Coronary heart disease is the leading cause of death in the United States. Each year, approximately 1.2 million Americans will have a new or recurrent event related to coronary heart disease.1 Furthermore, considering the increasing prevalence of type 2 diabetes in the U.S., it is important to note that cardiovascular disease is the leading cause of death among patients with both types of diabetes and accounts for two out of three diabetes-related deaths.2 Many patients who have diabetes with dyslipidemia remain poorly controlled despite recommendations for lower LDL cholesterol levels.3 Large, well-designed, placebo-controlled studies have shown that lowering LDL cholesterol level reduces coronary heart disease events. With so many patients in need of lipid-lowering therapy, this question arises: Are we treating LDL cholesterol levels sufficiently to achieve the desired goals? This article reviews the LDL cholesterol goals recommended by recent guidelines and focuses on barriers to achieving these goals, as well as some ways to overcome them.
Before considering some of the reasons why patients don't meet their LDL cholesterol goals, it is important to understand what those goals are and what the criteria for treatment is. In 2004, the National Cholesterol Education Program (NCEP) released a report that included an assessment of five major clinical trials published since the Adult Treatment Panel III (ATP III) issued guidelines in 2001. These trials--the Heart Protection Study (HPS), the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) study, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial–Lipid-Lowering Trial (ALLHAT-LLT), the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA), and the Pravastatin or Atorvastatin Evaluation and Infection-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial--contained information that had not been fully evaluated in previous studies.4
Based on review of these recent trials, NCEP updated the guidelines. (See Table 1 for risk levels and corresponding LDL cholesterol goals).4 The new guidelines include an optional therapeutic LDL cholesterol goal of less than 70 mg/dL for patients in the very high-risk category. Patients considered to be at very high risk are those with established cardiovascular disease plus one or more of the following: multiple risk factors (including diabetes), other severe or poorly-controlled risk factors (e.g., cigarette smoking), multiple risk factors of the metabolic syndrome (elevated triglyceride level >200 mg/dL plus non-HDL cholesterol level >130 mg/dL, with low HDL <40 mg/dL), and acute coronary syndromes. Both HPS and PROVE IT, as well as the recent Treating to New Targets (TNT) study, suggest that there is additional benefit by reducing LDL cholesterol levels to below 100 mg/dL.5
Guidelines in Clinical Practice
A review of the literature gives some insight into how successfully guidelines are implemented in clinical practice. The Lipid Treatment Assessment Process (L-TAP), a multicenter survey evaluating the number of patients on lipid-lowering therapy who have reached their LDL cholesterol goals, showed that 38% of patients achieved the targets specified by NCEP for LDL cholesterol, but only 18% of those with coronary heart disease met their goal.6 Some explanations for the low percentages include failure to increase lipid-lowering therapy, failure to use combination therapy, and poor patient adherence. In a study involving Veterans Affairs patients in Texas, a majority of patients received therapy for hypertension and dyslipidemia, but less than 50% met the therapeutic goals for each disease state.7 Findings from a managed care study showed that older individuals, men, and patients compliant with statin therapy were more likely to meet their LDL cholesterol goal. On the other hand, women, high-risk younger patients, and patients with fewer outpatient visits associated with dyslipidemia and cholesterol lab testing had a much lower level of compliance.8 Additionally, a retrospective review of 600 patients followed by cardiologists at a heart clinic revealed that only about 76% of patients achieved the recommended LDL cholesterol level of less than 100 mg/dL. Of these patients, 81% were on lipid-lowering therapy, but only 18% were taking the maximal dose, and 6% were taking combination therapy.9
Clearly, there is still some room for improvement across the board. Although the efficacy and benefits of lipid-lowering therapies are well documented, they are irrelevant if the patient is not compliant. Adherence is a complex topic, because there are several different aspects to consider that are related to the patient, the provider, and the medication regimen.10
Delaying Pharmacotherapy: Therapeutic lifestyle changes, which include diet, physical activity, and weight loss, remain first-line treatment for dyslipidemia. Therefore, it is not uncommon for treatment with medication to be delayed while patients first try diet and lifestyle changes. ATP III reduced the trial of therapeutic lifestyle changes from six months to 12 weeks and simplified the diet recommendations from a two-step to a one-step diet recommendation for all patients.11 Despite the guidelines for a shorter trial of therapeutic lifestyle changes, patients sometimes extend the trial period in order to postpone taking medication.
