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Application of Project ImPACT in the Pharmacy

Time Management: Many community pharmacists are now saying: “Sounds wonderful, but who has the time?” Not surprisingly, two critical, time-saving components in this study of care in the pharmacy were scheduling patient appointments and staffing. The average time spent with patients on their initial visit was 45 minutes (range 30–60 minutes), and that on follow-up visits was 22 minutes (range 10–30 minutes). No doubt pharmacists found ways to streamline these visits as they gained experience. Furthermore, these visits were often arranged by appointment, during mid-afternoons, early evenings and other slow times in the pharmacy. Additionally, pharmacists learned to organize the time they had available and to be creative in integrating the service into the flow of the pharmacy department. Pharmacists can also make optimal use of pharmacy technicians. For example, technicians can be taught to obtain the lipid profile with the desktop analyzer and provide the results to pharmacists for interpretation and counseling.

The Collaborative Care Model: In order for pharmacists to be effective purveyors of health education, disease prevention, and disease management, both they and physicians need to fully understand and embrace a collaborative care model. Collaboration means just that…working together to achieve common goals for the patient. This model deploys pharmacists to help support, encourage, and carry out physician-prescribed care. It does not replace the physician nor supplant his/her care plan. It takes full advantage of the pharmacist’s skill level, service capacity, and extensive know-ledge base. Unfortunately, as the healthcare market becomes more competitive and restrictive, primary care physicians could feel threatened by the pharmacist’s collaborative services. This happened in some cases during the early days of Project ImPACT. But initial suspicion quickly turned to strong professional support once physicians experienced first-hand how the pharmacists’ collaborative services complemented their own. Given the alarming number of hypercholesterolemic patients and their undertreatment, attention given to helping patients persist and comply with therapy is desperately needed to successfully manage this debilitating disease state.

Communication Links: The success of the collaborative care model concept depends upon quick, efficient dissemination of information. During the study, pharmacists recorded their findings and recommendations at the conclusion of each patient’s visit and transmitted this information via phone calls and faxes to the patient’s physician. Ideally, this communication should take place electronically and the feasibility of an electronic health record is being explored. Such a computerized record is envisioned to contain personal, claims transaction, clinical encounter, and quality event data. If a community pharmacy could electronically link itself with healthcare providers, a seamless flow of patient care information between pharmacists and physicians could truly be accomplished.

Opportunities for Reimbursement: An important extrapolation from this study is the issue of reimbursement for services. Even though reimbursement was not a study measure, participating pharmacists were encouraged to place a value for their services and either charge patients directly or seek compensation from third parties. The results were encouraging. An average assigned value per visit was $55; counseling services were $28 and lipid profiles were $27. Of the 232 patients who were asked for payment, 174 (75%) paid an average of $35 per visit. Of the 121 third party payers billed for services, 64 (53%) paid an average of $30 per visit. Compensation was more frequently received for lab services (i.e., the lipid profile) than counseling services, but as third parties learn more about the impact of pharmacists’ consulting services, interest in compensating pharmacists based on successfully maintaining patients at their treatment goal has grown. Interestingly, two project sites executed contracts with managed care organizations to deliver services to their health plan beneficiaries — one a fee-for-service arrangement and the other capitation. Therefore, the collaborative care model presents real opportunities for financial compensation, especially if it is successful in helping patients attain and maintain their treatment goals.

Discussion

Project ImPACT: Hyperlipidemia offers a contemporary view of the importance of pharmacists as providers of health promotion, disease prevention, and disease management. Pharmacists are in a unique position to support and empower patients to achieve therapeutic outcomes in the management of hypercholesterolemia and various other disease states. Pharmacists are ideally positioned to make the collaborative practice model work because of: 1) the growing self-care movement in which patients are taking increasing responsibility for their health, including asking more questions of all healthcare providers; 2) their accessibility to both patients and providers; 3) their ability to provide an advanced level of care; 4) their information management capabilities; 5) their motivation to expand care; 6) their education and training in the area of patient-focused disease management services; and 7) their understanding of how to be a team player.

