- Email: [email protected]
Are we aggressive enough in lowering cholesterol?
Are We Aggressive Enough in Lowering Cholesterol? David D. Waters,
MD
To date, 5 major randomized, placebo-controlled statin trials—the Scandinavian Simvastatin Survival Study, West of Scotland Coronary Prevention Study, Cholesterol and Recurrent Events trial, Long-term Intervention with Pravastatin in Ischaemic Disease, and Air Force/ Texas Coronary Atherosclerosis Prevention Study— have convincingly shown that total mortality and major coronary events can be significantly reduced by lowering levels of low-density lipoprotein cholesterol (LDL-C) with statin therapy. These results were achieved in a broad range of patients including those with and with-
out a history of coronary artery disease and with elevated or average LDL-C levels. The results also support the large body of epidemiologic evidence demonstrating that the lower the cholesterol level, the lower the cardiovascular risk. Evidence now substantially supports the urgency of physicians to aggressively target the lowering of LDL-C levels for the primary and secondary prevention of coronary disease. 䊚2001 by Excerpta Medica, Inc. Am J Cardiol 2001;88(suppl):10F–15F
oronary artery disease remains the leading cause of death in the United States. It is also costly: in C 1999, the cost of coronary artery disease, measured in
der,5,8 smoking status,6 – 8,10 diabetes,6 – 8 or hypertension.6 – 8,10
medical treatment and lost wages, was estimated at $100 billion per year.1 Thus, prevention of coronary artery disease is clearly a desirable goal, from both a public-health and an economic standpoint, particularly in the current era of managed-care and health-care cost containment. Yet, physicians have not wholeheartedly embraced the lowering of total cholesterol and, in particular, low-density lipoprotein cholesterol (LDL-C), as a means of decreasing the risk for coronary artery disease. This is despite LDL-C being the primary atherogenic lipoprotein2,3 and the recently published National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) advocating aggressive LDL-C lowering for primary and secondary prevention of coronary artery disease. In fact, a recent report indicates that physicians obtain an LDL-C value in their high-risk coronary artery disease patients only 50% of the time.4 As a result, substantial numbers of patients who may require and benefit from treatment are apparently going undiagnosed and untreated. An increasing body of compelling clinical trial evidence has accumulated during the past 5 years to warrant a reexamination of physician noncompliance. It is now clear from the results of numerous long-term clinical trials that hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins), which can lower LDL-C by 25% to 60%,2 can also dramatically reduce the rate of both nonfatal and fatal coronary events and, in some trials, overall mortality in the primary and secondary settings.5–10 Moreover, these reductions in risk are independent of age,5– 8,10 gen-
THE FIVE MAJOR STATIN TRIALS: ENDPOINT EVIDENCE
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From the Cardiology Division, Department of Medicine, San Francisco General Hospital, San Francisco, California, USA; and Department of Medicine, University of California, San Francisco, California, USA. Address for reprints: David D. Waters, MD, Cardiology Division, Room 5G1, San Francisco General Hospital, 1001 Potrero Avenue, San Francisco, California 94110. E-mail: [email protected].
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©2001 by Excerpta Medica, Inc. All rights reserved.
Since 1994, 5 major randomized, placebo-controlled cholesterol-lowering trials evaluating the effect of statins in almost 31,000 subjects with and without coronary artery disease have been completed. Of these, 3 studies5,7,8 evaluated the effect of cholesterol lowering in patients with coronary artery disease (secondary prevention) and 2 studies6,10 evaluated this effect in patients with no evidence of coronary artery disease (primary prevention). The Scandinavian Simvastatin Survival Study (4S)5 and the West of Scotland Coronary Prevention Study (WOSCOPS)6 enrolled patients with high or moderately elevated cholesterol levels. The Cholesterol and Recurrent Events (CARE) trial7 and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)10 enrolled patients with so-called average cholesterol levels, and the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study8 evaluated patients with a broad range of cholesterol levels. Of these, 3 trials (LIPID, WOSCOPS, CARE) studied the effects of pravastatin at a fixed dose, whereas the other 2 trials evaluated the effects of titrated doses of lovastatin and simvastatin. Nonetheless, these studies have many important common links: (1) all assessed longterm lipid lowering, particularly of LDL-C; (2) all included large study cohorts; and (3) all participants (both statin-treated and placebo-treated subjects) received dietary advice to lower cholesterol levels. Primary-prevention trials: In the WOSCOPS trial,6 aggressive lipid lowering with a statin, particularly LDL-C, in moderately hypercholesterolemic subjects with no evidence of coronary artery disease, reduced the risk for cardiac events and death by approximately 30% and overall death by 22% (Table 1). The AFCAPS/TexCAPS study10 similarly indicated that aggressive lowering of LDL-C can result in a ⬎30% 0002-9149/01/$ – see front matter PII S0002-9149(01)01871-9
TABLE 1 Overview of Randomized, Double-Blind, Placebo-Controlled Statin Trials for Primary Prevention of Coronary Artery Disease (CAD) Trial Characteristic
WOSCOPS
AFCAPS/TexCAPS
Patients randomized (n)
6,595 men
Mean age, yr (range)
55 (45–64)
5,608 men 997 women Men: 58 (45–73) Women: 62 (55–73) No history of CAD
Baseline coronary status
Mean baseline total cholesterol, mg/dL (mmol/L) Mean baseline LDL-C, mg/dL (mmol/L) Mean baseline HDL-C, mg/dL (mmol/L) Mean follow-up (yr) Statin treatment, dose (patients treated)
No history of MI; 5% w/stable angina; 8% w/ ECG ST-T changes 272 (7) 192 (5) 44 (1.1) 4.9 Pravastatin 40 mg daily fixed dose (n ⫽ 3,302)
⫺20 ⫺26 ⫹5
% Change in total cholesterol % Change in LDL-C % Change in HDL-C Risk reduction with treatment vs placebo (%) Nonfatal MI or CAD death
Nonfatal MI CAD mortality
31
31 28/33*
Stroke All cardiovascular mortality (including stroke) Noncardiovascular mortality All-cause mortality Coronary revascularization/ CABG
11 32 11 22 37
221 (5.7) 150 (3.9) Men: 36 (0.9) Women: 40 (1.03) 5.2 Lovastatin 20 mg to 40 mg daily titrated to achieve an LDL-C ⱕ110 mg/dL (2.9 mmol/L) (n ⫽ 2,805 men, n ⫽ 499 women) ⫺18 ⫺25 ⫹6 37 (includes unstable angina and sudden cardiac death) NA Too few events to detect treatment differences NA Too few events to detect treatment differences NA NA 33
AFCAPS/TexCAPS ⫽ Air Force/Texas Coronary Atherosclerosis Study; CABG ⫽ coronary artery bypass grafting; ECG ⫽ electrocardiogram; HDL-C ⫽ high-density lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein cholesterol; MI ⫽ myocardial infarction; NA ⫽ not available; WOSCOPS ⫽ West of Scotland Coronary Prevention Study. *Definite/definite plus suspected cases; not significant for definite cases; significant for definite plus suspected cases.
