Published in UAB Insight, Winter 2007

ABSTRACT: Accumulating evidence suggests aggressive cholesterol management significantly decreases cardiovascular mortality, incidence of recurring events, and need for interventions.

CME OBJECTIVE: Readers will understand how to stratify risks for cardiovascular disease and apply therapeutic options to achieve established LDL-C goals.
Vera A. Bittner, MD, MSPH, Grants/research support: NIH; Kos Pharmaceuticals; AthroGenics Inc; Pfizer; Merck & Co Inc. Consultant: CV Therapeutics Inc; Reliant Pharmaceuticals; Pfizer; Novartis

Elevated serum cholesterol is a major risk factor for coronary heart disease (CHD), the leading killer of US men and women. Recent clinical trials of statins provide evidence that aggressive cholesterol management improves survival, reduces coronary events and interventions, and improves quality of life.

Consequently, groups such as the American Heart Association (AHA) and the National Cholesterol Education Program¡¯s Adult Treatment Panel III (ATP III) continue to lower target low-density lipoprotein cholesterol (LDL-C) levels and strengthen recommendations for aggressive management of patients with coronary and other atherosclerotic vascular diseases.

After analyzing trial results, Grundy et al in 2004 recommended changes to ATP III guidelines: a target LDL-C of <100 mg/dL remains the minimum goal for high-risk patients, but for a subgroup of very high-risk patients, the panel added the option of lowering LDL-C to <70 mg/dL. Physicians also may extend this option to very high-risk patients with a baseline LDL-C <100 mg/dL (Circulation. 2004;110:227-239).

The panel recommends the following target LDL-Cs for other risk groups. For moderately high-risk patients: LDL-C should be <130 mg/dL and consideration should be given to lowering it to <100 mg/dL. For moderate-risk patients: LDL-C should be <130 mg/dL. For low-risk patients LDL-C should be <160 mg/dL.

¡°Based on evidence from large clinical trials, it is reasonable for physicians to push LDL-C as low as possible in certain high-risk groups,¡± says UAB cardiologist Vera A. Bittner, MD, MSPH. ¡°People at lower risk also may benefit from aggressive cholesterol lowering, but for now, there is not enough evidence to support such a recommendation.¡±

Risk Stratification
The ATP III algorithm includes 4 risk categories: High-risk patients are those with established CHD and CHD risk equivalents, which include diabetes, noncoronary atherosclerotic disease, and multiple (¡Ý2) risk factors conferring a 10-year CHD risk >20%. Those at moderately high risk have ¡Ý2 risk factors and a 10-year CHD risk of 10%-20%; moderate-risk patients have ¡Ý2 risk factors and a 10-year CHD risk <10%; while those at low risk have ¡Ü1 risk factor and 10-year CHD risk <10%.

Factors that bump patients into the very high risk category include acute coronary syndromes (the most compelling indication based on current data); established cardiovascular (CV) disease plus major risk factors, especially diabetes; severe and poorly controlled risk factors, particularly continued cigarette smoking; and components of the metabolic syndrome, including high triglycerides and low high-density lipoprotein cholesterol (HDL-C).

Lower is Better
The ATP III panel bases its rationale for the optional LDL-C goal of <70 mg/dL on results from two large randomized controlled trials: the Heart Protection Study (HPS), an investigation of more than 20,000 UK adults aged 40 to 80 years at high risk for a CV event, and the PROVE IT-TIMI 22 study (Pravastatin or Atorvastatin Evaluation and Infection ¡ª Thrombolysis in Myocardial Infarction 22), which compared two doses of two different statins in 4162 high-risk patients.

Investigators found statin therapy substantially reduced incidence of major vascular events in a wide range of high-risk patients, including patients without diagnosed CHD who had cerebrovascular disease, peripheral artery disease, or diabetes; those older and younger than 70 years; and those with low baseline LDL-C levels, including those with levels <100 mg/dL.

Unlike previous cholesterol-lowering trials, HPS included large numbers of women and older individuals and found benefits in both older and middle-aged patients and both men and women. Compared with the placebo group, patients taking 40 mg simvastatin had a 13% reduction in all-cause mortality, a 24% decrease in major vascular events, an 18% reduction in coronary death, and decreases in nonfatal myocardial infarction (MI) and coronary death (27%) and nonfatal or fatal stroke (25%) (Lancet. 2002;360[9326]:7-22).

