According to the National Cholesterol Education Program, patients with acute coronary syndromes or established cardiovascular disease and additional major risk factors are at very high risk for cardiovascular events. Accumulating evidence supports low-density lipoprotein cholesterol reductions of between 30% and 50% or even more, which can be safely accomplished with intensive statin therapy. However, physician awareness of the need for intensive treatment in very-high-risk patients is not reflected in surveys of lipid goal attainment, which show that patients at highest risk have the lowest rates of achieving their low-density lipoprotein cholesterol goals. Intensive statin therapy can be started in such patients, regardless of their baseline low-density lipoprotein cholesterol level. Options for reaching therapeutic goals in very-high-risk patients include monotherapy with a powerful statin, uptitrating the statin dose, and combining a statin with a second lipid-lowering agent.

In 2004, an update to the National Cholesterol Education Program (NCEP) Third Adult Treatment Panel (ATP III) guidelines introduced a subcategory to its classifications of high, moderate, and low cardiovascular (CV) risk.¹ The new category was the very-high-risk patient, who, according to accumulating evidence from clinical trials involving statin therapy,^2,3 could be expected to benefit from lower levels of low-density lipoprotein cholesterol (LDL-C) than previously recommended for high-risk patients. More recent data support this categorization, showing that lowering LDL-C beyond "target" or "normal" thresholds in very-high-risk patients safely provides additional incremental reductions in clinical events^4-6 and regression of coronary atherosclerosis.⁷

The value of using an intensive LDL-C–lowering regimen is underscored by recent surveys suggesting that in clinical practice, the highest-risk patients have the least success at reaching lipid goals.^8,9 In many cases, aggressive goals can be difficult to achieve, especially if the baseline LDL-C is high and the treating physician does not choose an appropriate statin or does not adjust the lipid-lowering drug regimen, or does not consistently follow up with the patient. There may also be fear of adverse effects from using high statin doses10 or from lowering LDL-C beyond a presumed level of safety.¹ Regardless of the obstacles, intensive therapy is an important treatment target in enabling high-risk patients to reach their LDL-C goals, having clearly shown the potential to prevent life-threatening events without compromising safety and tolerability. Physicians who have identified a patient as being at a very high risk need not accept moderate regimens or goals when more intensive management is warranted.

Who Is the Very-High-Risk Patient?

As shown in Table 1, the NCEP ATP III update added very high risk to its existing classification scheme for categorizing patients at various levels of CV risk.^1,11 Like high-risk patients, whose LDL-C goal is <100 mg/dL, very-high-risk patients have a 10-year risk for coronary heart disease (CHD) of >20% but an optional lower LDL-C goal of <70 mg/dL. The very-high-risk patient is characterized in Table 2. Accordingly, a middle-aged, obese man with a family history of CHD who has had coronary angioplasty and currently has the metabolic syndrome qualifies as a very-high-risk patient. So, too, does a chronic smoker with stable angina pectoris; an older woman with a previous myocardial infarction, hypertension, and diabetes mellitus; and the post–coronary artery bypass patient with elevated triglycerides and insulin resistance.

View Table 1 in a larger size.

The decision to establish an optional LDL-C goal of <70 mg/dL for very-high-risk patients—even for patients whose LDL-C is already <100 mg/dL—was based largely on findings from 2 major statin trials that included very-high-risk patients among their largely high-risk subjects—the Heart Protection Study (HPS)2 and the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) trial.³ Both trials reported additional reductions in risk of CV disease (CVD) when LDL-C was lowered to well below 100 mg/dL. In the HPS, even patients whose baseline LDL-C was already <100 mg/dL could expect another 20% to 30% reduction in CVD risk with a 30% reduction in LDL-C.²

The Case for Intensive Therapy

The HPS and PROVE IT trials are part of a body of statin trials that are exploring the limits of LDL-C reduction and the CV protection that intensive therapy can safely achieve. On the whole, these trials show an approximate one-to-one relationship between LDL-C reduction and relative CV risk, such that for every 1% reduction in LDL-C level, the relative risk of major CHD events is also reduced by 1%.^1,12 The relationship is approximately log-linear (Figure 1), implying that larger LDL-C reductions are likely to produce greater reductions in CV risk.^1,12 The association of lower LDL-C levels with greater reductions in CV events was confirmed in a recent meta-analysis of 14 randomized statin trials involving more than 90,000 patients, which showed that for every 39-mg/dL (1-mmol/L) decrease in LDL-C, an approximate 20% reduction occurred in the 5-year incidence of major coronary events, coronary revascularization, and stroke, as well as a 12% reduction in all-cause mortality.¹³

In very-high-risk patients, statin trials with both placebo and active controls have reported consistent results in event reduction with intensive therapy.^2-6,14,15 Several trials, including PROVE IT, have addressed patients with an acute coronary syndrome (ACS).