decrease in risk for first nonfatal or fatal coronary event, with no excess noncardiovascular mortality in persons with average or mildly elevated cholesterol levels. The rates of coronary angiography and revascularization were also significantly reduced. Although the AFCAPS/TexCAPS study was not powered to detect treatment differences in the low-frequency endpoints of cardiovascular mortality, overall mortality rates in both statin-treated and placebo-treated patients were low. An important element of the AFCAPS/ TexCAPS trial was the inclusion of a large number of women, as well as Hispanics, African Americans, and persons ⬎65 years of age. AFCAPS/TexCAPS thus extended our knowledge base to a wider segment of the population. Secondary-prevention trials: Similar benefits of cholesterol lowering were reported in secondary-prevention trials5,7,8 in which the incidence of recurrent myocardial infarction (MI) was decreased approxi-
mately 30% and the risk for coronary death decreased 20% to 40% (Table 2). The 4S study5 observed hypercholesterolemic patients with angina pectoris or a history of MI for 5 years. Intensive lowering of total cholesterol (by 25%) and LDL-C (by 35%) resulted in a 42% decrease in risk for coronary death and a 30% decrease in overall risk for death.5 The CARE trial7 observed patients with a history of MI but with average baseline cholesterol levels (mean total-cholesterol and LDL-C levels, 209 mg/dL [5.43 mmol/L] and 139 mg/dL [3.61 mmol/L], respectively) and was the first study to demonstrate the benefits of lipid lowering in this population. Significant reductions in levels of LDL-C (32%) and total cholesterol (20%) were accompanied by a 24% decrease in risk for cardiac death and a 23% decrease in the risk for nonfatal MI.7 Additional benefits included a decreased rate of coronary artery bypass grafting and angioplasty, and a significantly
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TABLE 2 Overview of Randomized, Double-Blind, Placebo-Controlled Statin Trials for Secondary Prevention of Coronary Artery Disease (CAD) Trial Characteristic Patients randomized Mean age, yr (range) Baseline coronary status Mean baseline total cholesterol, mg/dL (mmol/L) Mean baseline LDL-C, mg/dL (mmol/L) Mean baseline HDL-C, mg/dL (mmol/L) Follow-up (yr) Statin treatment, dose
4S
LIPID
3,614 men 827 women NA (35–70) History of angina or MI
CARE
259 (6.7)
7,498 men 1,516 women Median 62 (31–75) History of MI, unstable angina Median 218 (5.7)
209 (5.4)
187 (4.9)
Median 150 (3.9)
139 (3.6)
45 (1.2)
Median 36 (0.9)
39 (1.0)
5.4 (median) Simvastatin 20 mg daily titrated to attain total cholesterol of 115–200 mg/dL (3.0–5.2 mmol/L) Change in total cholesterol (%) ⫺25 Change in LDL-C (%) ⫺35 Change in HDL-C (%) ⫹8 Risk reduction with treatment vs placebo (%) Any major coronary event 34* Nonfatal MI 37 Fatal MI NA All CAD mortality 42 Fatal/nonfatal stroke 30 All cardiovascular mortality 35 (including stroke) Noncardiovascular mortality No difference All-cause mortality 30 Coronary angioplasty/CABG 37 (both)
6.1 (mean) Pravastatin 40 mg daily (fixed dose)
3,583 men 576 women 59 (21–75) History of MI
⫺18 ⫺25 ⫹5
5 (median) Pravastatin 40 mg daily (fixed dose) ⫹ cholestyramine 8–16 g, if needed to lower LDL-C ⬍175 mg/dL (4.5 mmol/L) ⫺20 ⫺28 ⫹5
NA 29 (any MI) NA 24 19 25
NA 23 37 20 31 NA
NA 22 19/22
NA NA 23/26
CARE ⫽ Cholesterol and Recurrent Events trial; CABG ⫽ coronary artery bypass grafting; 4S ⫽ Scandinavian Simvastatin Survival Study; HDL-C ⫽ high-density lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein cholesterol; LIPID ⫽ Long-term Intervention with Pravastatin in Ischaemic Disease trial; MI ⫽ myocardial infarction; NA ⫽ not available. *Defined as CAD death, nonfatal MI, resuscitated coronary arrest, silent MI.
lower incidence of stroke, with no excess risk for noncardiac mortality.7 The reduction in stroke risk observed in CARE was confirmed in a meta-analysis of 13 statin trials including ⬎20,000 patients, in which a decrease in risk for stroke of approximately 30% was observed.11 The LIPID study8 also observed patients with a history of MI or unstable angina, but included patients with a broad range of average-to-elevated total-cholesterol and LDL-C levels. Reductions in both totalcholesterol (18%) and LDL-C (25%) levels were associated with a significantly reduced risk for MI, death from coronary artery disease, or nonfatal MI combined, and overall mortality. Coronary revascularization rates were also reduced significantly.8 In a post hoc substudy of 522 men and women, treatment with the statin not only reduced the development of carotid atherosclerosis—a risk factor for coronary artery disease and cerebrovascular disease— but also prevented an increase in carotid-wall thickening over a treatment period of 4 years.9 These findings are consistent with those of other studies showing a regression of both carotid and coronary atherosclerosis with lowering of total cholesterol and LDL-C.12,13 12F THE AMERICAN JOURNAL OF CARDIOLOGY姞
These trials clearly confirm that the primary goal of cholesterol-lowering therapy is to lower LDL-C and the efficacy of statins in achieving this goal. A question that remains to be answered, however, is how aggressive physicians should be in treating elevated cholesterol levels.
