- Email: [email protected]
Treating to target with statins
Atherosclerosis Supplements 1 (2000) 21 – 25 www.elsevier.com/locate/atherosclerosis
Treating to target with statins P.J. Barter* Department of Medicine, Uni6ersity of Adelaide and the Di6ision of Cardio6ascular Ser6ices, Royal Adelaide Hospital, Adelaide, South Australia
Abstract Large-scale drug intervention trials have proven that cholesterol-lowering therapy reduces the risk of coronary events in a wide range of at-risk patient groups. This has led to a growing consensus that plasma total and low-density lipoprotein cholesterol (LDL-C) should be reduced to target levels that have been shown in population studies to be associated with low rates of coronary heart disease (CHD). Despite this consensus, however, a substantial proportion of patients at high coronary risk still do not receive lipid-lowering therapy. Furthermore, of those patients receiving therapy, many do not achieve the recommended targets. In order to address this problem, several treatment-to-target studies have been conducted to determine whether recommended targets are attainable with the lipid-lowering drugs that are currently available. These studies have confirmed that the statins are able to achieve recommended target levels in the majority of patients at risk. The studies have also demonstrated that most patients achieve a total cholesterol target with atorvastatin. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Atorvastatin; Coronary heart disease; Lipid-lowering therapy; Statins; Treatment-to-target
1. Introduction Raised plasma total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels have been shown repeatedly to be predictive of premature coronary heart disease (CHD) in many populations. The mechanism by which an elevated LDL-C level causes premature CHD, is becoming clearer as our understanding of the basic biology of the atherosclerotic plaque emerges [1]. Cause and effect has been demonstrated in a variety of animal studies in which genetically engineered elevations of plasma cholesterol have been shown to result in atherosclerosis [2–4]. The ultimate proof of cause and effect in humans, however, has emerged from several large-scale drug intervention trials. These trials have demonstrated beyond all reasonable doubt that lowering plasma total cholesterol and LDL-C levels reduces the risk of future coronary events in a wide range of subjects. The benefits of lipid-lowering therapy have been shown in individuals with [5 – 7] and without [8,9] prior CHD and in at-risk patient groups with both elevated [5,10] and even average [6 – 8] LDL-C levels. * Tel.:+ 61-8-82225608; fax: +61-8-82240620. E-mail address: [email protected] (P.J. Barter).
Having established the benefits of cholesterol lowering in at-risk patients, it is now necessary to address two additional questions of considerable practical importance: (i) What target plasma total cholesterol and LDL-C levels should be adopted in at-risk patients? (ii) Is it feasible to achieve such targets with currently available therapies? This paper will address each of these issues.
2. Target cholesterol levels
2.1. E6idence from population studies The largest reported prospective population study relating the concentration of plasma cholesterol to the future risk of CHD is the Multiple Risk Factor Intervention Trial (MRFIT) [9]. This study has followed more than 350 000 men for 10 years and found that the relationship between cholesterol levels at baseline and subsequent coronary death is continuous, with no evidence of a threshold cholesterol level below which CHD no longer occurs. The obvious question to ask is: does the continuous relationship observed in prospective population studies also apply to the lipid-lowering intervention trials?
0021-9150/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 2 1 - 9 1 5 0 ( 0 0 ) 0 0 5 6 4 - 5
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P.J. Barter / Atherosclerosis Supplements 1 (2000) 21–25
2.2. E6idence from inter6ention studies There have been no reports of intervention studies designed specifically to determine whether the reduction in CHD events is a direct function of the magnitude of the cholesterol reduction that is achieved. Nor have any of the reported trials, in isolation, been able to determine whether there is a threshold cholesterol level below which the benefits of lipid-lowering therapy are no longer apparent. Attempts have been made in some of the studies to address these issues by conducting retrospective subgroup analyses. However, the conclusions drawn from such analyses have been both conflicting and confusing. Subgroup analyses of the results from the WOSCOPS [11] and CARE studies with pravastatin [12] concluded that most, if not all, of the benefits of treatment are achieved with a 20% reduction in LDL-C levels, with little additional benefit resulting from greater reductions. Results from a comparable retrospective subgroup analysis of the simvastatin 4S trial were consistent with data from MRFIT and suggested that the benefits of treatment are proportional to the magnitude of cholesterol lowering [13]. These subgroup analyses should be interpreted with caution as the trials were not specifically designed to define optimal goals for LDL-C in primary and secondary prevention. However, the results do justify current guideline criteria for selection of patients for therapy and target cholesterol levels. In addition, they have highlighted that a trial specifically designed to address optimal
Fig. 1. The relationship between cholesterol lowering and reduction in coronary events. The reduction in coronary events is plotted against the mean reduction in plasma total cholesterol in seven major cholesterol-lowering trials. The LRC-CPPT study used cholestyramine, POSCH used ileal bypass surgery, 4S used simvastatin, WOSCOPS, CARE and LIPID used pravastatin and AFCAPS/TexCAPS used lovastatin. Note that the event reduction in the LRC-CPPT and POSCH studies is that observed after 5 years as reported by Law et al. [18]. The time-frame of the other studies is 5–6 years. It should be emphasized that these studies involved markedly different subject groups, that different treatments were used and that, strictly speaking, such studies cannot be directly compared. It is therefore possible that the observed linearity of the relationship between cholesterol lowering and the reduction in coronary events in these studies is coincidence.
