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Smith MEB, Lee NJ, Haney E, et al. Drug Class Review: HMG-CoA Reductase Inhibitors (Statins) and Fixed-dose Combination Products Containing a Statin: Final Report Update 5 [Internet]. Portland (OR): Oregon Health & Science University; 2009 Nov.

Cover of Drug Class Review: HMG-CoA Reductase Inhibitors (Statins) and Fixed-dose Combination Products Containing a Statin

Drug Class Review: HMG-CoA Reductase Inhibitors (Statins) and Fixed-dose Combination Products Containing a Statin: Final Report Update 5 [Internet].

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Introduction

In the United States, coronary heart disease and cardiovascular disease account for nearly 40% of all deaths each year. Coronary heart disease continues to be the leading cause of mortality and a significant cause of morbidity among North Americans. In 2006, coronary heart disease claimed 607 000 lives, translating into about 1 out of every 5 deaths in the United States.1 High levels of cholesterol, or hypercholesterolemia, are an important risk factor for coronary heart disease. The 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitors, also known as statins, are the most effective class of drugs for lowering serum low-density lipoprotein cholesterol concentrations. They are first-line agents for patients who require drug therapy to reduce serum low-density lipoprotein cholesterol concentrations.

Statins work by blocking the enzyme HMG-CoA reductase, the rate-limiting step in the manufacture of cholesterol. Statins reduce low-density lipoprotein cholesterol, total cholesterol, and triglycerides and slightly increase high-density lipoprotein cholesterol. Statins may also have anti-inflammatory and other pleiotroptic2 effects. A recent good-quality systematic review found that all statins are equally effective at lowering C-reactive protein levels, but do not affect fibrinogen or several other markers of inflammation.3

The third report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) was released in September 20024 and updated in August 2004 to include evidence from more recent trials.5 The report stressed that the intensity of treatment should be directed by the degree of cardiovascular risk. Target low-density lipoprotein cholesterol levels depend on the patient’s risk of heart disease, medical history, and initial low-density lipoprotein cholesterol level. For most patients who are prescribed a statin, the target will be less than 130 mg/dL or less than 100 mg/dL. In the Adult Treatment Panel III, patients who have type 2 diabetes without coronary heart disease, peripheral or carotid vascular disease, and patients who have multiple risk factors and a 10-year risk of coronary heart disease of greater than 20% are said to have “coronary heart disease equivalents.” This means that the criteria for using drug therapy and the low-density lipoprotein target (less than 100 mg/dL) is the same as for patients who have a history of coronary heart disease. A low-density lipoprotein cholesterol goal of less than 70 mg/dL for high-risk patients is a therapeutic option. Factors that place patients in the category of very high risk favor a decision to reduce low-density lipoprotein cholesterol levels to less than 70 mg/dL. These factors are the presence of established cardiovascular disease plus (1) multiple major risk factors (especially diabetes), (2) severe and poorly controlled risk factors (especially continued cigarette smoking), (3) multiple risk factors of the metabolic syndrome (triglycerides greater than 200 mg/dL plus non-high-density lipoprotein cholesterol greater than 130 mg/dL with low high-density lipoprotein cholesterol [less than 40 mg/dL]), and (4) patients with acute coronary syndromes. The optional goal of less than 70 mg/dL does not apply to individuals who are not high risk.

The 2006 update of the American Heart Association/American College of Cardiology consensus statement on secondary prevention states, “…low-density lipoprotein cholesterol (LDL-C) should be less than 100 mg/dL for all patients with coronary heart disease and other clinical forms of atherosclerotic disease, but in addition, it is reasonable to treat to LDL-C less than 70 mg/dL in such patients.” They assigned this recommendation a grade of II-1, meaning, “…there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment [but the]…weight of evidence/opinion is in favor of usefulness/efficacy.”

The American Heart Association/American College of Cardiology guidelines qualify this recommendation as follows:

“When the <70 mg/dL target is chosen, it may be prudent to increase statin therapy in a graded fashion to determine a patient’s response and tolerance. Furthermore, if it is not possible to attain low-density lipoprotein cholesterol <70 mg/dL because of a high baseline low-density lipoprotein cholesterol, it generally is possible to achieve low-density lipoprotein cholesterol reductions of >50% with either statins or low-density lipoprotein cholesterol–lowering drug combinations. Moreover, this guideline for patients with atherosclerotic disease does not modify the recommendations of the 2004 Adult Treatment Panel III update for patients without atherosclerotic disease who have diabetes or multiple risk factors and a 10-year risk level for coronary heart disease >20%. In the latter 2 types of high-risk patients, the recommended low-density lipoprotein cholesterol goal of <100 mg/dL has not changed. Finally, to avoid any misunderstanding about cholesterol management in general, it must be emphasized that a reasonable cholesterol level of <70 mg/dL does not apply to other types of lower-risk individuals who do not have coronary heart disease or other forms of atherosclerotic disease; in such cases, recommendations contained in the 2004 Adult Treatment Panel III update still pertain.”6

Six statins are available in the United States and Canada (Table 1).