LOW-DENSITY LIPOPROTEIN CHOLESTEROL GOAL LEVELS: ARE WE BEING AGGRESSIVE ENOUGH? The new NCEP ATP III guidelines identify LDL-C ⬍100 mg/dL as optimal.2 Drug therapy should be considered in any adult with an LDL-C level ⱖ190 mg/dL (ⱖ4.91 mmol/L) with 0 or 1 coronary artery disease risk factor, and in some cases for those with an LDL-C of 160 to 189 mg/dL. For patients with 2 or more risk factors, initiation of drug therapy should be based on LDL-C level and projections of 10-year absolute coronary artery disease risk (Table 3) using the Framingham assessment described in NCEP ATP III. For primary prevention, the minimal goal of cholesterol-lowering drug therapy is the same as for di-
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TABLE 3 Treatment Decisions Based on Low-Density Lipoprotein Cholesterol (LDL-C) According to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) Guidelines LDL-C Level at Which to Initiate Lifestyle Change, mg/dL (mmol/L)
Risk Category
LDL-C Goal, mg/dL (mmol/L)
CAD or CAD risk equivalents* (10-yr risk ⬎20%)
⬍100 (⬍2.6)
ⱖ100 (ⱖ2.6)
2⫹ risk factors (10-yr risk ⱕ20%)
⬍130 (⬍3.36)
ⱖ130 (ⱖ3.36)
0–1 risk factor
⬍160 (⬍4.14)
ⱖ160 (ⱖ4.14)
LDL-C Level at Which to Initiate Drug Therapy, mg/dL (mmol/L) ⱖ130 (ⱖ3.36) 100–129 (2.6–3.33) optional 10-yr risk 10%–20%: ⱖ130 (ⱖ3.36) 10-yr risk ⬍10%: ⱖ160 (ⱖ4.14) ⱖ190 (ⱖ4.91) 160–189 (4.14–4.88) optional
CAD ⫽ Coronary artery disease. *CAD equivalents include diabetes, other forms of atherosclerotic disease, and multiple risk factors conferring 10-year risk ⬎20% based on the risk scoring system. Adapted from JAMA.2
etary therapy—to lower LDL-C to ⬍160 mg/dL (⬍4.14 mmol/L) for those with 0 or 1 risk factor and to ⬍130 mg/dL (⬍3.36 mmol/L) if 2 or more risk factors are present. For secondary prevention, the goal is to achieve an LDL-C level of ⬍100 mg/dL (ⱕ2.6 mmol/L). Pharmacologic lipid-lowering therapy is indicated in patients with established coronary artery disease or coronary artery disease equivalents (diabetes, other atherosclerotic disease, or multiple risk factors conferring 10-year coronary artery disease risk ⬎20%) if LDL-C levels are ⱖ130 mg/dL (3.36 mmol/ L). In this group of patients, drug therapy may be started simultaneously with dietary therapy.2 Although none of the major statin trials specifically assessed the effect of lowering LDL-C to levels ⬍100 mg/dL, many of them included patients with low baseline levels or whose LDL-C had been lowered to ⬍100 mg/dL. The AFCAPS/TexCAPS primary-prevention trial analyzed risk reduction of the primary endpoint (fatal or nonfatal MI, unstable angina, or sudden cardiac death) according to LDL-C tertiles and found a consistent risk reduction benefit across all baseline LDL-C levels (range, 90 to 235 mg/dL [2.34 to 6.08 mmol/L]), with no reduction threshold.10 In contrast, a post hoc analysis of the primary-prevention WOSCOPS trial14 found no benefit at LDL-C levels ⬍146 mg/dL (⬍3.77 mmol/L). On the other hand, most patients who develop coronary disease in the United States have LDL-C levels between 100 and 150 mg/dL (2.6 and 3.9 mmol/L).15 Therefore, experts stress that an LDL-C level ⬍100 mg/dL is the optimal goal.2,16 Optimal benefit may ultimately be achieved by trying to surpass current NCEP target levels for LDL-C. Among secondary-prevention trials, the CARE study of patients with coronary artery disease with average cholesterol levels reported that the reduction in coronary mortality risk decreased as the baseline LDL-C decreased.7 Although a 26% reduction in major coronary events was noted at baseline LDL-C levels of 125 to 150 mg/dL (3.25 to 3.9 mmol/L), no reduction in risk was observed in patients with an LDL-C level ⬍125 mg/dL.7 In contrast to NCEP ATP III guidelines, the CARE investigators suggested that an LDL-C level of 125 mg/dL (3.25 mmol/L) may be
an approximate lower boundary for a clinically important influence of LDL-C level in secondary prevention of coronary artery disease. Furthermore, in a post hoc analysis of the CARE study,7 no benefit was noted when LDL-C levels were lowered to ⬍146 mg/dL (⬍3.80 mmol/L). Post hoc analyses such as this, however, are much weaker evidence than are main findings from prospectively designed trials. In contrast to the finding from CARE, a subgroup analysis8 of LIPID trial data in ⬎2,600 patients with a history of MI or unstable angina found an equivalent reduction in coronary artery disease death and nonfatal MI at baseline LDL-C levels ⬍135 mg/dL (⬍3.51 mmol/L, approximately 24% of the study cohort) as at higher initial levels. In addition, the 4S study5 noted significant risk reduction from lowering LDL-C to ⬍100 mg/dL (⬍2.6 mmol/L). Coronary angiographic studies have also consistently documented that cholesterol lowering retards the progression of coronary atherosclerosis.17 Further support for aggressive lowering of LDL-C levels to ⬍100 mg/dL comes from the Post-Coronary Artery Bypass Graft study,18 in which aggressive lowering of LDL-C to approximately 93 mg/dL (2.42 mmol/L) resulted in improved graft patency compared with moderate lowering to approximately 132 mg/dL. Progression of coronary disease during an angiographic trial is a strong, independent predictor of future coronary events.19 It should, therefore, be no surprise that during a longer period of follow-up of patients in the Post-Coronary Artery Bypass Graft study, those whose LDL-C had been aggressively lowered had a much lower event rate than those treated more moderately.20 The difference was 19.2% versus 27.3% for coronary revascularization procedures (p ⫽ 0.0006) and 15.1% versus 20.3% for cardiovascular death or MI (p ⫽ 0.03). The cardiovascular benefit of aggressive lipid lowering with statins has also been reported in a smaller endpoint study of patients with stable coronary artery disease. In the 18-month Atorvastatin Versus Revascularization Treatment (AVERT) study,21 the effects on LDL-C of atorvastatin, 80 mg daily, were compared with angioplasty and usual care in 341 patients with asymptomatic or mild-to-moderate angina pecto-
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ris and relatively normal left-ventricular function. In this study, LDL-C was significantly lowered by 46% (from approximately 140 mg/dL [3.64 mmol/L] to 77 mg/dL [2.0 mmol/L]), compared with an 18% reduction in LDL-C achieved with angioplasty and usual care. Atorvastatin-treated patients had a 36% lower incidence of ischemic events (13%) than angioplastytreated patients (21%). Although this difference just missed statistical significance, the time to first ischemic event was significantly longer in the statin-treated group. However, the AVERT study did not answer the question of whether patients with low baseline LDL-C levels would benefit similarly, or whether atorvastatin would provide additional coronary benefits over “standard” lipid-lowering therapy. A large, long-term, double-blind study of the effects of extremely aggressive LDL-C lowering (the Treating to New Targets [TNT] study22) is currently under way. High-risk patients (prior MI, angina pectoris, or coronary revascularization) are receiving treatment with atorvastatin 10 mg or 80 mg, with the goal of reducing LDL-C levels to 100 mg/dL in 1 group and 75 mg/dL in the other. This trial has enrolled ⬎10,000 men and women, and the results, which are expected in 5 years, should provide additional vital information about the value of lowering LDL-C to levels below the current NCEP ATP III guidelines. The effects of aggressive reduction of LDL-C levels by statin therapy on the prevention of stroke are also currently being investigated.23 A large-scale, short-term (16-week) trial of aggressive lipid lowering with 80 mg daily of atorvastatin within 1 to 4 days of hospitalization for unstable angina or non–Q-wave MI was recently completed.24,25 The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study is the first to investigate the clinical benefits of intensive lipid lowering with a statin in patients with unstable angina or acute MI, and whether such aggressive lipid lowering will reduce early, recurrent ischemic events. The study included ⬎3,000 patients with a broad range of baseline total cholesterol (ⱕ270 mg/dL [ⱕ6.98 mmol/L]) and LDL-C levels.24 Patients treated with atorvastatin had their mean LDL-C levels reduced from 123 mg/dL to 72 mg/dL (a 42% decrease).25 A primary endpoint event (death, nonfatal acute MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency rehospitalization) occurred in 228 patients in the atorvastatin group (14.8%) and in 269 patients in the placebo group (17.4%); this represents a 16% reduction in relative risk (p ⫽ 0.048). The reduction in risk was due primarily to an effect of atorvastatin on recurrent symptomatic ischemia requiring emergency rehospitalization.25 Another trial of 4,500 patients with acute coronary syndromes is in development and will test the effects of early versus delayed simvastatin therapy.26 If this trial, in addition to the MIRACL results, shows that cholesterol lowering has immediate effects on reducing recurrent cardiac events, much earlier institution 14F THE AMERICAN JOURNAL OF CARDIOLOGY姞
of lipid-lowering drug therapy in patients with coronary artery disease may be warranted. What do the completed statin studies mean for clinicians today? The accumulated evidence to date suggests that we can and should aggressively lower LDL-C in all patients safely and effectively with statins to levels at or below those currently recommended for patients with coronary artery disease (⬍100 mg/dL [⬍2.6 mmol/L]) and expect cardiac benefits for these patients, while we await the results of additional trials.