goals for lipid-lowering therapy is important in future research. One of the few reported studies that was designed to ask whether the benefits of therapy are proportional to the magnitude of cholesterol lowering is the Post Coronary Artery Bypass Graft (Post-CABG) trial [14]. In this placebo-controlled study, over 1300 men and women who had undergone bypass surgery and had an LDL-C level of 3.4–4.5 mmol/l (130–175 mg/dl) were randomized to aggressive (40 mg/day) or moderate (2.5 mg/day) treatment with lovastatin (plus cholestyramine if necessary). The target LDL-C level was B 2.2 mmol/l (85 mg/dl) in the aggressive treatment group and B3.6 mmol/l (140 mg/dl) in the moderate treatment group. When compared with moderate treatment, the progression of atherosclerosis in the group receiving grafts was significantly reduced in the aggressive treatment group. Another approach to this issue is to look at the results of intervention studies and ask whether the benefits are predicted by the on-treatment cholesterol levels achieved in the active and placebo groups. When comparing the results of several of the angiographic trials, this does appear to be the case [15]. It is also possible to look at whether the reduction in coronary events in the different studies bears any relationship to the magnitude of the cholesterol lowering achieved.
2.3. Relationship between reduction in CHD e6ents and the magnitude of cholesterol lowering Fig. 1 shows the 5-year results of two non-statin trials (LRC-CPPT with cholestyramine [16] and POSCH with ileal bypass [17]) and the five major statin trials (4S with simvastatin [5]; CARE [6], LIPID [7] and WOSCOPS [10] with pravastatin; and AFCAPS/TexCAPS with lovastatin [8]). (Note that the 5-year results for the LRC-CPPT and POSCH studies were obtained from a report by Law et al. [18].) Given that there were major differences in both the methods of cholesterol-lowering therapy and the types and numbers of subjects studied in each of these trials, the linearity of the relationship between the magnitude of cholesterol lowering and the reduction in coronary events is quite remarkable (Fig. 1). It is possible that the strength of this linear relationship is a coincidence. But it is also possible that the extent of the 5–6-year reduction in coronary events following cholesterol-lowering therapy is directly related to the magnitude (in mmol/l) of the reduction in plasma total cholesterol or LDL-C, regardless of whether this is achieved by a statin, cholestyramine, or even by non-drug therapy. In addition, such linearity suggests that the benefits of therapy over and above those explained by cholesterol lowering would be only minor.
P.J. Barter / Atherosclerosis Supplements 1 (2000) 21–25
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such levels can be realistically achieved in most people. The feasibility of realizing such targets has been addressed in several recent treatment-to-target studies.
4. Treatment-to-target studies
Fig. 2. The cumulative percentage of patients meeting the target plasma total cholesterol of B 5.0 mmol/L with increasing doses of atorvastatin and simvastatin. The values are expressed as percentages of the total groups, n = 691 for atorvastatin and n=337 for simvastatin. C= cholestyramine. Reproduced from Barter and O’Brien 2000, with permission from Elsevier Science.
Fig. 3. The percentage of patients meeting the target plasma cholesterol of B 5.0 mmol/l as a function of the baseline plasma total cholesterol level. This figure shows the results with atorvastatin over a daily dose range of 10–80 mg and with simvastatin over a daily dose range of 10 – 40 mg. The 40 mg simvastatin was supplemented if necessary with 4 g cholestyramine.