Table 1. Included statins.

Table 1

Included statins.

Three fixed-dose combination products containing a statin and another lipid-lowering drug are available in the United States while only 1 is currently available in Canada (Table 2). There are currently 3 fixed-dose combination products on the market in the United States that combine a statin medication with either extended release niacin or ezetimibe. Niacin is vitamin references.r3. Although its mechanism of action is not fully understood, it believed to be effective in improving the lipid profile by inhibiting lipolysis of adipose tissue, inhibiting hepatic synthesis of triglycerides, and likely suppressing apo A-1 hepatic removal.7 The result of this is reduction in triglycerides, elevation of high-density lipoprotein, and reduction of low-density lipoprotein. Niacin has been shown to reduce the risk of myocardial infarction.8 Ezetimibe inhibits the absorption of cholesterol from the small intestine by binding to the Niemann-Pick C1-Like 1 receptor on the brush border. The effect is a lowering of low-density lipoprotein cholesterol.9

Table 2. Included fixed-dose combination products.

Table 2

Included fixed-dose combination products.

Purpose and Limitations of Systematic Reviews

Systematic reviews, also called evidence reviews, are the foundation of evidence-based practice. They focus on the strength and limits of evidence from studies about the effectiveness of a clinical intervention. Systematic reviews begin with careful formulation of research questions. The goal is to select questions that are important to patients and clinicians then to examine how well the scientific literature answers those questions. Terms commonly used in systematic reviews, such as statistical terms, are provided in Appendix A and are defined as they apply to reports produced by the Drug Effectiveness Review Project.

Systematic reviews emphasize the patient’s perspective in the choice of outcome measures used to answer research questions. Studies that measure health outcomes (events or conditions that the patient can feel, such as fractures, functional status, and quality of life) are preferred over studies of intermediate outcomes (such as change in bone density). Reviews also emphasize measures that are easily interpreted in a clinical context. Specifically, measures of absolute risk or the probability of disease are preferred to measures such as relative risk. The difference in absolute risk between interventions depends on the number of events in each group, such that the difference (absolute risk reduction) is smaller when there are fewer events. In contrast, the difference in relative risk is fairly constant between groups with different baseline risk for the event, such that the difference (relative risk reduction) is similar across these groups. Relative risk reduction is often more impressive than absolute risk reduction. Another useful measure is the number needed to treat (or harm). The number needed to treat is the number of patients who would need be treated with an intervention for 1 additional patient to benefit (experience a positive outcome or avoid a negative outcome). The absolute risk reduction is used to calculate the number needed to treat.

Systematic reviews weigh the quality of the evidence, allowing a greater contribution from studies that meet high methodological standards and, thereby, reducing the likelihood of biased results. In general, for questions about the relative benefit of a drug, the results of well-executed randomized controlled trials are considered better evidence than results of cohort, case-control, and cross-sectional studies. In turn, these studies provide better evidence than uncontrolled trials and case series. For questions about tolerability and harms, observational study designs may provide important information that is not available from controlled trials. Within the hierarchy of observational studies, well-conducted cohort designs are preferred for assessing a common outcome. Case-control studies are preferred only when the outcome measure is rare and the study is well conducted.

Systematic reviews pay particular attention to whether results of efficacy studies can be generalized to broader applications. Efficacy studies provide the best information about how a drug performs in a controlled setting. These studies attempt to tightly control potential confounding factors and bias; however, for this reason the results of efficacy studies may not be applicable to many, and sometimes to most, patients seen in everyday practice. Most efficacy studies use strict eligibility criteria that may exclude patients based on their age, sex, adherence to treatment, or severity of illness. For many drug classes, including the antipsychotics, unstable or severely impaired patients are often excluded from trials. In addition, efficacy studies frequently exclude patients who have comorbiddisease, meaning disease other than the one under study. Efficacy studies may also use dosing regimens and follow-up protocols that are impractical in typical practice settings. These studies often restrict options that are of value in actual practice, such as combination therapies and switching to other drugs. Efficacy studies also often examine the short-term effects of drugs that in practice are used for much longer periods. Finally, efficacy studies tend to assess effects by using objective measures that do not capture all of the benefits and harms of a drug or do not reflect the outcomes that are most important to patients and their families.