CONCLUSION The clinical evidence clearly indicates that the time has come for physicians to more aggressively target LDL-C levels for reduction with drug therapy in addition to dietary modification, according to current guidelines.2 An important additional benefit of such therapy, as shown in the statin trials, is the concomitant reduction of cerebrovascular disease as well.7,8,27 Furthermore, the evidence also suggests that titration of statin therapy to reach, and even exceed current target LDL-C levels (⬍160 mg/dL to ⱕ100 mg/dL [⬍4.16 to ⱕ2.6 mmol/L] depending on the presence of risk factors and coronary artery disease) may afford superior protection from cardiovascular events than fixed-dose therapy. Finally, results of the major clinical trials also confirm the long-term safety of the statins in reducing LDL-C without excessive risk of adverse effects.
1. American Heart Association. 1999 Heart and Stroke Statistical Update. Dallas:
American Heart Association, 1999. 2. Executive Summary of the Third Report of the National Cholesterol Education
Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486 –2497. 3. Wood D, De Backer G, Faergeman O, Graham I, Mancia G, Pyora¨la¨ K. Prevention of coronary heart disease in clinical practice: recommendations of the Second Joint Task Force of European and other societies on coronary prevention. Eur Heart J 1998;19:1453–1503. 4. Frolkis JP, Zyzanski SJ, Schwarz JM, Suhan PS. Physician noncompliance with the 1993 National Cholesterol Education Program (NCEP-ATPII) guidelines. Circulation 1998;98:851– 855. 5. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389. 6. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301–1307. 7. Sacks FM, Pfeffer MA, Moye´ LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C-C, Davis BR, Braunwald E, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–1009. 8. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349 –1357. 9. MacMahon S, Sharpe N, Gamble G, Hart H, Scott J, Simes J, White H, on behalf of the LIPID Trial Research Group. Effects of lowering average or below-average cholesterol levels on the progression of carotid atherosclerosis: results of the LIPID Atherosclerosis Substudy. Circulation 1998;97:1784 –1790. 10. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:1615–1622. 11. Blauw GJ, Lagaay M, Smelt AHM, Westendorp RGJ. Stroke, statins, and cholesterol: a meta-analysis of randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors. Stroke 1997;28:946 –950. 12. Furberg CD, Adams HP Jr, Applegate WB, Byington RP, Espeland MA, Hartwell T, Hunninghake DB, Lefkowitz DS, Probstfield J, Riley MA, for the
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Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation 1994;90:1679 –1687. 13. Rossouw JE. Lipid-lowering interventions in angiographic trials. Am J Cardiol 1995;76(suppl):86C–92C. 14. West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998;97:1440 –1445. 15. Rubins HB, Robins SJ, Collins D, Iranmanesh A, Wilt TJ, Mann D, MayoSmith M, Faas FH, Elam MB, Rutan GH. Distribution of lipids in 8,500 men with coronary artery disease. Am J Cardiol 1995;75:1196 –1201. 16. Grundy SM. Small LDL, atherogenic dyslipidemia, and the metabolic syndrome. Circulation 1997;95:1– 4. 17. Waters D. Plaque stabilization: a mechanism for the beneficial effect of lipid-lowering therapies in angiographic studies. Prog Cardiovasc Dis 1994;37: 107–120. 18. The Post-Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997;336:153–162. 19. Waters D, Craven T, Lespe´rance J. Prognostic significance of progression of coronary atherosclerosis. Circulation 1993;87:1067–1075. 20. Knatterud GL, Rosenberg Y, Campeau L, Geller NL, Hunninghake DB, Forman SA, Forrester JS, Gobel FL, Herd JA, Hickey A, et al. Long-term effects on clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the Post Coronary Artery Bypass Graft trial. Circulation 2000;102:157–165. 21. Pitt B, Waters D, Brown WV, van Boven AJ, Schwartz L, Title LM,
Eisenberg D, Shurzinske L, McCormick LS, for the Atorvastatin Versus Revascularization Treatment Investigators. Aggressive lipid lowering compared with angioplasty in stable coronary artery disease. N Engl J Med 1999;341:70 –76. 22. LaRosa JC. Effect of lowering LDL-C beyond currently recommended minimum targets: the Treating to New Targets (TNT) study. In: Program and Abstracts of the XIII International Symposium on Drugs Affecting Lipid Metabolism. Florence, Italy, May 30 –June 3, 1998. 23. Welch KMA, for the SPARCL Steering Committee. Effect of atorvastatin compared with placebo on cerebrovascular endpoints in patients with a previous stroke or TIA: the SPARCL study. Abstract presented at the European Stroke Conference, May 27–30, 1998. 24. Schwartz GG, Oliver MF, Ezekowitz MD, Ganz P, Waters D, Kane JP, Texter M, Pressler ML, Black D, Chaitman BR, Olsson AG. Rationale and design of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study that evaluates atorvastatin in unstable angina pectoris and in nonQ-wave acute myocardial infarction. Am J Cardiol 1998;81:578 –581. 25. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T, for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in patients with acute coronary syndromes: the MIRACL Study—a randomized controlled trial. JAMA 2001;285:1711–1718. 26. Waters D. Cholesterol lowering: should it continue to be the last thing we do? Circulation 1999;99:3215–3217. 27. Pedersen TR, Kjekshus J, Pyo¨ra¨la¨ K, Olsson AG, Cook TJ, Musliner TA, Tobert JA, Haghfelt T. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol 1998;81:333–335.