3. Cholesterol treatment guidelines The results of population and intervention studies have provided the basis for a growing consensus that the plasma total cholesterol and LDL-C levels in at-risk patients should be reduced to target levels that have been shown in population studies to be associated with low rates of CHD. This consensus has culminated in the generation of guidelines for cholesterol management in several countries. Recommended target levels in atrisk patients range from 2 – 3 mmol/l (75 – 115 mg/dl) for LDL-C (depending on the degree of risk) and from 4 – 5 mmol/l (155–190 mg/dl) for plasma total cholesterol. However, despite widespread promotion of these guidelines, a substantial proportion of patients at high coronary risk are still not receiving lipid-lowering therapy and of those who are, many are not being treated to recommended target levels [19]. Clearly, the development of guidelines for cholesterol management is only the first step. The next is to achieve their widespread adoption. However, recommendations that at-risk patients should be treated to low total cholesterol and LDL-C levels are of little value unless
The largest of the treatment-to-target studies to date has recently been completed in Australia [20]. This study assessed the feasibility of achieving a target plasma total cholesterol level of B 5.0 mmol/l (190 mg/dl) in hypercholesterolemic men and women being treated in a primary care setting. A total of 1028 patients aged 18–75 years participated in an open-label, randomized, parallel-group, 6-month treatment-to-target study conducted in 240 general practices throughout Australia. The study compared atorvastatin monotherapy with simvastatin monotherapy or, if necessary, with the combination of simvastatin and cholestyramine, in terms of their abilities to achieve the total cholesterol target of B5.0 mmol/l (190 mg/dl). The initial daily dose of each drug was 10 mg. If the target was not achieved, the dose was doubled at 6-week intervals to a maximum daily dose of 80 mg atorvastatin or 40 mg simvastatin, with the simvastatin supplemented if necessary with 4 g cholestyramine for the last 6 weeks. Both agents were well tolerated, with 93% of the atorvastatin group and 95% of the simvastatin group completing the 24-week study. There were few adverse events in either group, with no significant difference in the frequency or severity of such events between the two treatment groups. Both drugs were highly effective in reducing the concentrations of plasma total cholesterol and LDL-C, although the reductions achieved with atorvastatin were greater than with mg equivalent doses of simvastatin. The reduction in plasma triglycerides was also greater with atorvastatin than with milligram equivalent doses of simvastatin. Both drugs raised HDL-C levels to a similar extent. Despite relatively high baseline levels of plasma total cholesterol (mean levels of 7.4 and 7.3 mmol/l in the atorvastatin and simvastatin groups, respectively) the majority of patients in each group achieved the plasma total cholesterol target of B5.0 mmol/l (190 mg/dl). Overall, significantly more patients reached the target with atorvastatin (83%) than with simvastatin or simvastatin plus cholestyramine (66%) (PB 0.001) (Fig. 2). The superiority of atorvastatin was also apparent at the starting doses of the drugs. The target was achieved with 10 mg atorvastatin in 38% of patients compared with 26% of the patients on 10 mg simvastatin (PB 0.001). Predictably, the proportion of subjects achieving the target with either drug was influenced by the baseline plasma total cholesterol level (Fig. 3). In patients with
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baseline plasma total cholesterol levels in the range 5.2 – 6.5 mmol/l, 95% of the atorvastatin group and 87% of the simvastatin group achieved the target plasma total cholesterol of B5.0 mmol/l (190 mg/dl). With baseline cholesterol levels in the range 6.6 – 7.5 mmol/l, the target was achieved in 90% of the atorvastatin group and in 72% of those taking simvastatin (including those receiving simvastatin plus cholestyramine). When the baseline plasma total cholesterol level was in the range 7.6–8.5 and 8.6 – 9.5 mmol/l, the percentage of patients achieving the target was 78 and 68%, respectively, in the atorvastatin group and 61 and 19%, respectively, in the simvastatin group. Lastly, with baseline levels \9.5 mmol/l, the target was achieved in 27% (nine of 33) of patients on atorvastatin but in none of 12 patients on simvastatin. In another treatment-to-target study conducted in the USA [21], a total of 318 men and women with atherosclerosis and baseline LDL-C levels ] 3.4 mmol/ l (130 mg/dl) were included. Patients were randomized to one of four treatment groups: atorvastatin 10 mg/ day, fluvastatin 20 mg/day, lovastatin 20 mg/day, or simvastatin 10 mg/day. Dose titration occurred at 12week intervals until the recommended US National Cholesterol Education Program (NCEP) LDL-C target for patients with CHD of 52.6 mmol/l (100 mg/dl) was achieved [22]. The doses of the statins could be increased to a maximum of 80 mg/day for atorvastatin, 40 mg/day for fluvastatin, 80 mg/day for lovastatin and 40 mg/day for simvastatin. If the target LDL-C was not achieved at the maximum dose of statin, colestipol was added to the patient’s regimen. At the starting dose, a significantly greater number of patients reached