The results of Project ImPACT should not be underestimated. In spite of effective treatment, which has been proven to reduce coronary artery disease events, most patients with a high CHD risk are not receiving treatment and those who are, are not being treated to goal. This project demonstrates that collaborative care provided by a community pharmacist can have a dramatic impact on treatment success. Project pharmacists produced a two- to four-fold improvement over existing systems in getting hyperlipidemic patients to treatment goals. There is nothing in the literature quite as powerful as these results. Not even interventions aimed at improving the impact of physicians themselves have been as successful. This project unquestionably presents pharmacists with a huge opportunity. The challenge is to take the next step.

Patients are not the only beneficiaries of pharmacists’ collaborative care — so are the pharmacists. Pharmacists involved in Project ImPACT were highly satisfied with their own professional role and 85% rated their relationship with patients very satisfying. The majority of project pharmacists also perceived that their patients and physicians highly valued their services. Perhaps even more telling is that the majority of pharmacists participating in the project (25 of the 26 sites) indicated that they planned to continue to provide these services.

Conclusion

Lipid-lowering goals are difficult to attain for patients with hyperlipidemia. A collaborative care approach that involves pharmacists in community settings working together with primary care providers to support and encourage patients can be instrumental in getting patients to their lipid goals. Project ImPACT offers a sound model for pharmacists. At the end of the day, involvement by pharmacists with hyperlipidemic patients presents a win-win situation: an enhanced quality of life for the patient and improved job satisfaction for the pharmacist.

Project ImPACT: Hyperlipidemia

Project ImPACT: Hyperlipidemia is a recently completed community pharmacy-based demonstration project. ImPACT is an acronym for Improve Persistence And Compliance with Therapy. The study began in March 1996 and concluded October 1999. There were four core objectives: 1) improve patient persistence and compliance with lipid-lowering therapy; 2) increase communication and the flow of clinical information among patients, pharmacists, and physicians; 3) improve the cholesterol levels of individual patients over time; and 4) increase the population of patients who reach and maintain their NCEP lipid goals.

A total of 26 pharmacy practice sites in 12 states participated in the study. These sites were chosen based on criteria that addressed the readiness of the pharmacy to provide basic pharmaceutical care services. Readiness was determined by the availability of a private or semiprivate area for patient consultation; technician support; a documentation system for recording, tracking, and reporting patient care interventions; experience with patient-focused disease state management programs; demonstrated communication skills; and the ability to implement point-of-care testing technologies. Fourteen of the pharmacies were independent, three were professional chain stores, one was a chain grocery, two were home health stores, four were clinic pharmacies, and two were managed care or health maintenance organization pharmacies.

Patients were identified through referrals by local physicians, project pharmacists, other healthcare providers, or by self-referral. They were either newly diagnosed with hyperlipidemia or already receiving lipid-lowering drugs but not yet at their target lipid goal. A fasting lipid profile was performed using the LDX Analyzer (Cholestech, Hayward, CA), which requires only a fingerstick blood sample, and results were obtained within five minutes. Initiation of lifestyle modification and pharmacologic therapy was then undertaken by the patient’s physician based on the lipid results. Pharmacists communicated clinical progress — in the areas of cholesterol test results, current health status, coronary artery disease risk, and NCEP goal achievement — to the patients as well as their physicians. Patients were seen monthly for the first three months and quarterly thereafter, and fasting lipid profiles were obtained during each visit. The practice archetype designed for the project was a collaborative care model that allowed flexibility in staffing and types of resources available at the various participating pharmacies. This practice model also established a process for the seamless flow of care data between the patient, pharmacist, and physician. And most importantly, the collaborative care structure organized methods for pharmacists to document, interpret, and report their lipid management interventions.

One of the endpoints of this study, persistence, was defined as a patient who started on medication during the study and remained on the medication as of his or her last study visit. A second study endpoint, compliance, was determined through an evaluation of the number of missed doses for each lipid-lowering medication and of refill timing. Any patient who missed five or more days of medication or who missed a scheduled refill visit by more than five days was judged to be noncompliant for that visit. Compliance as a percentage was calculated by dividing the number of visits at which patients were compliant by the total number of patient visits.