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MD
To date, 5 major randomized, placebo-controlled statin trials—the Scandinavian Simvastatin Survival Study, West of Scotland Coronary Prevention Study, Cholesterol and Recurrent Events trial, Long-term Intervention with Pravastatin in Ischaemic Disease, and Air Force/ Texas Coronary Atherosclerosis Prevention Study— have convincingly shown that total mortality and major coronary events can be significantly reduced by lowering levels of low-density lipoprotein cholesterol (LDL-C) with statin therapy. These results were achieved in a broad range of patients including those with and with-
out a history of coronary artery disease and with elevated or average LDL-C levels. The results also support the large body of epidemiologic evidence demonstrating that the lower the cholesterol level, the lower the cardiovascular risk. Evidence now substantially supports the urgency of physicians to aggressively target the lowering of LDL-C levels for the primary and secondary prevention of coronary disease. 䊚2001 by Excerpta Medica, Inc. Am J Cardiol 2001;88(suppl):10F–15F
oronary artery disease remains the leading cause of death in the United States. It is also costly: in C 1999, the cost of coronary artery disease, measured in
der,5,8 smoking status,6 – 8,10 diabetes,6 – 8 or hypertension.6 – 8,10
medical treatment and lost wages, was estimated at $100 billion per year.1 Thus, prevention of coronary artery disease is clearly a desirable goal, from both a public-health and an economic standpoint, particularly in the current era of managed-care and health-care cost containment. Yet, physicians have not wholeheartedly embraced the lowering of total cholesterol and, in particular, low-density lipoprotein cholesterol (LDL-C), as a means of decreasing the risk for coronary artery disease. This is despite LDL-C being the primary atherogenic lipoprotein2,3 and the recently published National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) advocating aggressive LDL-C lowering for primary and secondary prevention of coronary artery disease. In fact, a recent report indicates that physicians obtain an LDL-C value in their high-risk coronary artery disease patients only 50% of the time.4 As a result, substantial numbers of patients who may require and benefit from treatment are apparently going undiagnosed and untreated. An increasing body of compelling clinical trial evidence has accumulated during the past 5 years to warrant a reexamination of physician noncompliance. It is now clear from the results of numerous long-term clinical trials that hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins), which can lower LDL-C by 25% to 60%,2 can also dramatically reduce the rate of both nonfatal and fatal coronary events and, in some trials, overall mortality in the primary and secondary settings.5–10 Moreover, these reductions in risk are independent of age,5– 8,10 gen-
THE FIVE MAJOR STATIN TRIALS: ENDPOINT EVIDENCE
1
From the Cardiology Division, Department of Medicine, San Francisco General Hospital, San Francisco, California, USA; and Department of Medicine, University of California, San Francisco, California, USA. Address for reprints: David D. Waters, MD, Cardiology Division, Room 5G1, San Francisco General Hospital, 1001 Potrero Avenue, San Francisco, California 94110. E-mail: [email protected].
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©2001 by Excerpta Medica, Inc. All rights reserved.
Since 1994, 5 major randomized, placebo-controlled cholesterol-lowering trials evaluating the effect of statins in almost 31,000 subjects with and without coronary artery disease have been completed. Of these, 3 studies5,7,8 evaluated the effect of cholesterol lowering in patients with coronary artery disease (secondary prevention) and 2 studies6,10 evaluated this effect in patients with no evidence of coronary artery disease (primary prevention). The Scandinavian Simvastatin Survival Study (4S)5 and the West of Scotland Coronary Prevention Study (WOSCOPS)6 enrolled patients with high or moderately elevated cholesterol levels. The Cholesterol and Recurrent Events (CARE) trial7 and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)10 enrolled patients with so-called average cholesterol levels, and the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study8 evaluated patients with a broad range of cholesterol levels. Of these, 3 trials (LIPID, WOSCOPS, CARE) studied the effects of pravastatin at a fixed dose, whereas the other 2 trials evaluated the effects of titrated doses of lovastatin and simvastatin. Nonetheless, these studies have many important common links: (1) all assessed longterm lipid lowering, particularly of LDL-C; (2) all included large study cohorts; and (3) all participants (both statin-treated and placebo-treated subjects) received dietary advice to lower cholesterol levels. Primary-prevention trials: In the WOSCOPS trial,6 aggressive lipid lowering with a statin, particularly LDL-C, in moderately hypercholesterolemic subjects with no evidence of coronary artery disease, reduced the risk for cardiac events and death by approximately 30% and overall death by 22% (Table 1). The AFCAPS/TexCAPS study10 similarly indicated that aggressive lowering of LDL-C can result in a ⬎30% 0002-9149/01/$ – see front matter PII S0002-9149(01)01871-9
TABLE 1 Overview of Randomized, Double-Blind, Placebo-Controlled Statin Trials for Primary Prevention of Coronary Artery Disease (CAD) Trial Characteristic
WOSCOPS
AFCAPS/TexCAPS
Patients randomized (n)
6,595 men
Mean age, yr (range)
55 (45–64)
5,608 men 997 women Men: 58 (45–73) Women: 62 (55–73) No history of CAD
Baseline coronary status
Mean baseline total cholesterol, mg/dL (mmol/L) Mean baseline LDL-C, mg/dL (mmol/L) Mean baseline HDL-C, mg/dL (mmol/L) Mean follow-up (yr) Statin treatment, dose (patients treated)
No history of MI; 5% w/stable angina; 8% w/ ECG ST-T changes 272 (7) 192 (5) 44 (1.1) 4.9 Pravastatin 40 mg daily fixed dose (n ⫽ 3,302)
⫺20 ⫺26 ⫹5
% Change in total cholesterol % Change in LDL-C % Change in HDL-C Risk reduction with treatment vs placebo (%) Nonfatal MI or CAD death
Nonfatal MI CAD mortality
31
31 28/33*
Stroke All cardiovascular mortality (including stroke) Noncardiovascular mortality All-cause mortality Coronary revascularization/ CABG
11 32 11 22 37
221 (5.7) 150 (3.9) Men: 36 (0.9) Women: 40 (1.03) 5.2 Lovastatin 20 mg to 40 mg daily titrated to achieve an LDL-C ⱕ110 mg/dL (2.9 mmol/L) (n ⫽ 2,805 men, n ⫽ 499 women) ⫺18 ⫺25 ⫹6 37 (includes unstable angina and sudden cardiac death) NA Too few events to detect treatment differences NA Too few events to detect treatment differences NA NA 33
AFCAPS/TexCAPS ⫽ Air Force/Texas Coronary Atherosclerosis Study; CABG ⫽ coronary artery bypass grafting; ECG ⫽ electrocardiogram; HDL-C ⫽ high-density lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein cholesterol; MI ⫽ myocardial infarction; NA ⫽ not available; WOSCOPS ⫽ West of Scotland Coronary Prevention Study. *Definite/definite plus suspected cases; not significant for definite cases; significant for definite plus suspected cases.
