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How Low Can You Go . . . Safely?

Stephen D. Wiviott, MD*

A 55-year-old man presents at your hospital with a non–ST-segment elevation myocardial infarction (MI). His presenting low-density lipoprotein cholesterol (LDL-C) level is 104 mg/dL. He undergoes early cardiac catheterization with single-vessel angioplasty. His condition is stabilized and he is asymptomatic. You practice evidence-based medicine, and before this patient’s discharge you begin treatment with the highest dose of a potent statin in the hope of achieving a post-treatment LDL-C level of 70 mg/dL, the optional goal for high-risk patients set by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III).¹ The patient returns for follow up, and his lipid levels are measured. The laboratory reports that his LDL-C level is 45 mg/dL (outside the normal range for your laboratory). What do you do now?

The benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been observed in major primary^2-4 and secondary^3-7 prevention trials across a wide range of cholesterol levels in stable patients. Recent data have extended these observations to the early period following acute coronary syndromes (ACS).^8-10 The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) trial showed that intensive therapy (atorvastatin 80 mg/d), which achieved a median LDL-C level of 62 mg/dL, was superior to standard therapy (pravastatin 40 mg/d), which achieved a median LDL-C level of 95 mg/dL, in reducing clinical events after ACS.¹⁰ It is these data, in part, that have resulted in recommendations from ATP III for lower cholesterol targets, including an optional LDL-C goal of less than 70 mg/dL for patients at high or very high risk,¹ such as the one described above.

Intensive statin therapy may result in cholesterol levels well below these target levels,^1,11,12 raising concern about the safety of very low cholesterol levels. These concerns are not entirely unfounded, as cholesterol plays important roles in the composition of cell membranes, and especially in neuronal and optic development. In early animal studies of statins, dogs treated with lovastatin doses 180 times the maximum human doses developed hemorrhagic encephalopathy and degeneration of the optic nerve.¹³ Some epidemiologic studies have suggested a relationship between low cholesterol levels and total mortality or intracranial bleeding.^14-16 Furthermore, several studies have linked low levels of cholesterol to cancer, and some have suggested that there may be a causal relationship between low cholesterol levels and the development of cancer.^17,18 However, these studies have not defined causality, and they could indicate that low cholesterol levels can be the result of, or marker for, systemic illness, rather than its cause.¹⁹ Nonetheless, concern remains that pharmacologically lowering cholesterol well beyond current targets may be harmful.

The most common severe side effects of statin therapy, muscle and liver toxicity, appear to be agent- and dose-related, with higher doses of statins resulting in higher side effect rates.²⁰ Though increasing doses of statins result in lower LDL-C levels, no definitive relationship between achieved LDL-C levels and side effects has been reported. To evaluate this question directly, we analyzed the relationship between safety outcomes and achieved LDL-C levels of patients receiving intensive statin therapy with atorvastatin 80 mg/d in the PROVE IT–TIMI 22 trial. These results were published recently in the Journal of the American College of Cardiology.²¹

PROVE IT–TIMI 22 was a randomized controlled trial of intensive versus moderate cholesterol lowering with statins in patients whose condition was stabilized after an ACS.²² Patients were randomized to intensive therapy (atorvastatin 80 mg/d) or standard therapy (pravastatin 40 mg/d) and followed up for a mean of 2 years. For the analysis, we divided the subjects in the intensive therapy arm into 4 subgroups according to LDL-C levels achieved at 4 months (81-100, 61-80, 41-60, £40 mg/dL), a time at which they should have reached a steady state with respect to drug effect and the resolution of the presenting ACS event. Subjects with achieved LDL-C levels above 100 mg/dL were excluded from the analysis, as there is consensus that lowering LDL-C beyond this point is still warranted in high-risk patients.

Achieved Levels: How Low do They Go and Who Goes Lowest?
Among nearly 2000 subjects with 4 month LDL-C measurements, 10% had LDL-C levels of >100 mg/dL; LDL-C levels were 81-100 mg/dL in 14%, 61-80 mg/dL in 31%, 41-60 mg/dl in 34%, and £40 mg/dL in 11%.

Patients who achieved lower LDL-C levels were older, more likely to be male and to have type 2 diabetes mellitus, and less likely to have had a prior MI or prior coronary artery bypass graft surgery, to be a cigarette smoker, or to have taken a statin before study initiation. Unsurprisingly, those who achieved lower LDL-C levels had lower baseline total cholesterol and LDL-C levels.

Muscle side effects were infrequent, with no observed episodes of rhabdomyolysis, and no apparent relationship with achieved LDL-C levels (Table). Similar results were observed for liver-related side effects, with no relationship between achieved LDL-C levels and the frequency of either liver enzyme elevations or discontinuation because of abnormal liver enzyme levels (Figure1). Similarly, no significant association was observed between low achieved LDL-C levels and the frequency of adverse ophthalmologic events, suicide, trauma, all strokes, or intracranial hemorrhage. Patients who failed to achieve an LDL-C level below 100 mg/dL at 4 months were more likely to have discontinued study drug, including discontinuation because of adverse events. Not surprisingly, more patients who had adverse events and were not taking study drug did not achieve LDL-C goals. Beyond 4 months, however, the group of patients who at 4 months had LDL-C levels above 100 mg/dL had similar safety features compared with those who achieved lower LDL-C levels—that is, there was no excess hazard for higher achieved LDL-C levels.

