EDITORIAL COMMENT
Aggressive Therapy Is Not Always the Best Therapy*
Albert V.G. Bruschke, MD, PhD, FACC* and
J. Wouter Jukema, MD, PhD, FACC
Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
* Reprint requests and correspondence: Dr. Albert V. G. Bruschke, Staff Center Department of Cardiology, LUMC-C5-P, Postbus 9600, 2300RC Leiden, the Netherlands (Email: abruschke{at}freeler.nl).
Key Words: cholesterol • LDL-C • lipid lowering • clinical trials • statins
The 4S (Scandinavian Simvastatin Survival Study), which was published in 1994, was the first large clinical study to show a significant reduction of mortality and major coronary events in patients with coronary artery disease who were treated with 20 mg simvastatin (1). The reduction of relative risk seemed to be independent of baseline lipid levels; however, patients with a baseline serum cholesterol level of <213 mg/dl were not included in the study (2). At about the same time, the angiographic trial REGRESS (Regression Growth Evaluation Statin Study), which included patients with a baseline serum cholesterol level between 155 and 310 mg/dl, showed a highly significant beneficial effect of 40 mg pravastatin on progression of coronary atherosclerosis, and the magnitude of this effect seemed to be the same in all quartiles of baseline total cholesterol and low-density lipoprotein cholesterol (LDL-C) (to convert from mg/dl to mmol/l, multiply by 0.026) (3).
These and similar studies clearly showed that in the new era of statin treatment, old concepts about thresholds of serum lipid levels below which patients with coronary artery disease did not qualify for lipid-lowering therapy were no longer tenable. Now the main issues for discussion and research have become: 1) Does a threshold for baseline lipid levels exist below which lipid-lowering therapy is not beneficial, and if so, what are the threshold values? 2) If a patient qualifies for lipid-lowering therapy, then how intensive should statin therapy be to reach a threshold at which the benefits still outweigh potential adverse effects? Neither question has thus far been resolved, but recently more data are becoming available, such as the analysis by Giraldez et al. (4) presented in this issue of the Journal, which may eventually lead to definitive answers.
The CARE (Cholesterol And Recurrent Events) trial was the first study to indicate a therapeutic target LDL-C level (5). The trial showed that treatment with pravastatin reduced the coronary event rate significantly in patients who had experienced a myocardial infarction and who had average serum lipid levels. It also showed that the event rate declined as LDL-C levels achieved during follow-up decreased, but no further decline was seen in patients having LDL-C levels below 125 mg/dl, suggesting a target LDL-C between about 125 mg/dl and 100 mg/dl. A similar trial, named the LIPID (Long-term Intervention with Pravastatin in Ischemic Disease) trial, included 9,014 patients with a broad range of initial cholesterol levels. No significant relation between risk reduction and baseline lipid levels was found, that is, risk reduction was essentially the same in all subgroups of lipids, albeit that risk reduction in the predefined subgroup with the lowest LDL-C (<135 mg/dl) was somewhat lower than in the other LDL-C subgroups (16% vs. 26% and 30%, respectively) (6). Several large primary and secondary prevention trials have followed that all yielded basically the same results.
In 2005 a meta-analysis of data from 90,056 participants in 14 randomized trials of statins was published that confirmed the findings of most of the separate trials, namely that statin treatment significantly reduces the 5-year incidence of all major coronary events (7). The meta-analysis also showed that the relative risk reduction was related to the absolute reduction in LDL-C but largely unrelated to the initial lipid profile or other presenting characteristics.
This raises the question: should treatment with statins target at achieving maximal reduction of serum lipids? In other words, does the hypothesis "the lower the better" hold true? Surprisingly, in spite of the enormous number of participants, in none of the trials included in the meta-analysis was this question addressed directly because in each trial placebo was compared with a standard, by current criteria mostly moderate, dose of statin. It was not until 10 years after 4S was published that the first reports comparing different doses of statins were published.
The TNT (Treating to New Targets) trial compared the effects of 10 and 80 mg atorvastatin in 10,001 patients with clinically evident coronary heart disease and LDL levels <130 mg/dl over a median follow-up period of 4.9 years (8). The incidence of major cardiovascular events was 10.9% in the patients receiving 10 mg atorvastatin and 8.7% in the 80-mg group. The relative reduction in risk was higher in patients with baseline LDL  125 mg/dl as compared with patients with lower LDL-C levels (34% vs. 7% reduction of hazard ratio). The highest risk reduction occurred in patients with chronic kidney disease (n = 3,107), and if these patients were excluded, the relative risk reduction decreased from 22% to 15% overall (9).
The IDEAL (Incremental Decrease in End Points through Aggressive Lipid Lowering) study compared the effects of atorvastatin 80 mg and simvastatin 20 mg and found no significant difference between the 2 treatment groups for the primary outcome, but there were fewer occurrences of secondary end points in the atorvastatin 80-mg group (10). A relationship with baseline lipid levels could not be assessed because the majority of patients received statin treatment before enrollment.
The PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22) trial compared the effects of 40 mg pravastatin and 80 mg atorvastatin in patients who had recently been hospitalized for an acute coronary syndrome and had a serum total cholesterol level  240 mg/dl (11). After an average follow-up period of 24 months, there was a 16% reduction in the hazard ratio in favor of atorvastatin 80 mg. The current study by Giraldez et al. (4) is an important substudy of the PROVE IT–TIMI 22 trial in which they investigate the significance of baseline LDL-C in predicting which patients will benefit most from intensive treatment compared with moderate treatment. For this substudy, only statin-naïve patients (n = 2,986, which is 72% of the total cohort) were selected, which allows a reliable interpretation of LDL-C baseline levels and significantly contributes to the value of the findings. The study shows convincingly and in more detail than previous studies that the additional benefit of intensive treatment with statins compared with moderate treatment declines with decreasing baseline LDL-C levels and that a benefit is no longer demonstrable in patients with LDL-C levels 66 mg/dl. This finding has important clinical consequences in that it strongly suggests that intensive, also termed aggressive, treatment with statins may have more deleterious than beneficial effects in patients with low baseline LDL-C (< 70 mg/dl). The question now is: does the current analysis conclusively answer the issue of if and when aggressive treatment is warranted? Unfortunately, in spite of the strong evidence presented by the investigators, the answer must still be: no. Similar to any other study, this analysis is subject to limitations, most of which are addressed by the investigators themselves in their article. Furthermore, the follow-up period was relatively short, and it is not certain that the results obtained in patients with acute coronary syndrome may be extrapolated without restrictions to all patients with coronary artery disease. The fact that 2 different statins with slightly different effects on the lipid profile and perhaps different pleiotropic properties were used makes it difficult to ascertain whether all differences between the 2 regimens may solely be explained by the intensity of lipid lowering. In view of the important clinical as well as economical consequences, this study should be followed by studies that specifically address remaining questions. However, it is unrealistic to expect that the treatment of individual patients can be fully optimized by using the same target lipid levels for all patients. There are marked variations concerning the vascular susceptibility for lipids, as is shown by the fact that individuals with low lipid levels and no other obvious risk factors may be affected by coronary atherosclerosis and vice versa. Progress has already been made in identifying genetic factors that are helpful in predicting the clinical effect of treatment with statins (12,13), but much research is still needed to establish a sound basis for individualized treatment. In the meantime, the observations of Giraldez et al. (4), which indicate that there probably is an actual target LDL-C to reach by lipid-lowering therapies of different intensities, is of great practical importance and merit serious consideration in the treatment of patients. We also concur with their conclusion that the analyses corroborate current guideline recommendations. Aggressive lipid-lowering therapy may be warranted in certain cases, but moderation is likely indicated if baseline lipid levels so suggest.
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Footnotes
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Dr. Jukema has received research grants from Bristol-Myers Squibb, Pfizer, and AstraZeneca.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. 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.[CrossRef][Web of Science][Medline]2. Scandinavian Simvastatin Survival Study Group Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S) Lancet 1995;345:1274-1275.[Web of Science][Medline] 3. Jukema JW, Bruschke AVG, van Boven AJ, et al. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels: the Regression Growth Evaluation Statin Study (REGRESS) Circulation 1995;91:2528-2540.[Abstract/Free Full Text] 4. Giraldez RR, Giugliano RP, Mohanavelu S, et al. Baseline low-density lipoprotein cholesterol is an important predictor of the benefit of intensive lipid-lowering therapy: a PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22) analysis J Am Coll Cardiol 2008;52:914-920.[Abstract/Free Full Text] 5. Sacks FM, Moyé LA, Davis BR, et al. Relationship between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the cholesterol and recurrent events trial Circulation 1998;97:1446-1452.[Abstract/Free Full Text] 6. 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.[CrossRef][Web of Science][Medline] 7. Cholesterol Treatment Trialists' (CTT) Collaborators Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins Lancet 2005;366:1267-1278.[CrossRef][Web of Science][Medline] 8. LaRosa JC, Grundy SM, Kastelein JJP, Kostis JB, Greten H. Safety and efficacy of atorvastatin-induced very low-density lipoprotein cholesterol levels in patients with coronary heart disease (a post hoc analysis of the treating to new targets [TNT] study) Am J Cardiol 2007;100:747-752.[CrossRef][Web of Science][Medline] 9. Shepherd J, Kastelein JJP, Bittner V, et al. Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease J Am Coll Cardiol 2008;51:1448-1454.[Abstract/Free Full Text] 10. Pedersen TR, Faergeman O, Kastelein JJP, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction. The IDEAL study: a randomized controlled trial. JAMA 2005;294:2437-2445.[Abstract/Free Full Text] 11. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes N Engl J Med 2004;350:1495-1504.[CrossRef][Web of Science][Medline] 12. Iakoubova OA, Tong CH, Rowland CM, et al. Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials: the CARE and WOSCOPS trials J Am Coll Cardiol 2008;51:435-443.[Abstract/Free Full Text] 13. Kuivenhoven JA, Jukema JW, Zwinderman AH, et al. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group. N Engl J Med 1998;338:86-93.[CrossRef][Web of Science][Medline]
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