Treatment Adherence: Patients may not adhere to their prescribed treatment for a variety of reasons. Once patients are prescribed lipid-lowering agents, they may not understand the treatment regimen or why the medication(s) have been prescribed. The prevalence of multiple medications is increasing, since more than one lipid-lowering agent may be required to reach the newer goals. Patients may question why they must take many different medicines. Although dyslipidemia does not typically make patients feel sick, side effects of some of the medications prescribed may make them feel poorly. In addition, patients now use the Internet and other forms of media for medical information; incorrect or misunderstood information can influence a patient's decision to initiate or discontinue therapy. Without proper education, patients may decide not to follow prescribed therapy.
Adherence to lipid-lowering medications increases the success rate for attaining LDL cholesterol goals. Clinical trials demonstrate statin adherence rates of 80% to 87% over a period of three to four years.12 A study looking at pharmacy insurance claims projected an adherence rate of 78.5% in adults prescribed statin therapy for secondary prevention.13 However, a study of elderly patients found an adherence rate of 36.1% in patients with coronary artery disease.14 Therefore, it is important for clinicians to assess medication adherence before changing therapy when clinical goals are not met. 15
Financial Considerations: The patient's ability to afford the medication(s) should be discussed. If cost is a barrier, providers may need to emphasize diet and non-prescription alternatives or consider generic formulations. For the patient who has reached his or her goal on two lipid-lowering products, a combination product may save money, but health care providers may fail to offer this option because of the time and/or effort it would take to make the change. A combination product may not only offer financial savings but also simplify the regimen by decreasing the number of medications.
Poor Communication: To prevent patient-related factors from interfering with adherence, there must be open dialogue between the patient and provider. Providers have a pivotal role in screening, diagnosing, and treating dyslipidemia but often face constraints--lack of time to fully explain treatment, lack of reimbursement for counseling, inadequate counseling skills, and lack of educational support staff--that may interfere with providing the patient with the education necessary to maximize adherence. This may result in too many issues being addressed in one visit. Optimally, patient instructions should be given over several appointments.10
Number of Medications: For some patients, such as those with comorbid conditions, the number of medications they must take may seem unmanageable. For example, the average patient with diabetes takes eight medications, and approximately 25% of patients will require more than two lipid-lowering drugs to reach an LDL cholesterol level of less than 70 mg/dL.12 Pharmacists have been effective in reducing the burden for patients who are taking several medicines. For example, in one study, a pharmacy-care program used custom blister-packed medications to enhance adherence in elderly patients on complex medication regimens.16 Other alternatives to custom blister packs include weekly or monthly medication trays or boxes.
Adequate Dosing: Despite therapeutic lifestyle changes, many patients will require lipid-lowering therapy to reach their LDL cholesterol goal. HMG-CoA reductase inhibitors, or statins, are the most potent agents for lowering LDL cholesterol. They offer the ability to lower LDL cholesterol by 18% to 55%, depending on the strength of medication.11 Often, physicians initiate statin therapy at a low dose and then fail to titrate to the LDL cholesterol goal. In high-risk or moderately high-risk patients, statin therapy should be dosed to achieve a 30% to 40% reduction in LDL cholesterol levels.6 Lipid levels should be re-checked six weeks after initiation of therapy, and dosage adjustments should be decided at that time. 11
For patients who require lowering of their LDL cholesterol level by more than 40%, combination therapy may be considered. Combination therapy offers the advantage of lower doses of statins, which may minimize side effects, while enhancing LDL-lowering capabilities.17 For example, in a large community-based trial, the addition of ezetimibe to statin therapy allowed 71% of patients to reach their LDL cholesterol goal, compared with 20.6% of patients treated with statin therapy plus placebo.18 Some disadvantages of combination therapy include increased medications and cost, unless there is a combination product available.
Side Effects: Statins reduce coronary events, coronary heart disease mortality, coronary procedures, stroke, and total mortality, but as with any other medication, there are adverse effects to monitor,19 some of which may reduce compliance with treatment. Common side effects associated with statin therapy include gastrointestinal symptoms, headache, and rash.20 These side effects are often mild and transient. Bile acid sequestrants can be difficult to tolerate due to gastrointestinal side effects. Flushing decreases compliance with niacin. The FDA acknowledges that the incidence of side effects in clinical practice may be higher than in clinical trials where the patients are monitored more closely.