Efficacy Results: Possible Benefit to Achieving Very Low LDL-C Levels?
When the primary end point of the PROVE IT–TIMI 22 trial (composite of death from any cause, MI, unstable angina requiring rehospitalization, revascularization, and stroke) was examined, there was a trend toward the association of lower achieved LDL-C levels with lower event rates (81-100 mg/dL, 26 %; 61- 80 mg/dL, 22 %; 41-60 mg/dL, 20 %; and £40 mg/dL, 20 %; P = 0.1 for trend), with the lowest rates in the 41- to 60-mg/dl group and the <40-mg/dl group. In multivariable analysis accounting for baseline differences, the 2 lowest LDL-C groups, 41 to 60 mg/dL (hazard ratio [HR] = 0.67, 95% confidence interval [CI] 0.50-0.92) and £40 mg/dL (HR = 0.61, 95% CI 0.40-0.91) showed significantly lower end point rates than those achieving and LDL-C 81-100 mg/dL (Figure 2).

Though the efficacy data are intriguing, the use of an achieved parameter to stratify risk is inherently problematic. Patients were not randomized to be treated to specific varying LDL-C goals, the truest test of the safety and efficacy associated with very low LDL-C levels after treatment. Although multivariable analysis was performed, there may be differences among patients who achieved very low LDL-C levels that were not controlled for in the analysis. Despite these limitations, these results support a “lower is better” hypothesis but go beyond even what was seen in the overall PROVE IT–TIMI 22 trial.¹⁰ They suggest the possibility that further LDL-C lowering beyond the new guideline “optimal” goal of lower than 70 mg/dL ¹ may translate into additional clinical benefit. These data are consistent with previous trial results and epidemiologic data suggesting that there may be a direct relationship between achieved LDL-C levels and protection from cardiovascular events, and that benefit may extend to LDL-C levels below those achieved in recent trials.^1,23 Furthermore, cholesterol levels are in the range of 30 to 70 mg/dL in healthy neonates undergoing rapid development and 50 to 75 mg/dL in hunter/gatherer populations without evidence of atherosclerosis. Kindred studies of octogenarians with familial hypobetalipoproteinemia, a genetic condition in which heterozygotes have LDL-C levels of 20 to 40 mg/dL, have shown not only that their low cholesterol levels are “anti-risk” factors with regard to atherosclerosis, but also that they have normal endocrine function.²⁴ These groups do not appear to suffer from an increased incidence of ophthalmic complications, intracranial bleeding, stroke, and suicide, adding collateral support to the idea that very low cholesterol levels may be safe and desirable.²⁰

Implications
The results of recent trials of lipid-lowering treatment for patients with ACS suggest a paradigm shift in the management of lipids in high-risk patients.^1,25 An appropriate strategy for high-risk patients is to commence therapy with a high dose of a potent statin, monitor for side effects, and reduce the dose when adverse effects are seen, rather than follow the standard practice of starting at a low statin dose and titrating up to achieve a specific goal.

In this analysis, among patients treated with intensive lipid-lowering therapy there did not appear to be a relationship between achieved LDL-C levels and the likelihood of adverse events. These findings are consistent with previous pooled data from multiple trials showing no excess risk of adverse events for patients achieving LDL-C levels below 80 mg/dL with a range of doses of atorvastatin,²⁶ but extends the range down to below 40 mg/dL.

Statins have been extensively studied, and their side-effect profile is well characterized. However, specific statins and the statins as a class have not been without serious side effects, including rhabdomyolysis and renal failure.^27,28 Previous data suggest that the incidence of typical side effects associated with statins, such as myopathy and elevation of liver enzymes, is related to the specific statin and its dose, as well as concomitant medications and illnesses.^20,29

References

1. Grundy SM, Cleeman JI, Merz CN, et al; for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227-239.

2. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation. 1998;97:1440-1445.

3. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623-1630.

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

5. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.

6. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349-1357.

7. Larosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;

8. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285:1711-1718.

9. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004;292:1307-1316.

10. 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.

11. Grundy SM. United States Cholesterol Guidelines 2001: expanded scope of intensive low-density lipoprotein-lowering therapy. Am J Cardiol. 2001;88:23J-27J.

12. Grundy SM. Approach to lipoprotein management in 2001 National Cholesterol Guidelines. Am J Cardiol. 2002;90:11i-21i.

13. Berry PH, Macdonald JS, Alberts AW, et al. Brain and optic nerve pathology in hypocholesterolemic dogs treated with a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase Am J Pathol. 1988;132:427-443.

14. Neaton JD, Blackburn H, Jacobs D, et al. Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Multiple Risk Factor Intervention Trial Research Group. Arch Intern Med. 1992;152:1490-1500.