Results: A total of 574 patients were enrolled in the study. Of the 397 patients who completed the two-year study, 345 (86.9%) patients were treated with lipid-lowering medications and lifestyle modifications. The remaining 52 patients (13.1%) focused on lifestyle modifications only (diet and exercise) in an effort to reach target cholesterol goals. The distribution of lipid-lowering drugs used was 89% statins, 5% niacin, 4% fibrates, and 2% bile acid resins. Of the 345 patients started on medication, the medication persistence rate was 93.6%. Of the 2,817 documented visits for patients on medication, the per-visit medication compliance rate was 90.1%. Average fasting lipid levels for patients at the beginning and end of the study are shown in Table 2.

In the primary and secondary prevention groups, NCEP goal achievement at the end of the study was 67.4% and 47.5%, respectively. Furthermore, 248 of all 397 patients (62.5%) were at or below goal as of their last full lipid profile, representing up to a 100% improvement over goal-attaining rates reported in the literature (Figure 1). Finally, of the 346 pharmacist-recommended interventions, physician acceptance of their recommendations was 76.6%.

Figure 1

Persistence, Compliance, and Treatment to NCEP Goal in Dyslipidemic Patients (N=397)

There was a time when heart disease was considered a “man’s disease.” However, we now know that women are just as likely to be afflicted, especially after reaching the age of menopause. Coronary artery disease (CAD) is the number one killer of American women and men. Another way to interpret this startling statistic is that about every 29 seconds an American will suffer a coronary event, and about every minute someone will die from one. CAD is also the leading cause of premature, permanent disability in the United States labor force. The direct and indirect cost of coronary artery disease for the year 2000 was estimated at $118 billion.

Risk Factors for coronary artery disease

Many risk factors are involved in the development of CAD. Age, gender, smoking history, physical inactivity, obesity, hypertension, family history of premature coronary artery disease events (e.g., heart attack), diabetes, and cholesterol level are among the most important. Whereas a person cannot control his or her age, gender, or family history, he or she can control tobacco use, amount of physical activity, weight, blood pressure, blood sugar, and blood cholesterol levels. Of these, controlling cholesterol levels may be among the easiest, given the efficacy of the cholesterol-lowering drugs currently available. The second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II) affirms that an elevated low-density lipoprotein (LDL)-cholesterol level significantly increases the risk of CAD, and therefore makes its reduction a primary target for controlling hyperlipidemia. Close to 100 million American adults have borderline or high cholesterol levels. Furthermore, more than 50 million adults have an LDL-cholesterol level that is high enough to qualify them for treatment. Desirable LDL-cholesterol levels based on risk factors and primary and secondary prevention status can be found in Table 1.

Lowering Cholesterol Levels

The primary key to reducing cardiovascular morbidity and mortality in patients with clinically apparent coronary artery disease — as well as in patients without CAD — is to lower elevated LDL-cholesterol levels. Clinical trials have conclusively demonstrated this. Additionally, patients with low HDL-cholesterol also have a high CAD risk. Recent clinical trials in these patients also demonstrate that reducing LDL-C will reduce coronary artery disease events. These trials all point to the same conclusion: lowering elevated LDL-C levels to treatment goals reduces heart attacks and other CAD events.

One pharmacological approach that is highly effective in lowering LDL-cholesterol is the use of “statins” — HMG-CoA reductase inhibitors (e.g., atorvastatin/Lipitor, cerivastatin/Baycol, fluvastatin/ Lescol, lovastatin/Mevacor, pravastatin/Pravachol, and simvastatin/Zocor). The Scandinavian Simvastatin Survival Study Group (4S) was one of the first studies designed to test the hypothesis that lowering cholesterol with a statin would improve survival of patients with coronary artery disease. The results were impressive: Over 5 years, simvastatin significantly reduced LDL-cholesterol levels, and increased HDL-cholesterol levels, as compared with placebo. The 6-year probability of survival in the simvastatin group was 91.3% compared to 87.6% for those patients on placebo, but there was a 42% reduction in coronary deaths, which accounted for the improvement in survival. Subsequent randomized, placebo-controlled trials with other statins have showed that reducing LDL-cholesterol significantly decreased risk of CAD events in both primary and secondary populations.