Acute coronary syndromes
In PROVE IT, 4162 patients were randomized to standard-dose (40 mg/d) pravastatin sodium (Pravachol) or high-dose (80 mg/d) atorvastatin (Lipitor) within 10 days after hospitalization for ACS. Within 30 days, atorvastatin lowered LDL-C to a median of 62 mg/dL (versus 95 mg/dL with pravastatin, P <.001). This was associated with a significant 16% reduction (P = .005) over 2 years in the composite primary end point of death from any cause and major CV events.³ Another study of 4497 patients with ACS, the Aggrastat to Zocor (A to Z) trial, did not report a significant benefit with high-dose simvastatin (Zocor) therapy, either overall or in the first 4 months of treatment (a placebo-controlled period).⁴ In the last 20 months of the 2-year follow-up, however, the more intensive regimen significantly reduced CV events by 25% (P = .02). This occurred even though LDL-C levels at 2 years differed by only 15 mg/dL between the intensive and the low-dose groups (66 mg/dL versus 81 mg/dL, respectively; P <.001).⁴ In effect, intensive lipid therapy in the A to Z trial resulted in even greater long-term risk reduction than the small difference in LDL-C reduction would have predicted.

Stable CHD and major risk factors
Persons with stable coronary disease and multiple major risk factors have also benefited from intensive lipid lowering, as shown most clearly in HPS. About 10% (n = 1981) of the 20,536 patients in HPS had both CHD and diabetes mellitus, placing them in the very-high-risk category. Indeed, such patients who were assigned to receive placebo had the highest 5-year rate of a first major CV event (38%) of any HPS subgroup, and this rate was reduced by about one fourth among the patients assigned to simvastatin 40 mg/day. As in other subgroups of the trial, this approximate 25% reduction was largely unrelated to the baseline LDL-C level and was achieved with LDL-C levels averaging <77 mg/dL.^2,15

Figure 1—Current evidence shows that for every 1% reduction in LDL-C level, the relative CHD risk is also reduced by approximately 1%, even when LDL-C is well below 100 mg/dL. CHD = coronary heart disease; LDL-C = low-density lipoprotein cholesterol. Reprinted with permission from Grundy SM, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239. Copyright © 2004 Lippincott Williams & Wilkins.

Two other recent trials—the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL)⁶ and the Treating to New Targets (TNT)⁵ trials—enrolled patients with stable coronary disease, many of whom were at very high risk because of multiple major risk factors. In IDEAL, a comparative trial of moderate (simvastatin 20 mg/d) and intensive (atorvastatin 80 mg/d) therapy, about 20% of patients in each treatment arm were current smokers, 33% were hypertensive, and 12% had a history of diabetes.⁶

In TNT, which compared 10 mg/day and 80 mg/day of atorvastatin, 13% of patients in each arm were current smokers, 54% were hypertensive, and 15% had a history of diabetes. Intensive therapy in TNT lowered LDL-C levels to an average of 77 mg/dL (versus 101 mg/dL with the moderate regimen) and achieved a 22% relative reduction in the risk of a major CV event (P <.001).⁵ In TNT, patients with both CHD and diabetes (n = 1501 of 10,001 total), relative risk reduction was 25% (P = .026),¹⁶ similar to the rate seen for this population in HPS. In IDEAL, although atorvastatin 80 mg/day reduced LDL-C to 81 mg/dL (versus 104 mg/dL with simvastatin 20 mg/d), the greater decrease in LDL-C was not associated with a significant reduction in major coronary events, the primary end point. Nevertheless, the secondary end points of nonfatal myocardial infarction and any CV event were each significantly reduced (by 17%, P = .02, and 16%, P <.001, respectively). Moreover, had the primary end point in IDEAL included stroke, as in TNT, the outcome favoring high-dose therapy would have been significant (13%, P = .02).¹⁷

Atherosclerotic regression
Intravascular ultrasound studies have offered a physiologic basis for clinical event reduction by showing that intensive statin therapy can arrest the progression of atherosclerosis and even induce regression. The greatest effects are associated with LDL-C levels <70 mg/dL, according to studies of both the carotid^18-20 and coronary arteries.^7,21 For example, in a post-hoc analysis of the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) study, regression was almost twice as likely to occur in patients with LDL-C levels <70 mg/dL than in those with LDL-C levels >100 mg/dL.¹⁹

Figure 2—Regression of coronary atherosclerosis from baseline with rosuvastatin therapy. Greater LDL-C reductions resulted in significantly greater reductions in percent atheroma volume. Source: Reference 7.