¡°HPS data show statin therapy can benefit most high-risk patients but does not prove lipid-lowering alone produces these advantages. Other research suggests statins have anti-inflammatory, antithrombotic, and vascular effects that provide additional risk reduction,¡± Bittner says. ¡°But cholesterol levels are still important ¡ª every 1% drop in LDL-C produces a 1% reduction in coronary event risk.¡±

PROVE IT showed that, compared with lower-intensity treatment, high-dose statins produced greater reductions in coronary events in patients with an acute coronary syndrome. Investigators recruited participants who had been hospitalized for acute coronary syndromes within the previous 10 days to either 80 mg atorvastatin or 40 mg pravastatin. Participants had a median baseline LDL-C of 106 mg/dL, which fell to 95 mg/dL in the pravastatin group versus 62 mg/dL in patients taking 80 mg of atorvastatin. After 2 years of intensive therapy, statins produced a 16% reduction in the trial¡¯s composite cardiovascular endpoint of MI, documented unstable angina requiring hospitalization, revascularization, and stroke (N Engl J Med. 2004;350:1495-1504).

Recent data show patients at lower risk for CV disease than those in PROVE IT also benefit from intensive therapy. The Treating to New Targets (TNT) trial randomized 10,001 patients with stable CHD and LDL-Cs <130 mg/dL to a daily dose of 10 mg or 80 mg of atorvastatin. After a median follow-up of 4.9 years, patients taking high-dose statins had mean LDL-C of 77 mg/dL versus 101 mg/dL in the atorvastatin 10 mg group.

Patients taking 80 mg of atorvastatin had a 22% risk reduction in major CV events, including death from CHD, nonfatal MI, and fatal or nonfatal stroke. Despite these benefits, higher doses of statins did not reduce overall mortality.

A meta-analysis of 4 statin trials (including TNT and PROVE IT), which together had 27,548 participants and more than 100,000 patient-years of observation, compared results of intensive versus moderate statin therapy. The analysis found intensive therapy produced a highly significant 16% reduction in coronary death or MI and a 16% reduction in coronary death and any CV events. High-dose statins also showed a favorable trend in CV death reduction, but the predominant benefit was preventing nonfatal cardiac events.

After extrapolating data, the authors concluded that for every million patients with chronic or acute coronary artery diseases, intensive rather than standard doses of statins would prevent 35,000 CV events. This underscores the significant clinical benefits of intensive statin therapy in individuals treated immediately after acute coronary syndromes or for secondary prevention (J Am Coll Cardiol. 2006;48[3]:438-445).

Identifying patients at increased risk for adverse CV events such as MI and stroke helps define those who can derive the most benefit from intensive lipid-lowering, says Bittner, who notes, ¡°clinicians and patients must balance potential benefits against possible adverse effects and added expense.¡±

Statin Safety

High-dose statins produce moderate reductions in cardiac events compared with lower doses, but patients, who are often unwilling to accept potential adverse effects of standard statin therapy, may be even more uneasy about perceived increased risks of intensive therapy.

The National Lipid Association (NLA) has found less than half of Americans with a moderate or high risk of heart disease take statins, and that many patients refuse or stop the drugs because of worries about side effects.

Patients and physicians have had concerns about statins since the 2001 market withdrawal of cerivastatin (Baycol), which the manufacturer pulled because of its link to fatal rhabdomyolysis in more than 100 patients. Most cases occurred in individuals taking high doses of the statin or a combination of cerivastatin and the fibrate gemfibrozil.

¡°People often have trouble understanding the magnitude of these risks compared with the benefit of the drugs,¡± Bittner says. ¡°They hear statins confer a chance of death, or a chance of liver damage and are hesitant to take them. Physicians can help by providing a realistic perspective on how often such problems actually occur and how likely an individual is to experience side effects. For most people, the risk of fatal or debilitating cardiac events far exceed risks posed by statins.¡±

The NLA¡¯s Statin Safety Task Force recently issued a comprehensive, rigorous analysis of all currently commercially available statins and their effects on liver, muscle, renal, and neurological systems (Am J Cardiol. 2006;97[suppl]:3C-94C).

The task force looked at published clinical trial data and commissioned independent reviews of specialist literature on adverse reactions and drug interactions. The group also reviewed the most recent available data from the FDA¡¯s Adverse Event Reporting System, extensive data from new drug applications, and data on statin use and associated adverse events taken from a multimillion-person managed care database that included 490,000 patient-years of continuous statin use. The task force then commissioned independent reviews by specialists in muscle disease, liver disease, kidney disease, and neurological diseases.