decrease in risk for first nonfatal or fatal coronary event, with no excess noncardiovascular mortality in persons with average or mildly elevated cholesterol levels. The rates of coronary angiography and revascularization were also significantly reduced. Although the AFCAPS/TexCAPS study was not powered to detect treatment differences in the low-frequency endpoints of cardiovascular mortality, overall mortality rates in both statin-treated and placebo-treated patients were low. An important element of the AFCAPS/ TexCAPS trial was the inclusion of a large number of women, as well as Hispanics, African Americans, and persons ⬎65 years of age. AFCAPS/TexCAPS thus extended our knowledge base to a wider segment of the population. Secondary-prevention trials: Similar benefits of cholesterol lowering were reported in secondary-prevention trials5,7,8 in which the incidence of recurrent myocardial infarction (MI) was decreased approxi-
mately 30% and the risk for coronary death decreased 20% to 40% (Table 2). The 4S study5 observed hypercholesterolemic patients with angina pectoris or a history of MI for 5 years. Intensive lowering of total cholesterol (by 25%) and LDL-C (by 35%) resulted in a 42% decrease in risk for coronary death and a 30% decrease in overall risk for death.5 The CARE trial7 observed patients with a history of MI but with average baseline cholesterol levels (mean total-cholesterol and LDL-C levels, 209 mg/dL [5.43 mmol/L] and 139 mg/dL [3.61 mmol/L], respectively) and was the first study to demonstrate the benefits of lipid lowering in this population. Significant reductions in levels of LDL-C (32%) and total cholesterol (20%) were accompanied by a 24% decrease in risk for cardiac death and a 23% decrease in the risk for nonfatal MI.7 Additional benefits included a decreased rate of coronary artery bypass grafting and angioplasty, and a significantly
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TABLE 2 Overview of Randomized, Double-Blind, Placebo-Controlled Statin Trials for Secondary Prevention of Coronary Artery Disease (CAD) Trial Characteristic Patients randomized Mean age, yr (range) Baseline coronary status Mean baseline total cholesterol, mg/dL (mmol/L) Mean baseline LDL-C, mg/dL (mmol/L) Mean baseline HDL-C, mg/dL (mmol/L) Follow-up (yr) Statin treatment, dose
4S
LIPID
3,614 men 827 women NA (35–70) History of angina or MI
CARE
259 (6.7)
7,498 men 1,516 women Median 62 (31–75) History of MI, unstable angina Median 218 (5.7)
209 (5.4)
187 (4.9)
Median 150 (3.9)
139 (3.6)
45 (1.2)
Median 36 (0.9)
39 (1.0)
5.4 (median) Simvastatin 20 mg daily titrated to attain total cholesterol of 115–200 mg/dL (3.0–5.2 mmol/L) Change in total cholesterol (%) ⫺25 Change in LDL-C (%) ⫺35 Change in HDL-C (%) ⫹8 Risk reduction with treatment vs placebo (%) Any major coronary event 34* Nonfatal MI 37 Fatal MI NA All CAD mortality 42 Fatal/nonfatal stroke 30 All cardiovascular mortality 35 (including stroke) Noncardiovascular mortality No difference All-cause mortality 30 Coronary angioplasty/CABG 37 (both)
6.1 (mean) Pravastatin 40 mg daily (fixed dose)
3,583 men 576 women 59 (21–75) History of MI
⫺18 ⫺25 ⫹5
5 (median) Pravastatin 40 mg daily (fixed dose) ⫹ cholestyramine 8–16 g, if needed to lower LDL-C ⬍175 mg/dL (4.5 mmol/L) ⫺20 ⫺28 ⫹5
NA 29 (any MI) NA 24 19 25
NA 23 37 20 31 NA
NA 22 19/22
NA NA 23/26
CARE ⫽ Cholesterol and Recurrent Events trial; CABG ⫽ coronary artery bypass grafting; 4S ⫽ Scandinavian Simvastatin Survival Study; HDL-C ⫽ high-density lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein cholesterol; LIPID ⫽ Long-term Intervention with Pravastatin in Ischaemic Disease trial; MI ⫽ myocardial infarction; NA ⫽ not available. *Defined as CAD death, nonfatal MI, resuscitated coronary arrest, silent MI.
lower incidence of stroke, with no excess risk for noncardiac mortality.7 The reduction in stroke risk observed in CARE was confirmed in a meta-analysis of 13 statin trials including ⬎20,000 patients, in which a decrease in risk for stroke of approximately 30% was observed.11 The LIPID study8 also observed patients with a history of MI or unstable angina, but included patients with a broad range of average-to-elevated total-cholesterol and LDL-C levels. Reductions in both totalcholesterol (18%) and LDL-C (25%) levels were associated with a significantly reduced risk for MI, death from coronary artery disease, or nonfatal MI combined, and overall mortality. Coronary revascularization rates were also reduced significantly.8 In a post hoc substudy of 522 men and women, treatment with the statin not only reduced the development of carotid atherosclerosis—a risk factor for coronary artery disease and cerebrovascular disease— but also prevented an increase in carotid-wall thickening over a treatment period of 4 years.9 These findings are consistent with those of other studies showing a regression of both carotid and coronary atherosclerosis with lowering of total cholesterol and LDL-C.12,13 12F THE AMERICAN JOURNAL OF CARDIOLOGY姞
These trials clearly confirm that the primary goal of cholesterol-lowering therapy is to lower LDL-C and the efficacy of statins in achieving this goal. A question that remains to be answered, however, is how aggressive physicians should be in treating elevated cholesterol levels.