Intensive statin therapy effectively halted coronary disease progression in the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, a comparison of moderate (pravastatin 40 mg/d) and intensive (atorvastatin 80 mg/d) lipid lowering in 657 patients with a clinical indication for coronary angiography and at least 1 obstruction with at least a 20% luminal diameter narrowing in any coronary vessel.²¹ Over 18 months, LDL-C was lowered by 46% to a mean of 79 mg/dL with atorvastatin, and by 25% to a mean of 110 mg/dL with pravastatin (P <.001). Atherosclerosis (determined by percent change in atheroma volume) remained stable in the atorvastatin patients but progressed by a significant 2.7% (P = .001 versus baseline) in patients treated with pravastatin.²¹

In a subsequent investigation, the prospective, open-label, multicenter A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID), 507 patients with more than 20% baseline stenosis of at least 1 coronary artery were treated with very intensive therapy with rosuvastatin calcium (Crestor) 40 mg/day.⁷ Over 2 years, these patients achieved a mean decrease in LDL-C of 53.2% to 60.8 mg/dL (P <.001 versus baseline) and a mean increase in high-density lipoprotein cholesterol (HDL-C) of 14.7% (P <.001). These changes were associated with significant regression of the atherosclerotic plaque (P <.001) on several measures, including a decrease of 0.98% in mean percent atheroma volume for the entire vessel and a median change of –9.1% in atheroma volume in the most diseased subsegment. Patients with the lowest average on-treatment LDL-C had the greatest median change in percent atheroma volume (Figure 2).

Safety of Very-Low LDL-C Levels

One of the chief concerns of decreasing LDL-C to very-low levels is the possibility of increased non-CV mortality.¹⁸ In the TNT trial, concern was raised that LDL-C levels were too low, after a nonsignificant increase in non-CV deaths was reported in patients treated with high-dose (80 mg/d) atorvastatin.⁵ However, non-CV mortality did not increase in the more than 4440 patients treated with atorvastatin 80 mg/day in IDEAL,⁶ and a meta-analysis of the PROVE IT, TNT, A to Z, and IDEAL trials, covering more than 27,000 patients, showed nearly identical rates in non-CV deaths in the intensive (2.5%) and moderate (2.4%) lipid-lowering groups.¹⁴ Some authors refute concerns about dangerously low cholesterol, asserting that a physiologically normal LDL-C level in humans is between 50 mg/dL and 70 mg/dL.¹⁸ Indeed, the ultra-low LDL-C levels achieved with intensive statin therapy in ASTEROID (mean, 60.8 mg/dL)⁷ and PROVE IT (<40 mg/dL in 11% of patients)²² were well-tolerated.

Low Rates of Goal Achievement

According to recent surveys, patients at highest CV risk have the lowest rates of achieving LDL-C goal.^8,9 The NCEP Evaluation Project Utilizing Novel E-Technology (NEPTUNE) II, which surveyed physicians who were high prescribers of statins, reported that 60% of very-high-risk patients achieved LDL-C levels <100 mg/dL, the lowest rate for any risk group.⁸ Even worse, only 18% of very-high-risk patients reached the more stringent goal of <70 mg/dL. Nearly identical rates were reported by the Vascular Protection (VP) and the Guidelines Oriented Approach to Lipid Lowering (GOALL) registries: very-high-risk patients (with CVD and diabetes) had a 60% success rate for reaching the LDL-C goal of <100 mg/dL, and 21% reached the lower <70 mg/dL goal.⁹ In these registries, 90% of treatment failures occurred in patients receiving nonstatin therapy or submaximal statin doses, although no differences were found in treatment success by type of statin used.⁹ However, NEPTUNE II showed that success rates differed significantly (P <.001) between patients taking less effective statins (fluvastatin [Lescol], lovastatin [Mevacor], or pravastatin) and those taking more effective statins (atorvastatin or simvastatin; rosuvastatin calcium was not yet available). The difference in success was greatest (13%) in the very-high-risk patients.⁸

Treating the Very-High-Risk Patient

Practice guidelines and results of clinical trials of intensive statin treatment provide a basis for up-to-date strategies to achieve the more stringent LDL-C goal of <70 mg/dL in very-high-risk patients (Table 3). These strategies should be part of a comprehensive risk-management plan that includes smoking cessation, exercise, weight control, and setting blood pressure and glycemic goals.

