2 mg/dL was reduced to 110 mg/dL in the pravastatin group and to 79 mg/dL in the atorvastatin group (P < .001). C-reactive protein (CRP) levels were also measured, and these decreased by 5.2% with pravastatin and 36.4% with atorvastatin (P < .001). Overall, while progression of coronary atherosclerosis occurred in the pravastatin group (2.7%; P = .001) compared with the baseline level, progression did not occur in the atorvastatin group (-0.4%; P = .98). The study concluded that, for patients with CHD, intensive lipid-lowering treatment with atorvastatin instead of pravastatin significantly reduces the progression of coronary atherosclerosis. These differences may be related to the greater reduction in atherogenic lipoproteins and CRP in the patients treated with atorvastatin (Nissen, 2004).

The A-to-Z Trial

The Aggrastat to Zocor Trial (A-to-Z Trial) studied an early intensive versus a delayed conservative simvastatin treatment strategy in patients with ACS who were randomized to 40 mg/d of simvastatin for 1 month followed by 80 mg/d (n = 2265) or a placebo for 4 months followed by 20 mg/d of simvastatin (n = 2232). A total of 343 subjects (16.7%) in the placebo-plus-simvastatin group achieved the primary end point compared with 309 (14.4%) in the simvastatin-only group (40 mg/80 mg) (P = .14). This trial did not achieve the prespecified end point. However, among patients with ACS, the early initiation of an aggressive simvastatin regimen resulted in a favorable trend toward reduction of major cardiovascular events (de Lemos, 2004).

The TNT trial

Efficacy and safety of intensive statin therapy in reducing LDL-C levels to well below 100 mg/dL was examined in the 5-year Treating to New Targets (TNT) study, which involved a total of 10,001 patients with established CHD and LDL-C levels lower than 130 mg/dL. Patients were randomized to atorvastatin 10 mg/d or atorvastatin 80 mg/d. The mean LDL-C levels were 77 mg/dL within the 80-mg group and 101 mg/dL within the 10-mg group with primary events occurring in 434 patients (8.7%) receiving 80 mg versus 548 patients (10.9%) receiving 10 mg, representing a 22% relative reduction in risk (HR, 0.78; 95% CI, 0.69-0.89; P <.001). These findings indicate that the quantitative relationship between reduced LDL-C levels and reduced CHD risk demonstrated in previous secondary-prevention trials (eg, HPS, CARE, LIPID, 4S) remains true even at very low levels of LDL-C (LaRosa, 2005).

CONCLUSIONS

The 2004 update to the 2001 ATP III (2001) evidence-based guidelines for cholesterol management incorporated results from 5 major trials published since 2001. Overall, therapeutic lifestyle changes (TLCs) remain a crucial part of clinical management of dyslipidemia and atherosclerosis prevention. The recommendations in the update are not meant for everybody but rather for specific subsets of high-risk patients: those with ACS (as seen in the PROVE-IT-TIMI 22 trial), those with diabetes mellitus (as seen in the HPS), those with multiple risk factors of metabolic syndrome (also seen in the HPS), and those with severe risk factors such as long-term cigarette smoking (as seen in the ASCOT-LLA). Summary recommendations are as follows:

• For persons at high risk, the recommended LDL-C level goal is lower than 100 mg/dL.
  • However, when risk is “very high,” an LDL-C level goal of lower than 70 mg/dL is a therapeutic option.
  • This also applies to patients at very high risk who have a baseline LDL-C level of lower than 100 mg/dL.
• For persons at moderately high risk (>2 risk factors and 10-y Framingham risk of 10-20%), the recommended LDL-C level goal is lower than 130 mg/dL.
  • An LDL-C level goal of lower than 100 mg/dL is a therapeutic option.
  • An LDL-C level of lower than 100 is also desirable for persons at moderately high risk with baseline LDL-C levels of 100-129 mg/dL.
  • In addition, persons at high or moderately high risk who have metabolic syndrome (obesity, physical inactivity, elevated triglyceride level, or low HDL-C level) are candidates for TLC.
  • In such patients, a strategy of combining a fibrate or nicotinic acid with a statin should be considered.
• For persons in lower-risk subsets, recent clinical trials do not modify the goals and cut points of lipid treatment.

Since the 2004 ATP III update was published, an additional 5 trials have been reported. These trials lend further support to the fact that persons with significant cardiac risk factors, and stable as well as unstable coronary disease, would benefit from more aggressive TLC and lipid lowering.

References

ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. JAMA 2002; 288: 2998-3007.

Cannon CP, Braunwald E, McCabe CH, et al, Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators: Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350: 1495-504.

Colhoun HM, Betteridge DJ, Durrington PN, et al, on behalf of the CARDS investigators: Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004; 364: 685-96.

de Lemos JA, Blazing MA, Wiviott SD, et al, for the A to Z Investigators: Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004; 292: 1307-16.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). JAMA 2001; 285: 2486-97.

Grundy SM, Cleeman JI, Merz CN, et al: Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004; 110: 227-39.

Heart Protection Study (HPS) Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7-22.

Koren MJ, Hunninghake DB, on behalf of the ALLIANCE Investigators: Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the alliance study. J Am Coll Cardiol 2004; 44: 1772-9.

LaRosa, JC, Grundy, SM, Waters, DD, et al, for the TNT Investigators: Intensive lipid lowering with atorvastatin in patients with stable coronary disease. New Engl J Med 2005; 352 (23) 2389-97.

Nissen SE, Tuzcu EM, Schoenhagen P, et al: Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291: 1071-80.

Sever PS, Dahlof B, Poulter NR, et al, ASCOT Investigators: Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm: a multicentre randomised controlled trial. Lancet 2003; 361: 1149-58.

Shepherd J, Blauw GJ, Murphy MB, et al, PROSPER Study Group: Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. PROspective Study of Pravastatin in the Elderly at Risk. Lancet 2002; 360: 1623-30.

Singh VN, Deedwania PC, Sharma RK: Coronary artery atherosclerosis. eMedicine 2005; Available at: http://www.emedicine.com/med/topic446.htm.