LOW-DENSITY LIPOPROTEIN CHOLESTEROL GOAL LEVELS: ARE WE BEING AGGRESSIVE ENOUGH? The new NCEP ATP III guidelines identify LDL-C ⬍100 mg/dL as optimal.2 Drug therapy should be considered in any adult with an LDL-C level ⱖ190 mg/dL (ⱖ4.91 mmol/L) with 0 or 1 coronary artery disease risk factor, and in some cases for those with an LDL-C of 160 to 189 mg/dL. For patients with 2 or more risk factors, initiation of drug therapy should be based on LDL-C level and projections of 10-year absolute coronary artery disease risk (Table 3) using the Framingham assessment described in NCEP ATP III. For primary prevention, the minimal goal of cholesterol-lowering drug therapy is the same as for di-
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TABLE 3 Treatment Decisions Based on Low-Density Lipoprotein Cholesterol (LDL-C) According to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) Guidelines LDL-C Level at Which to Initiate Lifestyle Change, mg/dL (mmol/L)
Risk Category
LDL-C Goal, mg/dL (mmol/L)
CAD or CAD risk equivalents* (10-yr risk ⬎20%)
⬍100 (⬍2.6)
ⱖ100 (ⱖ2.6)
2⫹ risk factors (10-yr risk ⱕ20%)
⬍130 (⬍3.36)
ⱖ130 (ⱖ3.36)
0–1 risk factor
⬍160 (⬍4.14)
ⱖ160 (ⱖ4.14)
LDL-C Level at Which to Initiate Drug Therapy, mg/dL (mmol/L) ⱖ130 (ⱖ3.36) 100–129 (2.6–3.33) optional 10-yr risk 10%–20%: ⱖ130 (ⱖ3.36) 10-yr risk ⬍10%: ⱖ160 (ⱖ4.14) ⱖ190 (ⱖ4.91) 160–189 (4.14–4.88) optional
CAD ⫽ Coronary artery disease. *CAD equivalents include diabetes, other forms of atherosclerotic disease, and multiple risk factors conferring 10-year risk ⬎20% based on the risk scoring system. Adapted from JAMA.2
etary therapy—to lower LDL-C to ⬍160 mg/dL (⬍4.14 mmol/L) for those with 0 or 1 risk factor and to ⬍130 mg/dL (⬍3.36 mmol/L) if 2 or more risk factors are present. For secondary prevention, the goal is to achieve an LDL-C level of ⬍100 mg/dL (ⱕ2.6 mmol/L). Pharmacologic lipid-lowering therapy is indicated in patients with established coronary artery disease or coronary artery disease equivalents (diabetes, other atherosclerotic disease, or multiple risk factors conferring 10-year coronary artery disease risk ⬎20%) if LDL-C levels are ⱖ130 mg/dL (3.36 mmol/ L). In this group of patients, drug therapy may be started simultaneously with dietary therapy.2 Although none of the major statin trials specifically assessed the effect of lowering LDL-C to levels ⬍100 mg/dL, many of them included patients with low baseline levels or whose LDL-C had been lowered to ⬍100 mg/dL. The AFCAPS/TexCAPS primary-prevention trial analyzed risk reduction of the primary endpoint (fatal or nonfatal MI, unstable angina, or sudden cardiac death) according to LDL-C tertiles and found a consistent risk reduction benefit across all baseline LDL-C levels (range, 90 to 235 mg/dL [2.34 to 6.08 mmol/L]), with no reduction threshold.10 In contrast, a post hoc analysis of the primary-prevention WOSCOPS trial14 found no benefit at LDL-C levels ⬍146 mg/dL (⬍3.77 mmol/L). On the other hand, most patients who develop coronary disease in the United States have LDL-C levels between 100 and 150 mg/dL (2.6 and 3.9 mmol/L).15 Therefore, experts stress that an LDL-C level ⬍100 mg/dL is the optimal goal.2,16 Optimal benefit may ultimately be achieved by trying to surpass current NCEP target levels for LDL-C. Among secondary-prevention trials, the CARE study of patients with coronary artery disease with average cholesterol levels reported that the reduction in coronary mortality risk decreased as the baseline LDL-C decreased.7 Although a 26% reduction in major coronary events was noted at baseline LDL-C levels of 125 to 150 mg/dL (3.25 to 3.9 mmol/L), no reduction in risk was observed in patients with an LDL-C level ⬍125 mg/dL.7 In contrast to NCEP ATP III guidelines, the CARE investigators suggested that an LDL-C level of 125 mg/dL (3.25 mmol/L) may be
an approximate lower boundary for a clinically important influence of LDL-C level in secondary prevention of coronary artery disease. Furthermore, in a post hoc analysis of the CARE study,7 no benefit was noted when LDL-C levels were lowered to ⬍146 mg/dL (⬍3.80 mmol/L). Post hoc analyses such as this, however, are much weaker evidence than are main findings from prospectively designed trials. In contrast to the finding from CARE, a subgroup analysis8 of LIPID trial data in ⬎2,600 patients with a history of MI or unstable angina found an equivalent reduction in coronary artery disease death and nonfatal MI at baseline LDL-C levels ⬍135 mg/dL (⬍3.51 mmol/L, approximately 24% of the study cohort) as at higher initial levels. In addition, the 4S study5 noted significant risk reduction from lowering LDL-C to ⬍100 mg/dL (⬍2.6 mmol/L). Coronary angiographic studies have also consistently documented that cholesterol lowering retards the progression of coronary atherosclerosis.17 Further support for aggressive lowering of LDL-C levels to ⬍100 mg/dL comes from the Post-Coronary Artery Bypass Graft study,18 in which aggressive lowering of LDL-C to approximately 93 mg/dL (2.42 mmol/L) resulted in improved graft patency compared with moderate lowering to approximately 132 mg/dL. Progression of coronary disease during an angiographic trial is a strong, independent predictor of future coronary events.19 It should, therefore, be no surprise that during a longer period of follow-up of patients in the Post-Coronary Artery Bypass Graft study, those whose LDL-C had been aggressively lowered had a much lower event rate than those treated more moderately.20 The difference was 19.2% versus 27.3% for coronary revascularization procedures (p ⫽ 0.0006) and 15.1% versus 20.3% for cardiovascular death or MI (p ⫽ 0.03). The cardiovascular benefit of aggressive lipid lowering with statins has also been reported in a smaller endpoint study of patients with stable coronary artery disease. In the 18-month Atorvastatin Versus Revascularization Treatment (AVERT) study,21 the effects on LDL-C of atorvastatin, 80 mg daily, were compared with angioplasty and usual care in 341 patients with asymptomatic or mild-to-moderate angina pecto-
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ris and relatively normal left-ventricular function. In this study, LDL-C was significantly lowered by 46% (from approximately 140 mg/dL [3.64 mmol/L] to 77 mg/dL [2.0 mmol/L]), compared with an 18% reduction in LDL-C achieved with angioplasty and usual care. Atorvastatin-treated patients had a 36% lower incidence of ischemic events (13%) than angioplastytreated patients (21%). Although this difference just missed statistical significance, the time to first ischemic event was significantly longer in the statin-treated group. However, the AVERT study did not answer the question of whether patients with low baseline LDL-C levels would benefit similarly, or whether atorvastatin would provide additional coronary benefits over “standard” lipid-lowering therapy. A large, long-term, double-blind study of the effects of extremely aggressive LDL-C lowering (the Treating to New Targets [TNT] study22) is currently under way. High-risk patients (prior MI, angina pectoris, or coronary revascularization) are receiving treatment with atorvastatin 10 mg or 80 mg, with the goal of reducing LDL-C levels to 100 mg/dL in 1 group and 75 mg/dL in the other. This trial has enrolled ⬎10,000 men and women, and the results, which are expected in 5 years, should provide additional vital information about the value of lowering LDL-C to levels below the current NCEP ATP III guidelines. The effects of aggressive reduction of LDL-C levels by statin therapy on the prevention of stroke are also currently being investigated.23 A large-scale, short-term (16-week) trial of aggressive lipid lowering with 80 mg daily of atorvastatin within 1 to 4 days of hospitalization for unstable angina or non–Q-wave MI was recently completed.24,25 The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study is the first to investigate the clinical benefits of intensive lipid lowering with a statin in patients with unstable angina or acute MI, and whether such aggressive lipid lowering will reduce early, recurrent ischemic events. The study included ⬎3,000 patients with a broad range of baseline total cholesterol (ⱕ270 mg/dL [ⱕ6.98 mmol/L]) and LDL-C levels.24 Patients treated with atorvastatin had their mean LDL-C levels reduced from 123 mg/dL to 72 mg/dL (a 42% decrease).25 A primary endpoint event (death, nonfatal acute MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency rehospitalization) occurred in 228 patients in the atorvastatin group (14.8%) and in 269 patients in the placebo group (17.4%); this represents a 16% reduction in relative risk (p ⫽ 0.048). The reduction in risk was due primarily to an effect of atorvastatin on recurrent symptomatic ischemia requiring emergency rehospitalization.25 Another trial of 4,500 patients with acute coronary syndromes is in development and will test the effects of early versus delayed simvastatin therapy.26 If this trial, in addition to the MIRACL results, shows that cholesterol lowering has immediate effects on reducing recurrent cardiac events, much earlier institution 14F THE AMERICAN JOURNAL OF CARDIOLOGY姞
of lipid-lowering drug therapy in patients with coronary artery disease may be warranted. What do the completed statin studies mean for clinicians today? The accumulated evidence to date suggests that we can and should aggressively lower LDL-C in all patients safely and effectively with statins to levels at or below those currently recommended for patients with coronary artery disease (⬍100 mg/dL [⬍2.6 mmol/L]) and expect cardiac benefits for these patients, while we await the results of additional trials.