the LDL-C target with atorvastatin (32%) than those treated with fluvastatin (1%) or lovastatin (10%). The target was achieved in 53% of subjects on 10 or 20 mg atorvastatin and in 83% of subjects on 10, 20, 40 or 80 mg atorvastatin. In a second US treatment-to-target study, 344 men and women with coronary risk factors but without clinical CHD were included and grouped according to their risk factors: less than two risk factors for CHD and a mean LDL-C level of ]5 mmol/l (190 mg/dl) or two or more CHD risk factors and a mean LDL-C level of ] 4.1 mmol/l (160 mg/dl) [23]. Participants were again randomized to one of four treatment groups: atorvastatin 10 mg/day, fluvastatin 20 mg/day, lovastatin 20 mg/day, or simvastatin 10 mg/day. Dose titration occurred at 6-week intervals until the recommended NCEP LDL-C targets of B 4.1 mmol/l (160 mg/dl) for patients with less than two risk factors and B3.4 mmol/l (130 mg/dl) for patients with two or more risk factors were achieved. The dose of statin could be increased to a maximum of 80 mg/day for atorvastatin, 40 mg/day for fluvastatin, 80 mg/day for lovastatin and 40 mg/day for simvastatin. If the target
LDL-C was not achieved at the maximum dose of statin, colestipol was added to the patient’s regimen. At the end of the study, the percentage of patients reaching the target LDL-C level was significantly (P B 0.05) higher for atorvastatin-treated (95%) than fluvastatintreated (60%), lovastatin-treated (77%) or simvastatintreated (83%) patients. Overall, the target LDL-C level was achieved in more patients and at a lower dose with atorvastatin than with fluvastatin, lovastatin, or simvastatin. A third study was conducted in Europe in 336 men and women with atherosclerosis and baseline LDL-C levels ] 3.4 mmol/l (130 mg/dl) [24]. Patients were randomized to atorvastatin 10 mg/day, fluvastatin 20 mg/day, pravastatin 20 mg/day or simvastatin 10 mg/ day. Dose titration again occurred at 12-week intervals until a target LDL-C level of 5 2.6 mmol/l (100 mg/dl) was achieved and until the maximum statin dose was reached. For patients not achieving the LDL-C target at the maximum statin dose, cholestyramine was added to the patient’s regimen. In this study, patients treated with atorvastatin achieved LDL-C targets significantly (PB 0.05) faster, at lower doses of study drug and required significantly fewer clinic visits than the comparator statins. Consequently, the mean total cost of care to reach a target LDL-C level of 5 2.6 mmol/l (100 mg/dl) was lower with atorvastatin than with fluvastatin, pravastatin, or simvastatin.
5. Conclusions The importance of treating patients to lower cholesterol levels to lessen the risk of developing atherosclerosis is well accepted. However, the benefits of aggressive treatment for lowering LDL-C and whether there is a defined threshold below which lowering cholesterol is of little use are still questionable. The Post-CABG trial evaluated aggressive LDL-C lowering therapy versus moderate treatment goals and definitively demonstrated that in patients with a moderate increase in serum cholesterol, aggressive lipid lowering compares very positively with a moderate strategy. The benefits of decreasing cholesterol to very low levels are not yet certain; although epidemiological reviews strongly correlate lower cholesterol levels with lowered CHD mortality. On the basis of the recent treatment-to-target studies with statins, it may be concluded that: (i) with the statins currently available, recommended target levels of plasma total cholesterol and LDL-C are achievable in most hypercholesterolemic patients; (ii) more at-risk patients achieve recommended target levels of plasma total and LDL-C with atorvastatin than with other statins; and (iii) target levels of plasma total and LDL-C are achieved at lower doses and at a lower cost with atorvastatin than with any other statin.
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References [1] Libby P, Clinton SK. The role of macrophages in atherogenesis. Curr Opin Lipidol 1993;4:355–63. [2] Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, et al. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 1992;71:343–53. [3] Ishibashi S, Goldstein JL, Brown MS, Herz J, Burns DK. Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. J Clin Invest 1994;93:1885 – 93. [4] Purcell-Huynh DA, Farese RV, Johnson DF, Flynn LM, Pierotti V, Newland DL, et al. Transgenic mice expressing high levels of human apolipoprotein B develop severe atherosclerotic lesions in response to a high-fat diet. J Clin Invest 1995;95:2246 – 57. [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;344:1383–9. [6] Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–9. [7] 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;339:1349–57. [8] Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. J Am Med Assoc 1998;279:1615–22. [9] Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the multiple risk factor intervention trial (MRFIT). J Am Med Assoc 1986;256:2823–8. [10] Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301 – 7. [11] WOSCOPS Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland coronary prevention study (WOSCOPS). Circulation 1998;97:1440–5. [12] Sacks FM, Moye LA, Davis BR, Cole TG, Rouleau JL, Nash DT, et al. Relationship between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the cholesterol and recurrent events trial. Circulation 1998;15:1446 – 52.