15. Iso H, Naito Y, Kitamura A, et al. Serum total cholesterol and mortality in a Japanese population. J Clin Epidemiol. 1994;47:961-969.

16. Stemmermann GN, Chyou PH, Kagan A, Nomura AM, Yano K. Serum cholesterol and mortality among Japanese-American men. The Honolulu (Hawaii) Heart Program. Arch Intern Med. 1991;151:969-972.

17. McMichael AJ, Jensen OM, Parkin DM, Zaridze DG. Dietary and endogenous cholesterol and human cancer. Epidemiol Rev. 1984;6:192-216.

18. Hiatt RA, Fireman BH. Serum cholesterol and the incidence of cancer in a large cohort. J Chronic Dis. 1986;39:861-870.

19. Feinleib M. Review of the epidemiological evidence for a possible relationship between hypocholesterolemia and cancer. Cancer Res. 1983;43:2503s-2507s.

20. Pasternak RC, Smith SC, Jr., Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins. Stroke. 2002;33:2337-2341.

21. Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E; for the PROVE IT-TIMI 22 investigators. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 2005:46:1411-1416.

22. Cannon CP, McCabe CH, Belder R, Breen J, Braunwald E. Design of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT)-TIMI 22 trial. Am J Cardiol. 2002;89:860-861.

23. O'Keefe JH, Jr, Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol. 2004;43:2142-2146.

24. Glueck CJ, Gartside PS, Steiner PM, et al. Hyperalpha- and hypobeta-lipoproteinemia in octogenarian kindreds. Atherosclerosis. 1977;27:387-406.

25. Topol EJ. Intensive statin therapy - a sea change in cardiovascular prevention. N Engl J Med. 2004;350:1562-1564.

26. Bakker-Arkema RG, Nawrocki JW, Black DM. Safety profile of atorvastatin-treated patients with low LDL-cholesterol levels. Atherosclerosis. 2000;149:123-129.

27. Chang JT, Staffa JA, Parks M, Green L. Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy. Pharmacoepidemiol Drug Saf. 2004;13:417-426.

28. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346:539-540.

29. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. 2003;289:1681-1690.

30. Baigent C, Keach A, Kearney PM, et al; 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.

Table: Rates of muscle side effects (% of patients) by achieved LDL-C level (mg/dL)

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**P for trend.

LDL-C = low-density lipoprotein cholesterol; CK = creatine kinase; ULN = upper limit of the normal range; MI = myocardial infarction. Adapted from Wiviott SD, et al. J Am Coll Cardiol. 2005;46:1411-1416.²¹

Figure 1: Event rates (KM) of liver side effects by achieved LDL-C level (mg/dL)

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LDL-C = low-density lipoprotein cholesterol; KM = Kaplan-Meier; ALT = alanine aminotransferase; ULN = upper limit of the normal range; D/C = discontinuation; LE = liver enzyme. Adapted from Wiviott SD, et al. J Am Coll Cardiol. 2005;46:1411-1416.²¹

Figure 2: Multivariable-adjusted* hazard ratio (95% CI) of primary study end point^† by achieved LDL-C level (mg/dL)

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**Age, gender, DM, prior MI, baseline LDL-C. ^†Primary end point is a composite of death from any cause, MI, unstable angina requiring hospitalization, revascularization, and stroke. CI = confidence interval; LDL-C = low-density lipoprotein cholesterol; DM = diabetes mellitus; MI = myocardial infarction. Adapted from Wiviott SD, et al. J Am Coll Cardiol. 2005;46:1411-1416.²¹

Stephen D. Wiviott, MD*

Instructor of Medicine, Harvard Medical School

Investigator, TIMI Study Group

Associate Physician

Division of Cardiology

Brigham and Women’s Hospital

Boston, Massachusetts

Biographical Sketch

Stephen D. Wiviott, MD is a graduate of University of Pennsylvania (Mathematics, Magna Cum Laude) in 1990 and Harvard Medical School (Honors) in 1996. He served as a Medical House Officer and Chief Medical Resident at Brigham and Women’s Hospital. Following his medical residency training, he served as a Cardiology Fellow at Johns Hopkins Hospital and as a Cardiovascular Research Fellow with the TIMI Study Group of the Cardiovascular division of Brigham and Women’s Hospital. Following completion of his training he has joined the Cardiovascular Division of Brigham and Women’s Hospital and serves as an Instructor in Medicine at Harvard Medical School, and an investigator with the TIMI Study Group.

As a member of the prestigious TIMI study group he has played important roles in the planning, implementation and interpretation of multicenter national and international trials including the Aggrastat to Zocor (A to Z) trial and PROVE IT – TIMI 22. Dr. Wiviott is an author of multiple peer reviewed publications in major medical and cardiovascular journals. He has delivered local, national and international lectures in the field of acute coronary syndromes and cholesterol lowering. Areas of interest include acute coronary syndromes, cholesterol lowering therapy, and platelet biology.

Faculty Disclosure Statement

Dr. Wiviott has disclosed that he has received grants and research support from Bristol-Myers Squibb Company and Merck & Co., Inc.