Statins are associated with a variety of muscle effects ranging from mild pain to rhabdomyolysis. (The withdrawal of cerivastatin [Baycol] in 2001 due to fatal rhabdomyolysis may make providers and patients fearful of possible side effects with this class of drugs.) Drug interactions are a common cause of myopathy in patients taking statin therapy. Concurrent use of CYP3A4 inhibitors, such as itraconazole, ketoconazole, erythromycin, clarithromycin, and nefazodone, retroviral drugs used for HIV, and large amounts of grapefruit juice increase the risk of interactions. Fluvastatin, pravastatin, and rosuvastatin are not metabolized by the cytochrome system and are least affected by other drugs. Gemfibrozil inhibits the metabolism of statins and increases the risk of rhabdomyolysis when used in combination therapy.21,22
The monitoring of creatine phosphokinase (CPK) in patients taking statins remains controversial, and there is no evidence that routine monitoring of CPK reduces the risk of myopathy.23 However, baseline CPK does allow a comparison with subsequent levels if a patient develops myalgia.24 CPK levels should be assessed in patients who develop unexplained muscle pain/discomfort, generalized weakness, or brown urine.23 Elevations in transaminase levels typically occur during the first three months of therapy, and though usually asymptomatic, should be monitored.20,21
Some patients who cannot tolerate one statin may tolerate another. Because more patients are now eligible for statin therapy, this increases the risk of drug interactions and adverse reactions in a population that is on multiple medications.
Support Systems Enhance Compliance
Support systems are available to enhance patient adherence to treatment; for example, some providers have the option to refer for multidisciplinary services like nutrition or lipid clinics run by pharmacists. Individual pharmacists can also enhance patient adherence.
There is evidence from dietary studies that supports the reduction of LDL
cholesterol based on therapeutic lifestyle changes. A meta-analysis showed
NCEP's Step I and II diets lower LDL cholesterol by 12% to 16%.12
Factors that increase LDL cholesterol include saturated and trans fatty
acids, overweight, and dietary cholesterol. Nutritional counseling should
focus on the intake of heart-healthy foods and calorie restriction to improve
LDL cholesterol and body weight. In addition to dietary changes, the
beneficial effects of exercise are well documented and should be encouraged in
all patients.11 Lifestyle changes should include smoking cessation,
weight management, aerobic activity (30 minutes daily, most days of the week),
diet, and limiting alcohol consumption. Ongoing nutritional counseling, in
addition to an initial consultation, is key to achieving LDL cholesterol goals.
Lipid Clinics: There is a documented increase in compliance when patients are followed by pharmacist-managed clinics. A study at two Veterans Affairs medical centers in Texas compared a pharmacist-managed dyslipidemia clinic with usual care provided by other health professionals. The study found that two-thirds of patients enrolled in the lipid clinics had an LDL cholesterol level at or below the NCEP target compared to 16% of patients who received usual care. Interestingly, 94% of patients in the lipid clinic were on lipid-lowering agents, compared to 24% of patients receiving usual care.25 Other studies have documented improvement in glycosylated HbA1c, blood pressure, and LDL cholesterol in patients followed by a pharmacist-run diabetes drug therapy program.26 The literature and NCEP supports pharmacist management of lipids to increase compliance and achieve LDL cholesterol goals.27
Other systems that help pharmacists enhance patients' adherence to treatment allow tracking of refill history to assess compliance and accessing cholesterol lab values to review with patients. Other supportive steps pharmacists can take include simplifying regimens to reduce cost and/or number of medications, issuing refill reminders to patients by phone or mail, and discussing adherence with patients at every visit.
The data clearly show that aggressive treatment is needed to achieve LDL cholesterol goals and, in turn, reduce coronary heart disease mortality. Pharmacists have a unique opportunity to enhance cholesterol management by educating patients and providers about treatment guidelines and medications. A collaborative approach may help meet the patient's need for more extensive counseling regarding lifestyle changes and medications. Pharmacists have the skills to recommend optimal drug therapy and enhance patient compliance.
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