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[13] Pedersen TR, Olsson AG, Faergeman O, Kjekshus J, Wedel H, Berg K, et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 1998;97:1453– 60. [14] 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 – 62. [15] Ballantyne CM, Herd JA, Dunn JK, Jones PH, Farmer JA, Gotto AM. Effects of lipid lowering therapy on progression of coronary and carotid artery disease. Curr Opin Lipidol 1997;8:354 – 61. [16] The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. J Am Med Assoc 1984;251(3):351– 64. [17] Buchwald H, Varco RL, Matts JP, Long JM, Fitch LL, Campbell GS, et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. New Engl J Med 1990;323:946 – 55. [18] Law MR, Wald NJ, Thomson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? Br Med J 1994;308:367–73. [19] EUROASPIRE Study Group. A European Society of Cardiology survey of secondary prevention of coronary heart disease: principal results. Eur Heart J 1997;18:1569 – 82. [20] Barter PJ, O’Brien RC. Achievement of target plasma cholesterol levels in hypercholesterolaemic patients being treated in general practice. Atherosclerosis 2000;149:199 – 205. [21] Brown AS, Bakker-Arkema RG, Yellen L, Henley RW, Guther R, Campbell CF, et al. Treating patients with documented atherosclerosis to national cholesterol education program-recommended low-density-lipoprotein cholesterol goals with atorvastatin, fluvastatin, lovastatin and simvastatin. J Am Coll Cardiol 1998;32:665 – 72. [22] National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 1994;89(3):1333– 445. [23] Hunninghake D, Bakker-Arkema RG, Wigand JP, Drehobl M, Schrott H, Early JL, et al. Treating to meet NCEP-recommended LDL cholesterol concentrations with atorvastatin, fluvastatin, lovastatin, or simvastatin in patients with risk factors for coronary heart disease. J Fam Prac 1998;47:349 – 56. [24] Smith DG, Leslie SJ, Szucs TD, McBride S, Campbell LM, et al. Cost of treating to a modified european atherosclerosis society LDL-C target. Comparison of atorvastatin versus fluvastatin, pravastatin and simvastatin. Clin Drug Invest 1999;17(3):185– 93.
Treating to target with statins P.J. Barter* Department of Medicine, Uni6ersity of Adelaide and the Di6ision of Cardio6ascular Ser6ices, Royal Adelaide Hospital, Adelaide, South Australia
Abstract Large-scale drug intervention trials have proven that cholesterol-lowering therapy reduces the risk of coronary events in a wide range of at-risk patient groups. This has led to a growing consensus that plasma total and low-density lipoprotein cholesterol (LDL-C) should be reduced to target levels that have been shown in population studies to be associated with low rates of coronary heart disease (CHD). Despite this consensus, however, a substantial proportion of patients at high coronary risk still do not receive lipid-lowering therapy. Furthermore, of those patients receiving therapy, many do not achieve the recommended targets. In order to address this problem, several treatment-to-target studies have been conducted to determine whether recommended targets are attainable with the lipid-lowering drugs that are currently available. These studies have confirmed that the statins are able to achieve recommended target levels in the majority of patients at risk. The studies have also demonstrated that most patients achieve a total cholesterol target with atorvastatin. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Atorvastatin; Coronary heart disease; Lipid-lowering therapy; Statins; Treatment-to-target
1. Introduction Raised plasma total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels have been shown repeatedly to be predictive of premature coronary heart disease (CHD) in many populations. The mechanism by which an elevated LDL-C level causes premature CHD, is becoming clearer as our understanding of the basic biology of the atherosclerotic plaque emerges [1]. Cause and effect has been demonstrated in a variety of animal studies in which genetically engineered elevations of plasma cholesterol have been shown to result in atherosclerosis [2–4]. The ultimate proof of cause and effect in humans, however, has emerged from several large-scale drug intervention trials. These trials have demonstrated beyond all reasonable doubt that lowering plasma total cholesterol and LDL-C levels reduces the risk of future coronary events in a wide range of subjects. The benefits of lipid-lowering therapy have been shown in individuals with [5 – 7] and without [8,9] prior CHD and in at-risk patient groups with both elevated [5,10] and even average [6 – 8] LDL-C levels. * Tel.:+ 61-8-82225608; fax: +61-8-82240620. E-mail address: [email protected] (P.J. Barter).
Having established the benefits of cholesterol lowering in at-risk patients, it is now necessary to address two additional questions of considerable practical importance: (i) What target plasma total cholesterol and LDL-C levels should be adopted in at-risk patients? (ii) Is it feasible to achieve such targets with currently available therapies? This paper will address each of these issues.
2. Target cholesterol levels
2.1. E6idence from population studies The largest reported prospective population study relating the concentration of plasma cholesterol to the future risk of CHD is the Multiple Risk Factor Intervention Trial (MRFIT) [9]. This study has followed more than 350 000 men for 10 years and found that the relationship between cholesterol levels at baseline and subsequent coronary death is continuous, with no evidence of a threshold cholesterol level below which CHD no longer occurs. The obvious question to ask is: does the continuous relationship observed in prospective population studies also apply to the lipid-lowering intervention trials?