Treatment and Compliance Issues

Despite the clear demonstration that lowering LDL-cholesterol improves cardiovascular risk, most adults who are eligible for cholesterol-lowering therapy do not receive it, including over half of those who qualify for drug therapy. The discouraging statistics continue. The compliance rate for patients with hyperlipidemia, even those with clinically apparent coronary artery disease, is dismal — only 40% to 60% remain on their lipid-lowering medication therapy after one year. As any good pharmacist knows, it does not matter how well drug studies are performed, how conclusive their results, or how superior a drug may be; if the patient does not swallow the pill it will not make a difference. Furthermore, too often studies do not address compliance issues; compliance is taken for granted. A recent study asked whether compliance rates reported in clinical trials reflect rates in primary care settings. Not surprising to healthcare providers, the answer was an emphatic “No.” Discontinuation of medications is much less in clinical trials than in routine practice.

In addition to the undertreatment of hyperlipidemia and noncompliance with antihyperlipidemic medication, there is a third area of concern — the number of patients taking lipid-lowering agents who are not reaching treatment goals. In primary care settings, successful attainment of NCEP goals ranges from only 8% to 38%.These numbers are disheartening. Even if patients could be appropriately identified for treatment and receive appropriate intervention, they will not obtain the full therapeutic benefit if they do not comply with therapy. What can be done? What healthcare professional can make an impact in these three troubling areas? Answer: the pharmacist.

Adverse Reactions

In clinical trials, all doses of colesevelam were generally well tolerated. Colesevelam is not absorbed in the digestive tract, reducing the potential for systemic adverse side effects. Also, its water-retaining ability creates a soft, gelatinous material that minimizes the potential for gastrointestinal irritation. The most common side effects reported by patients in clinical trials of colesevelam HCl were flatulence (12% for colesevelam vs. 14% for placebo) and constipation (11% for colesevelam vs. 7% for placebo). The incidence of gastrointestinal side effects was less than that associated with other drugs in its class. Less than 3% of the trial patients discontinued colesevelam therapy as a result of GI tract adverse reactions. There were no clinically significant changes in serum chemistry parameters from baseline to the end of treatment. In general, the change from baseline for indicators of kidney and liver function did not differ among treatment groups, with the exception of a modest, non-dose-related increase in alkaline phosphatase. No clinically significant changes were noted during clinical trials to date for hematologic parameters, serum levels of vitamins A and E, prothrombin time, partial thromboplastin time, estradiol levels, body weight, pulse, and systolic and diastolic blood pressure.

Drug Interactions

In clinical studies, coadministration of colesevelam with atorvastatin, lovastatin, or simvastatin did not interfere with the lipid-lowering activity of the HMG-CoA reductase inhibitor. Colesevelam is reported to decrease the C_max and AUC of sustained-release verapamil (Calan SR) by approximately 31% and 11%, respectively. Since there is a high degree of variability in the bioavailability of verapamil, the clinical significance of this finding is unclear. Colesevelam HCl was found to have no significant effect on the bioavailability of digoxin, lovastatin, metoprolol, quinidine, valproic acid, and warfarin. When administering other drugs for which alterations in blood levels could have a clinically significant effect on safety or efficacy, monitoring drug levels or effects should be considered.

Dosage, Administration and Patient Information

Colesevelam is supplied as an off-white tablet containing 625 mg of the active drug. The recommended initial dose of colesevelam monotherapy is three tablets twice daily or six tablets once daily. Colesevelam should always be taken with a liquid and a meal. The dose of colesevelam may be increased to seven tablets, depending upon the desired therapeutic effect. When used with an HMG-CoA reductase inhibitor, the recommended dose of colesevelam is three tablets taken twice daily with meals or six tablets taken once daily. Colesevelam and the HMG-CoA reductase inhibitor do not need to be administered at the same time. Patients should be instructed to adhere to their National Cholesterol Education Program recommended diet and inform their physicians if they are pregnant, are intending to become pregnant, or are breastfeeding. Colesevelam is contraindicated in individuals with bowel obstruction and in individuals who have shown hypersensitivity to any of the components of the drug product.