CONCLUSION The clinical evidence clearly indicates that the time has come for physicians to more aggressively target LDL-C levels for reduction with drug therapy in addition to dietary modification, according to current guidelines.2 An important additional benefit of such therapy, as shown in the statin trials, is the concomitant reduction of cerebrovascular disease as well.7,8,27 Furthermore, the evidence also suggests that titration of statin therapy to reach, and even exceed current target LDL-C levels (⬍160 mg/dL to ⱕ100 mg/dL [⬍4.16 to ⱕ2.6 mmol/L] depending on the presence of risk factors and coronary artery disease) may afford superior protection from cardiovascular events than fixed-dose therapy. Finally, results of the major clinical trials also confirm the long-term safety of the statins in reducing LDL-C without excessive risk of adverse effects.
1. American Heart Association. 1999 Heart and Stroke Statistical Update. Dallas:
American Heart Association, 1999. 2. Executive Summary of the Third Report of the National Cholesterol Education
Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486 –2497. 3. Wood D, De Backer G, Faergeman O, Graham I, Mancia G, Pyora¨la¨ K. Prevention of coronary heart disease in clinical practice: recommendations of the Second Joint Task Force of European and other societies on coronary prevention. Eur Heart J 1998;19:1453–1503. 4. Frolkis JP, Zyzanski SJ, Schwarz JM, Suhan PS. Physician noncompliance with the 1993 National Cholesterol Education Program (NCEP-ATPII) guidelines. Circulation 1998;98:851– 855. 5. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389. 6. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301–1307. 7. Sacks FM, Pfeffer MA, Moye´ LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C-C, Davis BR, Braunwald E, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–1009. 8. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349 –1357. 9. MacMahon S, Sharpe N, Gamble G, Hart H, Scott J, Simes J, White H, on behalf of the LIPID Trial Research Group. Effects of lowering average or below-average cholesterol levels on the progression of carotid atherosclerosis: results of the LIPID Atherosclerosis Substudy. Circulation 1998;97:1784 –1790. 10. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:1615–1622. 11. Blauw GJ, Lagaay M, Smelt AHM, Westendorp RGJ. Stroke, statins, and cholesterol: a meta-analysis of randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors. Stroke 1997;28:946 –950. 12. Furberg CD, Adams HP Jr, Applegate WB, Byington RP, Espeland MA, Hartwell T, Hunninghake DB, Lefkowitz DS, Probstfield J, Riley MA, for the
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Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation 1994;90:1679 –1687. 13. Rossouw JE. Lipid-lowering interventions in angiographic trials. Am J Cardiol 1995;76(suppl):86C–92C. 14. West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998;97:1440 –1445. 15. Rubins HB, Robins SJ, Collins D, Iranmanesh A, Wilt TJ, Mann D, MayoSmith M, Faas FH, Elam MB, Rutan GH. Distribution of lipids in 8,500 men with coronary artery disease. Am J Cardiol 1995;75:1196 –1201. 16. Grundy SM. Small LDL, atherogenic dyslipidemia, and the metabolic syndrome. Circulation 1997;95:1– 4. 17. Waters D. Plaque stabilization: a mechanism for the beneficial effect of lipid-lowering therapies in angiographic studies. Prog Cardiovasc Dis 1994;37: 107–120. 18. The Post-Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997;336:153–162. 19. Waters D, Craven T, Lespe´rance J. Prognostic significance of progression of coronary atherosclerosis. Circulation 1993;87:1067–1075. 20. Knatterud GL, Rosenberg Y, Campeau L, Geller NL, Hunninghake DB, Forman SA, Forrester JS, Gobel FL, Herd JA, Hickey A, et al. Long-term effects on clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the Post Coronary Artery Bypass Graft trial. Circulation 2000;102:157–165. 21. Pitt B, Waters D, Brown WV, van Boven AJ, Schwartz L, Title LM,
Eisenberg D, Shurzinske L, McCormick LS, for the Atorvastatin Versus Revascularization Treatment Investigators. Aggressive lipid lowering compared with angioplasty in stable coronary artery disease. N Engl J Med 1999;341:70 –76. 22. LaRosa JC. Effect of lowering LDL-C beyond currently recommended minimum targets: the Treating to New Targets (TNT) study. In: Program and Abstracts of the XIII International Symposium on Drugs Affecting Lipid Metabolism. Florence, Italy, May 30 –June 3, 1998. 23. Welch KMA, for the SPARCL Steering Committee. Effect of atorvastatin compared with placebo on cerebrovascular endpoints in patients with a previous stroke or TIA: the SPARCL study. Abstract presented at the European Stroke Conference, May 27–30, 1998. 24. Schwartz GG, Oliver MF, Ezekowitz MD, Ganz P, Waters D, Kane JP, Texter M, Pressler ML, Black D, Chaitman BR, Olsson AG. Rationale and design of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study that evaluates atorvastatin in unstable angina pectoris and in nonQ-wave acute myocardial infarction. Am J Cardiol 1998;81:578 –581. 25. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T, for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in patients with acute coronary syndromes: the MIRACL Study—a randomized controlled trial. JAMA 2001;285:1711–1718. 26. Waters D. Cholesterol lowering: should it continue to be the last thing we do? Circulation 1999;99:3215–3217. 27. Pedersen TR, Kjekshus J, Pyo¨ra¨la¨ K, Olsson AG, Cook TJ, Musliner TA, Tobert JA, Haghfelt T. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol 1998;81:333–335.
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