Given its proven impact on post-ACS mortality, intensive statin therapy should be considered promptly in all hospitalized patients with ACS. The treatment regimen should be based largely on measurement of baseline LDL-C within 24 hours of admission.¹ In cases where baseline LDL-C is already low, standard statin doses capable of producing LDL-C reductions of 30% to 40% may be sufficient.¹ For higher baseline LDL-C levels, a more powerful statin or a higher-dose statin, or the combination of a statin with ezetimibe (Zetia), a bile acid sequestrant, or nicotinic acid may be appropriate. Even patients with ACS who have very-low LDL-C levels at baseline may benefit from early statin therapy. A retrospective study of 155 patients with ACS who had a mean baseline LDL-C of 63 mg/dL showed that those who were taking a statin had a 9.5% risk of death, reinfarction, or stroke at 6 months compared with 29% among those who did not receive a statin (P = .005).²³

In other high-risk patients, a reduction of at least 30% to 40% in LDL-C should be the objective, regardless of baseline LDL-C.¹ If the baseline LDL-C is relatively high (eg, >150 mg/dL), however, a reduction of >50% may be needed to achieve the <100 mg/dL LDL-C goal, which may be difficult or even impossible to accomplish with some of the statins, even at their highest doses.^1,11 In such cases it may be necessary to use or switch to a statin with the capacity for large reductions. The Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin (STELLAR) trial, a comparison of atorvastatin, pravastatin, rosuvastatin, and simvastatin in 2431 patients, showed that rosuvastatin doses as low as 10 to 20 mg/day reduced LDL-C by about 50%, as did atorvastatin 40 to 80 mg/day and simvastatin 80 mg/day.²⁴

Large reductions in LDL-C were also seen in the Measuring Effective Reductions in Cholesterol Using Rosuvastatin Therapy (MERCURY) II trial, in which 1011 very-high-risk patients who switched to rosuvastatin 10 or 20 mg/day after therapy with atorvastatin 10 to 20 mg/day or simvastatin 20 to 40 mg/day for 8 weeks were significantly more successful in reaching their LDL-C goal of <70 mg/dL than those who did not switch (within-arm comparisons, P <.01).²⁵ Rosuvastatin reduced LDL-C by about 50% during the trial; the other regimens produced changes ranging from 30% to 40%.

Combination therapy can also produce LDL-C reductions of >50%.^1,11 For example, the combination of ezetimibe 10 mg/day and rosuvastatin 40 mg/day in the Examination of Potential Lipid Modifying Effects of Rosuvastatin in Combination with Ezetimibe versus Rosuvastatin Alone (EXPLORER) study was reported to lower LDL-C by an average of 70% in patients with very high baseline LDL-C levels.²⁶ In the Vytorin Versus Atorvastatin (VYVA) study, ezetimibe plus simvastatin (Vytorin) was more effective than atorvastatin alone across all dose ranges.²⁷ Overall, LDL-C was reduced by a mean 53.4% in patients using combination therapy and by 45.3% in those taking atorvastatin alone (P <.001). A fibrate or niacin in combination with a statin can be considered for very-high-risk patients with low HDL-C and/or elevated triglycerides. However, if a fibrate is used, fenofibrate (eg, Lofibra, Tricor, Triglide) is a safer choice; unlike gemfibrozil (Lopid), fenofibrate does not significantly inhibit glucuronidation, the process by which most statins are eliminated from the body.²⁸

One recently proposed strategy for achieving intensive LDL-C goals is to set the target lower than the actual treatment goal—that is, to set a target of 50 mg/dL to improve the chances of reaching <70 mg/dL in very-high-risk patients.¹⁰ Selecting the starting dose of a statin with a lower LDL-C goal in mind could reduce the need for frequent uptitrating of a statin dose, a practice that could undermine patient adherence to therapy and that physicians may resist out of perceived risks of increased side effects.¹⁰ The net effect of this approach could be to increase the total number of patients that reach intensive lipid goals.