Pharmacology and Pharmacokinetics

Bile acids are formed from cholesterol in a series of reactions regulated by the enzyme 7-alpha- hydroxylase. During normal digestion, bile acids are secreted into the intestine. A major portion of bile acids are then absorbed from the intestinal tract and returned to the liver via the enterohepatic circulation. Colesevelam is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed (less than 0.05% absorption) from the GI tract. It binds bile acids in the intestine, impeding their reabsorption and facilitating elimination. As the bile acid pool becomes depleted, the hepatic enzyme cholesterol 7-alpha-hydroxylase is upregulated, increasing the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in both increased transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increased numbers of hepatic low-density lipoprotein (LDL) receptors. These compensatory effects result in increased clearance of LDL-C from the blood, thereby decreasing serum LDL-C levels. Furthermore, studies have shown that the combination of colesevelam and an HMG-CoA reductase inhibitor is effective in further lowering serum total-C and LDL-C levels beyond that achieved by either agent alone.

Therapeutics

The effectiveness of colesevelam in lowering LDL-C has been demonstrated in a number of controlled clinical trials involving approximately 1,400 patients who were treated for 4–50 weeks. Colesevelam taken alone was found to be effective for patients with mild-to-moderate hypercholesterolemia, producing a maximum therapeutic response within two weeks; this effect was maintained during long-term therapy. In a study in patients with LDL-C between 130 and 220 mg/dL (mean 158 mg/dL), colesevelam was given for 24 weeks in divided doses with the morning and evening meals. In this study, the mean LDL-C reductions were 15% with a 3.8 g dose of colesevelam and 18% with a 4.5 g dose. The mean total-C reductions were 7% and 10%, respectively, and the mean Apo B reductions were 12% in both treatment groups. Colesevelam at both doses also resulted in a 3% increase in HDL-C. There were also small increases in triglycerides (TG) at both colesevelam HCl doses but these were not statistically different from placebo.

In a study of nearly 100 patients with LDL-C between 145 and 250 mg/dL (mean 169 mg/dL), 3.8 g of colesevelam was given for six weeks as a single dose with breakfast, a single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the three dosing regimens, respectively. The reductions with these three regimens were not statistically different from one another. Coadministration of colesevelam and an HMG-CoARI (atorvastatin, lovastatin, or simvastatin) produced an additive reduction of LDL-C in several clinical studies. Colesevelam doses of 2.3 g to 3.8 g resulted in additional 8% to 16% reductions in LDL-C above that seen with the HMG-CoARI alone. It should be noted that the specific effects of colesevelam, either alone or with an HMG-CoA reductase inhibitor, on cardiovascular morbidity and mortality have not been determined at this time.

Based on these studies, colesevelam, administered alone or in combination with an HMG-CoA reductase inhibitor, is indicated as adjunctive therapy to diet and exercise for the reduction of elevated LDL-C in patients with primary hypercholesterolemia who are at significant increased risk for atherosclerotic vascular disease. Prior to initiating colesevelam therapy, it is necessary to first exclude secondary causes of hypercholesterolemia, such as poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease or other drug therapy. Also, a lipid profile should be obtained to assess total-C, HDL-C, and TG and periodic serum cholesterol levels, determined as outlined in the National Cholesterol Education Program (NCEP) guidelines to confirm a favorable initial and long-term response. Colesevelam should be used with caution in patients with gastrointestinal disorders (e.g., dysphagia, swallowing disorders, severe gastrointestinal motility disorders, or major gastrointestinal tract surgery) since the safety and efficacy of this drug has not been established in such patients.

What does the pharmacist need to know to counsel patients about colesevelam?

Development

Epidemiological studies have established that elevated levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipo-protein B (Apo B), as well as decreased levels of HDL-cholesterol (HDL-C), are associated with an increased risk of atherosclerosis and cardiovascular-related mortality. Furthermore, it has been documented through numerous trials that aggressive reduction of lipid levels can significantly reduce the risk of cardiovascular disease. It is estimated that more than 50 million Americans currently have at least mild elevations of cholesterol (hyper-cholesterolemia or Fredrickson Type IIa hyperlipidemia) and would benefit from some form of lipid-lowering therapy. