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There is an apparent divergence between guidelines and the use oflipid-lowering statins in clinical practice. This is despite the 2001 NationalCholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III)recommendations for lipid-lowering medications in addition to therapeuticlifestyle changes for the management of patients with high bloodcholesterol.
In 2002, U.S. physicians prescribed statin therapy to just 19% of patientswith the highest cardiovascular disease (CVD) risk, and to a mere 11% ofpatients with multiple riskfactors.1
More recently, the 2004 update of NCEP ATPIII2 and the 2005American Diabetes Association (ADA) Clinical PracticeRecommendations3suggest statin therapy in addition to therapeutic lifestyle changes forpatients at moderately high to very high risk of CVD events. And researchcontinues to tout the benefits of statins for reducing CVD events, especiallyin patients with diabetes, metabolic syndrome, or recent myocardialinfarction.4–7
A recent prospective meta-analysis of data from >90,000 individualsparticipating in 14 randomized statin trials, published online in TheLancet, suggests statin therapy incidence of major coronary events andstroke by about 20% per mmol/l reduction in LDL cholesterol, irrespective ofindividual characteristics such as age, sex, or pre-existing disease, orpretreatment cholesterol concentrations. This LDL reduction equates to 48fewer major vascular events per 1,000 study participants with pre-existingcoronary heart disease (CHD) at baseline and 25 fewer major events per 1,000participants with no pre-existingCHD.8
UNDERSTANDING RISK
The difference between statin therapy recommendations and their apparentunder-prescribing in clinical practice may be due to the assessment of risk.Research studies often assess relative risk between exposed andnonexposed study groups. But clinicians often look for the absoluterisk reduction their patients may achieve from a specific treatment.
"The relative risk reduction afforded by a statin is in therange of 30–40%, and that seems to be pretty constant across allstudies," says Theodore G. Ganiats, MD, of the University of California,San Diego, and NCEP coordinating committee member for the American Academy ofFamily Physicians.
For high-risk patients, a 30–40% risk reduction is significant,Ganiats says, but for lower-risk patients, the absolute riskreduction benefits from statin therapy are less. The ATP III update statesthat those with low LDL but other coronary risk factors (see risk chart) havethe same absolute risk as patients with high LDL and attain the sameabsolute benefit for a given mg/dl lowering of LDL. But those withlow LDL and little or no absolute coronary risk attain lessabsolute benefit from lipid-loweringtherapy.2
Editorials accompanying often-cited statin research also call forrisk-benefit statin therapy assessments. In a 2003 commentary accompanying theASCOT-LLA study in The Lancet, Lars H. Lindholm, MD, of UmeåUniversity Hospital in Umeå, Sweden, and Ola Samuelsson, MD, ofSahlgrenska University Hospital/Östra in Göteborg, Sweden, suggestthat guideline committees "balance the limited absolute benefits againstthe treatment cost of lipidlowering."9
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The Collaborative Atorvastatin Diabetes Study(CARDS)5 suggestspeople with type 2 diabetes could benefit from statin therapy to reduce CVDrisk, even when they do not have high cholesterol (DOC News, July2004). Yet in the accompanying commentary in The Lancet, AbhimanyuGarg, MD, of University of Texas Southwestern Medical Center in Dallas,writes, "It is still prudent to assess an individual's risk-benefitratio before recommending long-term statin therapy.... For patients with type2 diabetes at moderate to low risk of coronary heart disease, maximal loweringof lipids with diet, exercise, weight loss, and rigorous glycemic control mustbe attempted before considering lipid-loweringdrugs."10
WHERE AND HOW STATINS FIT INTO THERAPY
John Abramson, MD, clinical professor at Harvard Medical School and authorof OverdosedAmerica,11says he is concerned that the focus on pharmacological agents clouds thebenefits of diet and exercise. Since most heart disease is the result ofunhealthy lifestyle, Abramson says everyone should exercise for a half hourthree to five times weekly, eat a Mediterranean-style diet, not smoke, drinkalcohol in moderation, if at all, and address issues of chronicstress.
Ganiats also suggests initially managing patients with diet and exercise,but he notes that those with diabetes and significant CVD show high enoughrisk to benefit from a statin. Once risk is established, Ganiats says, thequestion is how much statin patients should be on.
"Myopathy is more likely to occur at higher statin doses than atlower doses," reports the American College of Cardiology, the AmericanHeart Association, and the National Heart, Lung and Blood Institute ClinicalAdvisory Group on Statins. "For this reason, doses should not exceedthose required to attain the ATP III goal oftherapy."12
Ganiats treats with diet and exercise first and adds a statin if necessary.If the LDL goal is 100 mg/dl, therapeutic interventions have lowered LDL from140 to 105, "and to go further adversely affects the patient [with] newside effects, increased out-of-pocket costs, etc.," the clinician andpatient may opt to accept the benefit already obtained as adequate, he says.Alternatively, for a similar patient who can tolerate statins without concernfor cost, side effects, or drug interactions, Ganiats says he would increasethe statin dosage as tolerated "because bringing their LDL down to 80lowers their risk even more.
"Cardiac risk goes down, as far as we can tell, for everybody takinga statin at whatever cholesterol level they have," Ganiats says. Theproblem with statin therapy among low-risk populations "is the absolutereduction may not justify the economic, social, or side-effect cost thepatient pays," he adds. "But from a cardiovascular standpointthere is still abenefit."
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One of the most important lessons from recent studies, including PROVEIT13 and theTreating to New Targets (TNT)trial,14 "isthat high-dose statin therapy seems to be more effective than low-dose statintherapy, especially in patients who are at higher risk," says Stephen D.Wiviott, MD, of Brigham and Women's Hospital in Boston. Wiviott is a member ofthe Thrombosis in Myocardial Infarction (TIMI) study group, which has examinedthrombolytic and antithrombolytic regimens in patients with acute coronarysyndromes since 1984.
For patients with no cardiac risk factors and LDL levels slightly above theguideline (see risk chart), Wiviott recommends therapeutic lifestyle changes.Alternatively, he would start a statin drug therapy and recommend healthylifestyle changes for a patient with high blood pressure, an LDL 165 mg/dl,and a parent with significant coronary disease.
However, a patient with diabetes who has not yet had a heart attack is atextremely high risk, Wiviott says, "and should be thought of in theprimary care office... as someone who has already had a heart attack in termsof the importance of prevention measures."
The 2005 ADA Clinical Practice Recommendations call for statin therapy inpatients with type 2 diabetes >40 years, without overt CVD, and with atotal cholesterol 
135 mg/dl; and for pharmacological therapy among those<40 years, without overt CVD, but with other cardiovascular risk factors orlong-standing diabetes when lifestyle modifications have not lowered LDL to<100 mg/dl.3 Thegoal here should be to reduce the LDL by 30–40%. In those very high-riskpatients with both diabetes and overt CVD, even more aggressivetherapy is advisable, targeting an LDL of 70 mg/dl. 
Footnotes
You can download the National Cholesterol Education Program's
ATP III Guidelines At-A-Glance Quick Desk Reference from the Website of the National Heart, Lung, and Blood Institute, National Institutes ofHealth:www.nhlbi.nih.gov/guidelines/cholesterol/atglance.pdf.
References
2. Grundy SM, Cleeman JI, Merz CN, et al., for the CoordinatingCommittee of the National Cholesterol Education Program: Implications ofrecent clinical trials for the National Cholesterol Education Program AdultTreatment Panel III guidelines. Circulation 110: 227–239, 2004.
3. American Diabetes Association: Standards of medical care indiabetes (Position Statement). Diabetes Care 28: S4–S36, 2005.
4. Beckley ET: Cardiologists share CVD risk-reduction research.DOC News 2:1, 2005.
5. Colhoun HM, Betteridge DJ, Durrington PN, et al., for the CARDSinvestigators: Primary prevention of cardiovascular disease with atorvastatinin type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS):Multicentre randomised placebo-controlled trial.Lancet 364:685–696, 2004.[Medline]
6. de Lemos JA, Blazing MA, Wiviott SD, et al.: Early intensive vs. adelayed conservative simvastatin strategy in patients with acute coronarysyndromes: Phase Z of the A to Z trial. JAMA 292: 1307–1316, 2004.
7. Sever PS, Dahlof B, Poulter NR, et al., for the ASCOTinvestigators: Prevention of coronary and stroke events with atorvastatin inhypertensive patients who have average or lower-than-average cholesterolconcentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—LipidLowering Arm (ASCOT-LLA): A multicentre randomised controlled trial.Lancet 361:1149–1158, 2003.[Medline]
8. Baigent C, Keech A, Kearney PM, et al., for the CholesterolTreatment Trialists' Collaborators: Efficacy and safety ofcholesterol-lowering treatment: Prospective meta-analysis of data from 90,056participants in 14 randomised trials of statins.Lancet 366:1267–1278, 2005.[Medline]
9. Lindholm LH, Samuelsson O, for ASCOT: What are the odds at ASCOTtoday? Lancet 361:1144–1145, 2003.[Medline]
10. Garg A: Statins for all patients with type 2 diabetes: Not so soon.Lancet 364:641–642, 2004.[Medline]
11. Abramson J: Overdosed America: The Broken Promise ofAmerican Medicine. New York, N.Y., HarperCollins, 2004.
12. Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al., for the AmericanCollege of Cardiology, the American Heart Association, and the National Heart,Lung and Blood Institute: ACC/AHA/NHLBI clinical advisory on the use andsafety of statins. J Am Coll Cardiol 40: 567–572, 2002.
13. Cannon CP, Braunwald E, McCabe CH, et al., for the Pravastatin orAtorvastatin Evaluation and Infection Therapy—Thrombolysis in MyocardialInfarction 22 (PROVE IT-TIMI 22) investigators: Intensive versus moderatelipid lowering with statins after acute coronary syndromes. N EnglJ Med 350:1495–1504, 2004.
14. LaRosa JC, Grundy SM, Waters DD, et al., for the Treating to NewTargets (TNT) Investigators: Intensive lipid lowering with atorvastatin inpatients with stable coronary disease. N Engl J Med 352: 1425–1435, 2005.
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30-40% reduction in LDL levels