Conclusion

Evidence from clinical trials of statin therapy has confirmed that the higher a patient's CV risk, the more that patient warrants intensive LDL-C reduction. According to this approach, the goal of <100 mg/dL LDL-C is no longer considered sufficiently robust in very-high-risk patients. Such patients may require LDL-C reductions of >50% if they are to gain the CV protection offered by goal levels of <70 mg/dL. Powerful statins, as well as statin–nonstatin combinations, are available that can achieve this goal, but the evidence shows they are being used tentatively at best in the patients who need them most. The lesson from the continuing research is that this practice should change to one of intensive therapy in all appropriate patients.

Disclosure statement
This article was supported by an unrestricted educational grant from AstraZeneca. The author had full control over the contents of this manuscript. Dr Toth receives grant/research support from AstraZeneca, Novartis, and Merck; is a consultant to AstraZeneca, Merck/Schering-Plough, and Pfizer; and is a member of the Speaker's Bureau of AstraZeneca, GlaxoSmithKline, Kos, Merck/ Schering-Plough, Pfizer, and Takeda.

SELF-ASSESSMENT TEST

1. The update to the NCEP ATP III guidelines defines a patient with CVD plus diabetes as:

1. Very high risk
2. High risk
3. Moderate risk
4. Low risk

2. What is the recommended LCL-C goal in very-high-risk patients?

1. <60 mg/dL
2. <70 mg/dL
3. <80 mg/dL
4. <100 mg/dL

3. Which of the following patients would not qualify as very high risk?

1. A chronic smoker with stable angina
2. An older woman with hypertension, diabetes, and previous myocardial infarction
3. A middle-aged man with the metabolic syndrome
4. A post–coronary artery bypass patient with insulin resistance

4. A recent meta-analysis of 14 randomized statin trials that included more than 90,000 patients showed that for every 39-mg/dL decrease in LDL-C, the 5-year incidence of CV events was reduced by approximately what percentage?

1. 10%
2. 15%
3. 20%
4. 50%

5. All the following regimens are capable of lowering LDL-C by approximately 50%, except:

1. Atorvastatin 40-80 mg/day
2. Rosuvastatin 10-20 mg/day
3. Simvastatin 80 mg/day
4. Pravastatin 40-80 mg/day

(Answers at end of references list)

References

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2. Heart Protection Study 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.
3. Cannon CP, Braunwald E, McCabe CH, et al, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes [published correction appears in N Engl J Med. 2006;354:778]. N Engl J Med. 2004;350:1495-1504.
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8. Davidson MH, Maki KC, Pearson TA, et al. Results of the National Cholesterol Education Program (NCEP) Evaluation Project Utilizing Novel E-Technology (NEPTUNE) II survey and implications for treatment under the recent NCEP writing group recommendations. Am J Cardiol. 2005;96:556-563.
9. Yan AT, Yan RT, Tan M, et al, for the Vascular Protection (VP) and Guidelines Oriented Approach to Lipid Lowering (GOALL) registries investigators. Contemporary management of dyslipidemia in high-risk patients: targets still not met. Am J Med. 2006;119:676-683.
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14. Cannon CP, Steinberg BA, Murphy SA, et al. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol. 2006;48:438-445.
15. Collins R, Armitage J, Parish S, et al, for the Heart Protection Study collaborative group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361:2005-2016.
16. Shepherd J, Barter P, Carmena R, et al, for the Treating to New Targets investigators. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes. Diabetes Care. 2006;29:1220-1226.
17. Cannon CP. The IDEAL cholesterol: lower is better [published correction appears in JAMA. 2005;294:2973]. JAMA. 2005;294:2492-2494.
18. O’Keefe JH, Cordain L, Harris WH, et al. Optimal low-density lipoprotein is 50 to 70 mg/dL: lower is better and physiologically normal. J Am Coll Cardiol. 2004;43:2142-2146.
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25. Ballantyne CM, Bertolami M, Hernandez Garcia HR, et al. Achieving LDL cholesterol, non-HDL cholesterol, and apolipoprotein B target levels in high-risk patients: Measuring Effective Reductions in Cholesterol Using Rosuvastatin Therapy (MERCURY) II. Am Heart J. 2006;151:975.e1-975.e9.
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27. Ballantyne CM, Abate N, Yuan Z, et al. Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study [published correction appears in Am Heart J. 2005;149:882]. Am Heart J. 2005;149:464-473.
28. Toth PP. Combination therapy for the treatment of complex dyslipidemias. Cardiol Spec Ed. 2005;11:7-11.

Answers: 1. A; 2. B; 3. C; 4. C; 5. D.