Rodney A. Hayward, MD; Timothy P. Hofer, MD, MSc; Sandeep Vijan, MD, MSc
Acknowledgments: The authors thank Robert Chang, MD, for assistance with the literature review and David Kent, MD, MSc, for reviewing an earlier draft of this manuscript.
Grant Support: By the VA Health Services Research and Development Service's Quality Enhancement Research Initiative (QUERI DIB 98-001) and by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (P60 DK-20572).
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Rodney A. Hayward, MD, VA Center for Practice Management and Outcomes Research, P.O. Box 130170, Ann Arbor, MI 48113-0170; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Hayward, Hofer, and Vijan: VA Center for Practice Management and Outcomes Research, P.O. Box 130170, Ann Arbor, MI 48113-0170.
Recent national recommendations have proposed that physicians should titrate lipid therapy to achieve low-density lipoprotein (LDL) cholesterol levels less than 1.81 mmol/L (<70 mg/dL) for patients at very high cardiovascular risk and less than 2.59 mmol/L (<100 mg/dL) for patients at high cardiovascular risk. To examine the clinical evidence for these recommendations, the authors sought to review all controlled trials, cohort studies, and case–control studies that examined the independent relationship between LDL cholesterol and major cardiovascular outcomes in patients with LDL cholesterol levels less than 3.36 mmol/L (<130 mg/dL).
For those with LDL cholesterol levels less than 3.36 mmol/L (<130 mg/dL), the authors found no clinical trial subgroup analyses or valid cohort or case–control analyses suggesting that the degree to which LDL cholesterol responds to a statin independently predicts the degree of cardiovascular risk reduction. Published studies had avoidable limitations, such as a reliance on ecological (aggregate) analyses, use of analyses that ignore statins' other proposed mechanisms of action, and failure to account for known confounders (especially healthy volunteer effects). Clear, compelling evidence supports near-universal empirical statin therapy in patients at high cardiovascular risk (regardless of their natural LDL cholesterol values), but current clinical evidence does not demonstrate that titrating lipid therapy to achieve proposed low LDL cholesterol levels is beneficial or safe.
Appendix Table 1. Known Lipid-Independent Effects of Statins*
Recent clinical trials nonetheless have documented … that for every 1% reduction in LDL-C [low-density lipoprotein cholesterol] levels, relative risk for major CHD [coronary heart disease] events is reduced by approximately 1%. HPS [Heart Protection Study] data suggest that this relationship holds for LDL-C levels even below 100 mg/dL [2.59 mmol/L].
The diminishing returns of the hypothesized log-linear relationship.
The log-linear low-density lipoprotein (LDL) hypothesis suggests that relative risk reduction is constant but that there are diminishing absolute benefits. For example, reducing LDL cholesterol level by 0.78 mmol/L (30 mg/dL) is associated with a 24% relative risk reduction in all instances, but the amount of absolute benefit is much greater when LDL cholesterol level is reduced from 5.69 mmol/L (220 mg/dL) to 4.91 mmol/L (190 mg/dL) than from 2.59 mmol/L (100 mg/dL) to 1.81 mmol/L (70 mg/dL). Absolute benefit is also greater when higher-risk patients (top) compared with lower-risk patients (bottom) are being treated. The top panel predicts reduction in cardiovascular (CV) risk for a 65-year-old white woman with type 2 diabetes mellitus and systolic blood pressure of 145 mm Hg, high-density lipoprotein cholesterol level of 0.54 mmol/L (21 mg/dL), triglyceride level of 3.39 mmol/L (300 mg/dL),
and hemoglobin A1c level of 7%. The bottom panel predicts reduction in CV risk for a 60-year-old white woman with type 2 diabetes mellitus and systolic blood pressure of 125 mm Hg, high-density lipoprotein cholesterol level of 1.42 mmol/L (55 mg/dL), triglyceride level of 1.13 mmol/L (100 mg/dL), and hemoglobin A1c level of 7%. To convert LDL cholesterol values to mmol/L, multiply by 0.02586.
Results for the Heart Protection Study.