0021-9150/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 2 1 - 9 1 5 0 ( 0 0 ) 0 0 5 6 4 - 5
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P.J. Barter / Atherosclerosis Supplements 1 (2000) 21–25
2.2. E6idence from inter6ention studies There have been no reports of intervention studies designed specifically to determine whether the reduction in CHD events is a direct function of the magnitude of the cholesterol reduction that is achieved. Nor have any of the reported trials, in isolation, been able to determine whether there is a threshold cholesterol level below which the benefits of lipid-lowering therapy are no longer apparent. Attempts have been made in some of the studies to address these issues by conducting retrospective subgroup analyses. However, the conclusions drawn from such analyses have been both conflicting and confusing. Subgroup analyses of the results from the WOSCOPS [11] and CARE studies with pravastatin [12] concluded that most, if not all, of the benefits of treatment are achieved with a 20% reduction in LDL-C levels, with little additional benefit resulting from greater reductions. Results from a comparable retrospective subgroup analysis of the simvastatin 4S trial were consistent with data from MRFIT and suggested that the benefits of treatment are proportional to the magnitude of cholesterol lowering [13]. These subgroup analyses should be interpreted with caution as the trials were not specifically designed to define optimal goals for LDL-C in primary and secondary prevention. However, the results do justify current guideline criteria for selection of patients for therapy and target cholesterol levels. In addition, they have highlighted that a trial specifically designed to address optimal
Fig. 1. The relationship between cholesterol lowering and reduction in coronary events. The reduction in coronary events is plotted against the mean reduction in plasma total cholesterol in seven major cholesterol-lowering trials. The LRC-CPPT study used cholestyramine, POSCH used ileal bypass surgery, 4S used simvastatin, WOSCOPS, CARE and LIPID used pravastatin and AFCAPS/TexCAPS used lovastatin. Note that the event reduction in the LRC-CPPT and POSCH studies is that observed after 5 years as reported by Law et al. [18]. The time-frame of the other studies is 5–6 years. It should be emphasized that these studies involved markedly different subject groups, that different treatments were used and that, strictly speaking, such studies cannot be directly compared. It is therefore possible that the observed linearity of the relationship between cholesterol lowering and the reduction in coronary events in these studies is coincidence.
goals for lipid-lowering therapy is important in future research. One of the few reported studies that was designed to ask whether the benefits of therapy are proportional to the magnitude of cholesterol lowering is the Post Coronary Artery Bypass Graft (Post-CABG) trial [14]. In this placebo-controlled study, over 1300 men and women who had undergone bypass surgery and had an LDL-C level of 3.4–4.5 mmol/l (130–175 mg/dl) were randomized to aggressive (40 mg/day) or moderate (2.5 mg/day) treatment with lovastatin (plus cholestyramine if necessary). The target LDL-C level was B 2.2 mmol/l (85 mg/dl) in the aggressive treatment group and B3.6 mmol/l (140 mg/dl) in the moderate treatment group. When compared with moderate treatment, the progression of atherosclerosis in the group receiving grafts was significantly reduced in the aggressive treatment group. Another approach to this issue is to look at the results of intervention studies and ask whether the benefits are predicted by the on-treatment cholesterol levels achieved in the active and placebo groups. When comparing the results of several of the angiographic trials, this does appear to be the case [15]. It is also possible to look at whether the reduction in coronary events in the different studies bears any relationship to the magnitude of the cholesterol lowering achieved.
2.3. Relationship between reduction in CHD e6ents and the magnitude of cholesterol lowering Fig. 1 shows the 5-year results of two non-statin trials (LRC-CPPT with cholestyramine [16] and POSCH with ileal bypass [17]) and the five major statin trials (4S with simvastatin [5]; CARE [6], LIPID [7] and WOSCOPS [10] with pravastatin; and AFCAPS/TexCAPS with lovastatin [8]). (Note that the 5-year results for the LRC-CPPT and POSCH studies were obtained from a report by Law et al. [18].) Given that there were major differences in both the methods of cholesterol-lowering therapy and the types and numbers of subjects studied in each of these trials, the linearity of the relationship between the magnitude of cholesterol lowering and the reduction in coronary events is quite remarkable (Fig. 1). It is possible that the strength of this linear relationship is a coincidence. But it is also possible that the extent of the 5–6-year reduction in coronary events following cholesterol-lowering therapy is directly related to the magnitude (in mmol/l) of the reduction in plasma total cholesterol or LDL-C, regardless of whether this is achieved by a statin, cholestyramine, or even by non-drug therapy. In addition, such linearity suggests that the benefits of therapy over and above those explained by cholesterol lowering would be only minor.
P.J. Barter / Atherosclerosis Supplements 1 (2000) 21–25
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such levels can be realistically achieved in most people. The feasibility of realizing such targets has been addressed in several recent treatment-to-target studies.