Systematic reviews highlight studies that reflect actual clinical effectiveness in unselected patients and community practice settings. Effectiveness studies conducted in primary care or office-based settings use less stringent eligibility criteria, more often assess health outcomes, and have longer follow-up periods than most efficacy studies. The results of effectiveness studies are more applicable to the “average” patient than results from the highly selected populations in efficacy studies. Examples of effectiveness outcomes include quality of life, frequency or duration of hospitalizations, social function, and the ability to work. These outcomes are more important to patients, family, and care providers than surrogate or intermediate measures, such as scores based on psychometric scales.

Efficacy and effectiveness studies overlap. For example, a study might use very narrow inclusion criteria like an efficacy study, but, like an effectiveness study, might examine flexible dosing regimens, have a long follow-up period, and measure quality of life and functional outcomes. For this report we sought evidence about outcomes that are important to patients and would normally be considered appropriate for an effectiveness study. However, many of the studies that reported these outcomes were short-term and used strict inclusion criteria to select eligible patients. For these reasons, it was neither possible nor desirable to exclude evidence based on these characteristics. Labeling a study as either an efficacy or an effectiveness study, although convenient, is of limited value; it is more useful to consider whether the patient population, interventions, time frame, and outcomes are relevant to one’s practice or to a particular patient.

Studies anywhere on the continuum from efficacy to effectiveness can be useful in comparing the clinical value of different drugs. Effectiveness studies are more applicable to practice, but efficacy studies are a useful scientific standard for determining whether characteristics of different drugs are related to their effects on disease. Systematic reviews thoroughly cover the efficacy data in order to ensure that decision makers can assess the scope, quality, and relevance of the available data. This thoroughness is not intended to obscure the fact that efficacy data, no matter how large the quantity, may have limited applicability to practice. Clinicians can judge the relevance of studies’ results to their practice and should note where there are gaps in the available scientific information.

Unfortunately, for many drugs there exist few or no effectiveness studies and many efficacy studies. Yet clinicians must decide on treatment for patients who would not have been included in controlled trials and for whom the effectiveness and tolerability of the different drugs are uncertain. Systematic reviews indicate whether or not there exists evidence that drugs differ in their effects in various subgroups of patients, but they do not attempt to set a standard for how results of controlled trials should be applied to patients who would not have been eligible for them. With or without an evidence report, these decisions must be informed by clinical judgment.

In the context of development of recommendations for clinical practice, systematic reviews are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of an intervention are based on strong evidence from clinical studies. By themselves, they do not say what to do. Judgment, reasoning, and applying one’s values under conditions of uncertainty must also play a role in decision making. Users of an evidence report must also keep in mind that not proven does not mean proven not; that is, if the evidence supporting an assertion is insufficient, it does not mean the assertion is untrue. The quality of the evidence on effectiveness is a key component, but not the only component, in making decisions about clinical policy. Additional criteria include acceptability to physicians and patients, potential for unrecognized harm, applicability of the evidence to practice, and consideration of equity and justice.

Scope and Key Questions

The purpose of this review is to compare the efficacy and adverse effects of different statins. The Oregon Evidence-based Practice Center wrote preliminary key questions, identifying the populations, interventions, and outcomes of interest, and based on these, the eligibility criteria for studies. These were reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project. The participating organizations of the Drug Effectiveness Review Project are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to clinicians and patients. Since the last review, the participating organizations have decided to include pediatric population and fixed-dose combination products containing a statin and another lipid-lowering drug. The participating organizations approved the following key questions to guide this review:

  1. How do statins and fixed-dose combination products containing a statin and another lipid-lowering drug compare in their ability to reduce low-density lipoprotein cholesterol?
    1. Are their doses for each statin or fixed-dose combination product containing a statin and another lipid-lowering drug that produce similar percent reduction in low-density lipoprotein cholesterol between statins?
    2. Is there a difference in the ability of a statin or fixed-dose combination product containing a statin and another lipid-lowering drug to achieve National Cholesterol Education Panel goals?
  2. How do statins and fixed-dose combination products containing a statin and another lipid-lowering drug compare in their ability to raise high-density lipoprotein cholesterol?
    1. Are there doses for each statin or fixed-dose combination product containing a statin and another lipid-lowering drug that produce similar percent increase in high-density lipoprotein cholesterol between statins?
    2. Is there a difference in the ability of a statin or fixed-dose combination product containing a statin and another lipid-lowering drug to achieve National Cholesterol Education Panel goals?
  3. How do statins and fixed-dose combination products containing a statin and another lipid-lowering drug compare in their ability to reduce the risk of nonfatal myocardial infarction, coronary heart disease (angina), coronary heart disease mortality, all-cause mortality, stroke, hospitalization for unstable angina, or need for revascularization (coronary artery bypass graft, angioplasty, or stenting)?
  4. Are there differences in effectiveness of statins and fixed-dose combination products containing a statin and another lipid-lowering drug in different demographic groups or in patients with comorbid conditions (e.g., diabetes, obesity)?
  5. Are there differences in the harms of statins or fixed-dose combination products containing a statin and another lipid-lowering drug when used in the general population of children or adults?
  6. Are there differences in the harms of statins or fixed-dose combination products containing a statin and another lipid-lowering drug when used in special populations or with other medications (drug-drug interactions)? In addressing this question, we will focus on the following populations:
    1. Patients with HIV
    2. Organ transplant recipients
    3. Patients at high risk for myotoxicity (e.g., patients with a history of statin-associated muscle-related harms due to drug-drug/drug-food interactions, patients co-administered fibrates, patients taking potent 3A4 inhibitors, elderly patients, especially elderly females)
    4. Patients at high risk for hepatotoxicity
    5. Patients using fibrates (gemfibrozil, fenofibrate, fenofibric acid) or niacin
    6. Children with nephrotic syndrome

The choice of key questions reflects the view that the following criteria may be used to select a statin: (1) the ability to lower low-density lipoprotein cholesterol, (2) the ability to raise high-density lipoprotein cholesterol, (3) the amount of information on cardiovascular outcomes available for each statin or fixed-dose combination product containing a statin and another lipid-lowering drug, (4) adverse effects, and (5) effects in demographic subgroups and in patients with concurrent medical conditions and drug therapies.

Inclusion Criteria

Populations

  • Outpatients targeted for primary or secondary prevention of coronary heart disease or non-coronary forms of atherosclerotic disease with or without hypercholesterolemia
  • Inpatients with acute coronary syndrome or undergoing revascularization (if the statin was continued after hospital discharge and if health outcomes were reported)
  • Adults and children with familial hypercholesterolemia (homozygous or heterozygous).
  • Exclusions: Adults with rare, severe forms of hypercholesterolemia (low-density lipoprotein cholesterol greater than or equal to 250 mg/dL)

Interventions

Individual statins
Atorvastatin (Lipitor®)
Fluvastatin (Lescol®)
Fluvastatin extended release (Lescol XL®)
Lovastatin (Mevacor®)
Lovastatin extended release (Altoprev®a)
Pravastatin (Pravachol®)
Rosuvastatin (Crestor®)
Simvastatin (Zocor®)
Fixed-dose combination products containing a statin
Lovastatin, niacin extended release (Advicor®)
Simvastatin, ezetimibe (Vytorin®a)
Simvastatin, niacin extended release (Simcor®a)
a

Not available in Canada.

We did not include products that contained a statin and a non-lipid-lowering drug such as Caduet® (atorvastatin; amlodipine).

Comparators

For effectiveness and harms of individual statins:

  • For Key Questions 1 and 2, head-to-head trials comparing one statin to another
  • For other key questions, trials comparing a statin to placebo or another active comparator

For effectiveness and harms of fixed-dose combination products containing a statin:

  • Head-to-head trials comparing one fixed-dose combination product to another
  • Trials comparing a fixed-dose combination product to an individual statin, placebo, or another active comparator
  • Exclusions: Trials comparing a fixed-dose combination product to the product’s individual components given separately (co-administration)

Outcomes

Intermediate outcomes

  • Low-density lipoprotein cholesterol-lowering ability
  • High-density lipoprotein cholesterol-raising ability

Health outcomes

  • Reduction in nonfatal myocardial infarction, coronary heart disease, mortality (coronary heart disease and all-cause), stroke, and need for revascularization (including coronary artery bypass grafting, angioplasty, and coronary stents)

Harms outcomes

  • Overall adverse events
  • Withdrawals due to adverse events
  • Serious adverse events
  • Specific adverse events (including, but not limited to, hepatotoxicity, myopathy, rhabdomyolysis, renal toxicity, and myalgia)

Study designs

Based on the “hierarchy of evidence” approach, controlled clinical trials and systematic reviews were considered for assessment of effectiveness, whereas for the assessment of harms, controlled clinical trials, observational studies, and systematic reviews were considered. If higher-level evidence was not available and a gap existed then the authors considered other levels of evidence. However, studies that did not provide original data (editorials, letters), were shorter than 4 weeks in duration, did not have an English-language title or abstract, or were published only in abstract form, were excluded.

Copyright © 2009, Oregon Health & Science University, Portland, Oregon.
Bookshelf ID: NBK47270

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