No statistically or clinically significant difference was seen in relative benefit of statin therapy by low-density lipoprotein (LDL) cholesterol level at baseline or prerandomization LDL response. To convert LDL cholesterol values to mg/dL, divide by 0.02586.
A hypothetical example of the limitations of dose-titration studies and the importance of controlling for treatment exposure when examining the benefits of reaching treatment targets.
*In this hypothetical example, megastatin reduces both cardiovascular (CV) risk and levels of low-density lipoprotein (LDL) cholesterol, but reduction of the latter is not related to megastatin's benefits. The maximum relative risk reduction (RRR) for CV events is achieved with 40 mg of megastatin, and maximum reduction in LDL cholesterol levels is achieved with 80 mg of megastatin. All results can be calculated from the assumptions in section A or can be obtained from the first author by request. † The adjusted observational (cohort) analysis controls for dose of megastatin and finds that reaching the LDL cholesterol goal is not an independent predictor of degree of CV risk reduction. To convert LDL cholesterol values to mmol/L, multiply by 0.02586.
Appendix Table 2. Key Factors That Influence whether a Participant Reaches a Treatment Target in a Clinical Trial
Summary of lipid studies.
Top. Event rate assuming a single association between low-density lipoprotein (LDL) cholesterol and outcome. Bottom. The LDL–outcome associations found within each study. 4S= Scandinavian Simvastatin Survival Study; CARE= Cholesterol and Recurrent Events Study; HPS= Heart Protection Study; LIPID= Long-Term Intervention with Pravastatin in Ischaemic Disease Study; TNT= Treating to New Targets Study. To convert LDL cholesterol values to mmol/L, multiply by 0.02586.
Diagram of a cohort study assessing whether lipid lowering is an independent predictor for the degree of benefit derived from statin therapy.
Experiments (top) generally assess interventions but can rarely directly assess their mechanisms of action. Cohort analyses (bottom) can provide evidence for or against proposed mechanisms of action by examining whether a marker for the proposed mechanism of action (i.e., low-density lipoprotein [LDL] cholesterol level) is an independent predictor of lower risk after controlling for treatment exposure, adherence, and other known risk factors for the outcome being studied. CV= cardiovascular.
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Department of Geriatrics, Krankenhaus Lindenbrunn, Lindenbrunn 1, Coppenbruegge 31863, Germany
October 10, 2006
Statins and quality of research
TO THE EDITOR: The review of Hayward et al. (1) is nice to read and lead "“ I hope so "“ the view of clinicians and researchers to a lot of problems in now published research. But also this paper neglected two key problems. First, the limited representation of study populations "“ usual white men in the sixties "“ and the missing of representative proportions of women, elderly and ethnicity minorities (2,3). This, together with the almost "“ sometimes overwhelming "“ generalizing conclusions and recommendations without recognizing this limitations and the missing critical discussion about the limitations of a study and the results led to lots of doubt. Second, the point of the role of study sponsor and the interaction of the physician-industrial relationship (4,5) is usual not enough recognized, also in the accompanying editorials (6,7). For both points the now published secondary analysis of the Treatment to New Target trial is a good example (8,9). Overall, evidence-based medicine (EBM) stands at the crossroads. If EBM will be recognised as a serious and truthfull tool in future its necessary to take account for a better quality of studies and publishing.
1. Hayward RA, Hofer TP, Vijan S. Narrative review: Lack of evidence for recommended low-density lipoprotein treatment targets. Ann Intern Med 2006;145:520-30.
2. Birch LM "“ Unanswered questions: The use of statins in older people to prevent cardiovascular event effects of statins on risk of coronary disease: A meta-analysis of randomized controlled trials. J Am Ger Soc 2002;50:391-93.
3. Bartlett C, Davey P, Dieppe P, et al. "“ Women, older persons, and ethnic minorities: factors associated with their inclusion in randomised trials of statin 1990 to 2001. Heart 2003;89:327-28.
4. Bhandari M, Busse JW, Jackowski D, et al. Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials. CMAJ 2004;170:477-80.
5. Lexchin J, Bero LA, Djulbegovic B, et al. Pharmaceutical industry sponsorship and research outcome and quality: a systematic review. BMJ 2003;326:1167-70.
6. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with Atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35.
7. Pitt B. Low-density lipoprotein cholesterol in patients with stable coronary heart disease "“ is it time to shift our goals? N Engl J Med 2005;352:1483-4.
8. Deedwania P, Barter P, Carmena R, et al. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study. Lancet 2006;368:919-28.
9. Gogol M. TNT study. Lancet 2006; http://www.thelancet.com/journals/lancet/article/PIIS0140673606692921/comments?action=view&totalComments=1
October 15, 2006
Lowest possible statin dose better than a low LDL cholesterol
Hayward and coworkers rightly point to the extreme weakness of ecological comparisons between statin trials (1). Their concern is justified by the lack of dose-response between degree of cholesterol lowering and clinical (2,3) or angiographic (4) outcome found in the trials where dose-response was calculated using individual data. That those with the worst prerandomization LDL response received the same benefit as those with the best one strongly indicate that most if not all benefits from the statins are mediated through their pleiotropic effects, not through cholesterol lowering. But even if cholesterol lowering is unimportant we should have expected dose-response because both cholesterol lowering and the pleiotropic effects are due to the same drug. The lack of dose-response suggests that high LDL cholesterol may have a protective effect and thus counteracts the expected (but false) dose-response in accordance with the findings. Indeed, numerous observations and experiments have shown that cholesterol, or rather the LDL molecule itself, protects against infections, probably by binding and inactivating bacterial endotoxin (5). In accordance, many cohort studies have shown that high cholesterol is not a risk factor for old people and that old people with high cholesterol live longer than old people with low cholesterol (5). As statin treatment is aimed for the rest of the patientÂ´s life it would therefore be more relevant to find the lowest effective statin dose rather than to titrate to an arbitrarily determined unnecessarily low LDL level.Â
1.Â Â Â Â Â Hayward RA, Hofer TP,Â Vijan S.Narrative Review: Lack of Evidence for Recommended Low-Density Lipoprotein Treatment Targets: A Solvable Problem. Ann Intern Med. 2006; 145: 520-30 [Abstract] [Full text] [PDF]
2.Â Â Â Â Â 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; 97:1446"“52.[Abstract/Free FullÂ Text]
3.Â Â Â Â Â Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D et al. Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001; 285:1711"“18. [Abstract]
4.Â Â Â Â Â Ravnskov U. Is atherosclerosis caused by high cholesterol? QJM. 2002; 95: 397-403 [Abstract/FreeFull Text] [PDF]
5.Â Â Â Â Â Ravnskov U. High cholesterol may protect against infections and atherosclerosis. QJM. 2003;96:927-34. [Abstract/Free Full Text] [PDF]
Paul J Rosch
New York Medical College, American Institute of Stress
October 17, 2006
Why Current Guidelines For Statin Therapy Should Be Revised Immediately
As indicated, there is no evidence that increasing statin dosage to achieve arbitrarily selected low LDL levels is either salubrious or safe. (1) The observation that any cardioprotective rewards are similar regardless of LDL cholesterol concentrations (2) and the rapidity of clinical improvement with statins in acute coronary syndromes (3) suggests that any such benefits are not due to lipid lowering but reduction of inflammation or other pleiotrophic effects. Support comes from one study showing that the incidence of recurrent myocardial infarction or coronary mortality was lower for patients in whom statin therapy resulted in CRP levels < 2 mg/l regardless of the level of LDL cholesterol achieved. (4) The proposal that the lower the LDL the better as well as current guidelines for statin therapy that mandate lowering LDL to a goal that is often difficult to attain will only result in higher and higher doses that provide no benefit but will significantly increase serious side effects. As with aspirin, the statin dosage required to reduce inflammation may be much lower than that commonly used for other indications. In view of the millions of healthy people taking statins because of an elevated cholesterol or LDL, current treatment guidelines and objectives should be revised as soon as possible.
1. Hayward RA, Hofer TP, Vijan S. Narrative Review: Lack of Evidence for Recommended Low-Density Lipoprotein Treatment Targets: A Solvable Problem. Ann Intern Med. 2006; 145: 520-30.
2. 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; 97:1446"“52.
3. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D et al. Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001; 285:1711"“18.
4. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005; 352:20-8.
Pontificia Universidad CatÃ³lica, Chile
October 19, 2006
Positive evidence for further lowering of LDL cholesterol?
We read with much interest the review article of Hayward et al. on the currently available evidence for recommending low LDL cholesterol treatment goals (1). We agree with the authors that there are no well-designed clinical studies demonstrating unequivocally that titration of cholesterol-lowering therapy to achieve lower LDL cholesterol targets is indeed the leading beneficial mechanism of statins on atherosclerotic cardiovascular disease. As an important caveat against the recommendation that "lower LDL cholesterol is better", authors propose that previous studies have not considered alternative hypothesis as confounding factors, including treatment exposure (what type and and dose of statin was used in low-dose vs. high-dose statin comparisons) (2).
However, a post-hoc analysis of the PROVE-IT trial (2,3) somewhat addressed this latter criticism. Wiviott et al. examined the clinical benefit and safety of patients obtaining very low levels of cholesterol within the intensive statin treatment group (3). This approach avoided potential confounding effects of the interaction between LDL cholesterol levels achieved and the specific statin and dosing to which patients were randomized. When the primary end point of the trial (death, myocardial infarction, stroke, revascularization and unstable angina requiring hospitalization) was examined, there was a trend to better clinical outcomes in the groups achieving lower LDL levels, even after adjustments for age, gender, baseline calculated LDL cholesterol, diabetes, and prior myocardial infarction. Even though the findings of this postrandomization analysis were based on observational cohort data, they are consistent with the hypothesis that reaching lower LDL cholesterol targets can improve clinical events independent of statin type and dosing.
We hope that further properly designed and conducted studies will more unambiguously address this clinically and scientifically relevant issue.
Attilio Rigotti, MD, and Antonio Arteaga, MD, Escuela de Medicina, Pontificia Universidad CatÃ³lica, Santiago, Chile,
REFERENCES 1. Hayward RA, Hofer TP, Vijan S. Lack of evidence for recommended low- density lipoprotein treatment targets: a solvable problem. Ann Intern Med. 2006; 145: 520-530
2. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004; 350:1495-1504
3. Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E; 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
Kenneth A Hoekstra
Western States Chiropractic College
November 6, 2006
The other benefits of statins
The recent review article by Hayward et al. highlight the importance of continued statin therapy in patients at high risk for cardiovascular disease (1). To further emphasize the importance of statin therapy outside of lowering serum LDL levels in hypercholesterolemic patients, Minami et al. (2) have shown that elevated cholesterol levels themselves are involved in the regulation of blood pressure, and following a course ofcholesterol-lowering therapy lipid levels normalized and patients were normotensive (3). Furthermore, support for 'aggressive' statin therapy lies well beyond lower LDL levels as heart failure events are reported to be lower (4), and psychological stress levels may be decreased (3, 5).
1.Hayward RA, Hofer TP, Vijan S.Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem. Ann Intern Med. 2006 Oct 3;145(7):520-30.
2. Minami M, Atarashi K, Ishiyama A, Hirata Y, Goto A, Omata M. Pressor hyperreactivity to mental and hand-grip stresses in patients with hypercholesterolemia. J Hypertens. 1999 Feb;17(2):185-92.
3. Minami M, Atarashi K, Ishiyama A, Hirata Y, Goto A, Omata M. Effects of cholesterol-lowering therapy on pressor hyperreactivity to stress in hypercholesterolemic patients.Hypertens Res. 2003 Apr;26(4):273- 80.
4. Go AS, Lee WY, Yang J, Lo JC, Gurwitz JH. Statin therapy and risks for death and hospitalization in chronic heart failure. JAMA. 2006 Nov 1;296(17):2105-11.
5. Sebregts EH, Falger PR, Bar FW, Kester AD, Appels A. Cholesterol changes in coronary patients after a short behavior modification program. Int J Behav Med. 2003;10(4):315-30.
Geoffrey A. Modest
Boston University School of Medicine
LDL Treatment Goals
Although the Narrative Review on LDL Treatment Targets (1) raises several important issues, one glaring ommision in the relevant studies is that HDL values are not incorporated into the model. Many clinical studies have found that the relationship between LDL and HDL is more predictive of cardiac events than LDL alone (2). There are impressive data that HDL is cardioprotective through several mechanisms, including its role in reverse transport of LDL as well as its role through transporting antioxidants to LDL, making the LDL less susceptible to oxidation and presumably less atherogenic. In addition HDL decreases blood viscosity, improves endothelial dysfunction (it is nitric oxide-promoting), stabilizes prostacyclin, inhibits platelets, inhibits adhesion molecule expression, and blocks matrix metalloproteinase expression (3). It might well be that a patient with coronary artery disease whose LDL is brought down to 100 mg/dl but has an HDL of 55 mg/dl might have a lower likelihood of another cardiac event than one with an LDL of less than 70 mg/dl but an HDL of 35 mg/dl. This information is extremely important clinically and may dictate a more rational use of lipid-lowering agents. Some data may be gleaned from further analysis of previous studies which have reported LDL goals only and should be evaluated prospectively in future studies.
1.Hayward RA, Hofer TP, Vigan S. Narrative review: Lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem. Ann Intern Med 2006; 145: 520-30.
2.Kinosian B, Glick H, Garland G: Cholesterol and coronary heart disease: predicting risks by levels and ratios. Ann Intern Med 1994; 121: 641-647.
3.Brewer HB, Jr. Increasing HDL cholesterol levels. N Engl J Med 2004; 350: 1491-4.
Rodney A Hayward
VA & University of Michigan
December 18, 2006
Response to letters
Response to Letters,
We agree with Dr. Modest that there is considerable evidence that HDL is an important risk factor in predicting cardiovascular (CV) risk, but disagree that is was a "glaring omission" in our paper (1).1 Space constraints prevented us from discussing details of each CV risk factor, but our paper highlighted the critical importance of overall CV risk, mentions the complexities of risk factor interactions and included references that discuss HDL effects in detail (2-3) However, although we agree that HDL is an important independent risk factor, we could find no clinical evidence meeting our inclusion criteria (valid epidemiological evaluations in patients with LDL < 130mg/dl) assessing whether HDL is any more important than any other cardiovascular risk factor in terms of predicting the benefits from statin therapy. Future work should examine whether HDL is important simply because it is one of many risk factors or whether there are HDL- specific interaction effects.
We disagree with Dr. RavnskovÃ†s assessment when he suggests that there is substantial clinical evidence suggesting that there are harmful effects related to achieving very low LDLÃ†s. As we stated in our paper, "Our point is not that there is strong evidence against the current recommendations; it is that there is no valid clinical evidence to suggest that using treatments other than statins to pursue proposed LDL cholesterol goals is either safe or effective." We hope that our study will stimulate those with access to the clinical trial data to more rigorously assess these questions using the methodological approaches outlined in our paper.
Rodney A. Hayward, MD Director, HSR&D Center of Excellence, VA Ann Arbor Healthcare System Professor of Medicine and Public Health, University of Michigan email@example.com
1. Hayward RA, Hofer TP, Vijan S. Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem. Ann Intern Med. 2006 Oct 3;1945(7):520-30.
2. Byung-Ho Nam, PhD, William B. Kannel, MD, Ralph B. DÃ†Agostino, PhD. Search for an Optimal Atherogenic Lipid Risk Profile: From the Framingham Study. Am J Cardiol 2006; 97:372-375.
3. Olsson AB, Schwartz GG, Szarek M, Sasiela WJ, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A. High-density lipoprotein, but not low- density lipoprotein cholesterol levels influence short-term prognosis after acute coronary syndrome: results from the MIRACL trial. Eur Heart J. 2005 May: 26(9):853-5.
Hayward RA, Hofer TP, Vijan S. Narrative Review: Lack of Evidence for Recommended Low-Density Lipoprotein Treatment Targets: A Solvable Problem. Ann Intern Med. 2006;145:520-530. doi: 10.7326/0003-4819-145-7-200610030-00010
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