4. Treatment-to-target studies
Fig. 2. The cumulative percentage of patients meeting the target plasma total cholesterol of B 5.0 mmol/L with increasing doses of atorvastatin and simvastatin. The values are expressed as percentages of the total groups, n = 691 for atorvastatin and n=337 for simvastatin. C= cholestyramine. Reproduced from Barter and O’Brien 2000, with permission from Elsevier Science.
Fig. 3. The percentage of patients meeting the target plasma cholesterol of B 5.0 mmol/l as a function of the baseline plasma total cholesterol level. This figure shows the results with atorvastatin over a daily dose range of 10–80 mg and with simvastatin over a daily dose range of 10 – 40 mg. The 40 mg simvastatin was supplemented if necessary with 4 g cholestyramine.
3. Cholesterol treatment guidelines The results of population and intervention studies have provided the basis for a growing consensus that the plasma total cholesterol and LDL-C levels in at-risk patients should be reduced to target levels that have been shown in population studies to be associated with low rates of CHD. This consensus has culminated in the generation of guidelines for cholesterol management in several countries. Recommended target levels in atrisk patients range from 2 – 3 mmol/l (75 – 115 mg/dl) for LDL-C (depending on the degree of risk) and from 4 – 5 mmol/l (155–190 mg/dl) for plasma total cholesterol. However, despite widespread promotion of these guidelines, a substantial proportion of patients at high coronary risk are still not receiving lipid-lowering therapy and of those who are, many are not being treated to recommended target levels [19]. Clearly, the development of guidelines for cholesterol management is only the first step. The next is to achieve their widespread adoption. However, recommendations that at-risk patients should be treated to low total cholesterol and LDL-C levels are of little value unless
The largest of the treatment-to-target studies to date has recently been completed in Australia [20]. This study assessed the feasibility of achieving a target plasma total cholesterol level of B 5.0 mmol/l (190 mg/dl) in hypercholesterolemic men and women being treated in a primary care setting. A total of 1028 patients aged 18–75 years participated in an open-label, randomized, parallel-group, 6-month treatment-to-target study conducted in 240 general practices throughout Australia. The study compared atorvastatin monotherapy with simvastatin monotherapy or, if necessary, with the combination of simvastatin and cholestyramine, in terms of their abilities to achieve the total cholesterol target of B5.0 mmol/l (190 mg/dl). The initial daily dose of each drug was 10 mg. If the target was not achieved, the dose was doubled at 6-week intervals to a maximum daily dose of 80 mg atorvastatin or 40 mg simvastatin, with the simvastatin supplemented if necessary with 4 g cholestyramine for the last 6 weeks. Both agents were well tolerated, with 93% of the atorvastatin group and 95% of the simvastatin group completing the 24-week study. There were few adverse events in either group, with no significant difference in the frequency or severity of such events between the two treatment groups. Both drugs were highly effective in reducing the concentrations of plasma total cholesterol and LDL-C, although the reductions achieved with atorvastatin were greater than with mg equivalent doses of simvastatin. The reduction in plasma triglycerides was also greater with atorvastatin than with milligram equivalent doses of simvastatin. Both drugs raised HDL-C levels to a similar extent. Despite relatively high baseline levels of plasma total cholesterol (mean levels of 7.4 and 7.3 mmol/l in the atorvastatin and simvastatin groups, respectively) the majority of patients in each group achieved the plasma total cholesterol target of B5.0 mmol/l (190 mg/dl). Overall, significantly more patients reached the target with atorvastatin (83%) than with simvastatin or simvastatin plus cholestyramine (66%) (PB 0.001) (Fig. 2). The superiority of atorvastatin was also apparent at the starting doses of the drugs. The target was achieved with 10 mg atorvastatin in 38% of patients compared with 26% of the patients on 10 mg simvastatin (PB 0.001). Predictably, the proportion of subjects achieving the target with either drug was influenced by the baseline plasma total cholesterol level (Fig. 3). In patients with