Much of the concern surrounding statin use has focused on the drugs¡¯ potential to cause muscle pain, weakness, or cramps and rhabdomyolysis. The muscle safety task force concluded that myopathies and rhabdomyolysis are associated with statin therapy as a class effect and that risk for these conditions rises along with statin dose and serum levels. These risks also are increased by drugs that retard statin metabolism, particularly gemfibrozil and CYP-3A4 inhibitors.

Patients should understand that statins can produce muscle problems, which can very rarely lead to serious complications, the NLA task force says. In its final conclusions, the task force noted findings from 21 clinical trials showed myopathy (defined as muscle symptoms plus creatine kinase [CK] >10 times the upper limit of normal [ULN]) occurs in 5 patients per 100,000 person-years, and rhabdomyolysis in 1.6 patients per 100,000 person-years (Am J Cardiol. 2006;97[suppl]:89C-94C).

In clinical practice settings incidence of muscle complaints from statin-treated patients ranges from 0.3% to 33%. Higher figures in such settings may be due to the exclusion of statin-intolerant patients and those with risk factors for myopathies from clinical trials.

When physicians encounter muscle symptoms or increased CK levels, they should rule out other etiologies, which are the most likely cause. Pretreatment CK levels may be considered in patients at high risk of muscle toxicity, including older individuals or those taking a statin plus a drug associated with myotoxicity. Monitoring CK levels in asymptomatic patients is not necessary, the task force says.

All statins may cause elevated serum aminotransferase (ALT) levels in a dose-dependant fashion, but the liver function task force found statin-associated ALT increases are not linked to acute or chronic liver injury. Large, sustained ALT level elevations are rare and usually associated with potential drug interactions, comorbidities, or using the highest dose of a statin. ALT or aspartate aminotransferase (AST) liver enzymes >3 times the ULN occur in <1% of patients taking initial and intermediate doses of statins and in 2% to 3% of those taking 80 mg per day. Elevations of this level spontaneously resolve in about 70% of cases even with continued statin dosing.

Liver failure occurs very rarely in patients receiving statin therapy. ¡°The task force found that 1 in 1 million patients taking statins experience liver failure ¡ª about the same incidence in people not taking the drugs,¡± Bittner says.

The group concluded that patients taking statins do not need routine liver function tests, although physicians should be alert to reports of jaundice, malaise, fatigue, lethargy, and other symptoms of hepatoxicity. They also advise the drugs are safe for individuals with hepatic conditions, with the exception of those with decompensated cirrhosis or acute liver failure.

The task force notes their recommendations regarding liver function monitoring are at odds with current statin package inserts, and states, ¡°Until the FDA-approved prescribing information for statins changes, physicians should continue to measure transaminase levels before starting therapy, 12 weeks after initiating therapy, after a dose increase, and periodically thereafter.¡±

The task force on renal issues reported marketed doses of statins do not have any direct adverse effects on the kidney. The group assessing statins¡¯ neurological effects found the drugs do not cause peripheral neuropathy, and no evidence links statins to impaired memory or cognitive function.

The chair of the NLA Statin Safety Task Force noted, ¡°The problem is not that too many patients are having too many side effects. The problem is that too many patients are not being treated to reduce their risk of heart disease.¡±

Combined Therapy
Despite using statin therapy, many Americans with CHD still have a high risk of adverse CV events. The increasing prevalence of obesity, diabetes, and insulin resistance contributes to this risk and also presents a constellation of lipid abnormalities that are not effectively targeted by LDL-C-focused therapies.

Combining a statin with agents that have broader effects on dyslipidemias may improve outcomes, says Bittner, who is recruiting patients for an NIH-funded randomized controlled trial comparing simvastatin alone with a combination of simvastatin and Niaspan. During 4 years of follow-up, investigators will determine whether the niacin-statin combination can delay time to a first major CV disease outcome more than simvastatin alone. Candidates for the study, called AIM HIGH, are individuals aged ¡Ý45 years at high risk for recurrent CV events (established vascular disease) and two dyslipidemic features, eg, low HDL-C and high triglycerides.

Bittner and other experts, including the ATP III panel, the AHA, and the American College of Cardiology, continue to stress the importance of lifestyle changes for cholesterol management. ¡°Getting patients to lose weight, exercise, stop smoking, and improve their diet is quite difficult,¡± she says. ¡°But physicians can never know when advice will trigger a change and should continue counseling patients about benefits of lifestyle changes. Physicians should also remind patients that they should never stop medications without clearance from their doctors.

For more information
Dr. Vera Bittner
1.800.UAB.MIST
mist@uabmc.edu