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baseline plasma total cholesterol levels in the range 5.2 – 6.5 mmol/l, 95% of the atorvastatin group and 87% of the simvastatin group achieved the target plasma total cholesterol of B5.0 mmol/l (190 mg/dl). With baseline cholesterol levels in the range 6.6 – 7.5 mmol/l, the target was achieved in 90% of the atorvastatin group and in 72% of those taking simvastatin (including those receiving simvastatin plus cholestyramine). When the baseline plasma total cholesterol level was in the range 7.6–8.5 and 8.6 – 9.5 mmol/l, the percentage of patients achieving the target was 78 and 68%, respectively, in the atorvastatin group and 61 and 19%, respectively, in the simvastatin group. Lastly, with baseline levels \9.5 mmol/l, the target was achieved in 27% (nine of 33) of patients on atorvastatin but in none of 12 patients on simvastatin. In another treatment-to-target study conducted in the USA [21], a total of 318 men and women with atherosclerosis and baseline LDL-C levels ] 3.4 mmol/ l (130 mg/dl) were included. Patients were randomized to one of four treatment groups: atorvastatin 10 mg/ day, fluvastatin 20 mg/day, lovastatin 20 mg/day, or simvastatin 10 mg/day. Dose titration occurred at 12week intervals until the recommended US National Cholesterol Education Program (NCEP) LDL-C target for patients with CHD of 52.6 mmol/l (100 mg/dl) was achieved [22]. The doses of the statins could be increased to a maximum of 80 mg/day for atorvastatin, 40 mg/day for fluvastatin, 80 mg/day for lovastatin and 40 mg/day for simvastatin. If the target LDL-C was not achieved at the maximum dose of statin, colestipol was added to the patient’s regimen. At the starting dose, a significantly greater number of patients reached the LDL-C target with atorvastatin (32%) than those treated with fluvastatin (1%) or lovastatin (10%). The target was achieved in 53% of subjects on 10 or 20 mg atorvastatin and in 83% of subjects on 10, 20, 40 or 80 mg atorvastatin. In a second US treatment-to-target study, 344 men and women with coronary risk factors but without clinical CHD were included and grouped according to their risk factors: less than two risk factors for CHD and a mean LDL-C level of ]5 mmol/l (190 mg/dl) or two or more CHD risk factors and a mean LDL-C level of ] 4.1 mmol/l (160 mg/dl) [23]. Participants were again randomized to one of four treatment groups: atorvastatin 10 mg/day, fluvastatin 20 mg/day, lovastatin 20 mg/day, or simvastatin 10 mg/day. Dose titration occurred at 6-week intervals until the recommended NCEP LDL-C targets of B 4.1 mmol/l (160 mg/dl) for patients with less than two risk factors and B3.4 mmol/l (130 mg/dl) for patients with two or more risk factors were achieved. The dose of statin could be increased to a maximum of 80 mg/day for atorvastatin, 40 mg/day for fluvastatin, 80 mg/day for lovastatin and 40 mg/day for simvastatin. If the target
LDL-C was not achieved at the maximum dose of statin, colestipol was added to the patient’s regimen. At the end of the study, the percentage of patients reaching the target LDL-C level was significantly (P B 0.05) higher for atorvastatin-treated (95%) than fluvastatintreated (60%), lovastatin-treated (77%) or simvastatintreated (83%) patients. Overall, the target LDL-C level was achieved in more patients and at a lower dose with atorvastatin than with fluvastatin, lovastatin, or simvastatin. A third study was conducted in Europe in 336 men and women with atherosclerosis and baseline LDL-C levels ] 3.4 mmol/l (130 mg/dl) [24]. Patients were randomized to atorvastatin 10 mg/day, fluvastatin 20 mg/day, pravastatin 20 mg/day or simvastatin 10 mg/ day. Dose titration again occurred at 12-week intervals until a target LDL-C level of 5 2.6 mmol/l (100 mg/dl) was achieved and until the maximum statin dose was reached. For patients not achieving the LDL-C target at the maximum statin dose, cholestyramine was added to the patient’s regimen. In this study, patients treated with atorvastatin achieved LDL-C targets significantly (PB 0.05) faster, at lower doses of study drug and required significantly fewer clinic visits than the comparator statins. Consequently, the mean total cost of care to reach a target LDL-C level of 5 2.6 mmol/l (100 mg/dl) was lower with atorvastatin than with fluvastatin, pravastatin, or simvastatin.
5. Conclusions The importance of treating patients to lower cholesterol levels to lessen the risk of developing atherosclerosis is well accepted. However, the benefits of aggressive treatment for lowering LDL-C and whether there is a defined threshold below which lowering cholesterol is of little use are still questionable. The Post-CABG trial evaluated aggressive LDL-C lowering therapy versus moderate treatment goals and definitively demonstrated that in patients with a moderate increase in serum cholesterol, aggressive lipid lowering compares very positively with a moderate strategy. The benefits of decreasing cholesterol to very low levels are not yet certain; although epidemiological reviews strongly correlate lower cholesterol levels with lowered CHD mortality. On the basis of the recent treatment-to-target studies with statins, it may be concluded that: (i) with the statins currently available, recommended target levels of plasma total cholesterol and LDL-C are achievable in most hypercholesterolemic patients; (ii) more at-risk patients achieve recommended target levels of plasma total and LDL-C with atorvastatin than with other statins; and (iii) target levels of plasma total and LDL-C are achieved at lower doses and at a lower cost with atorvastatin than with any other statin.
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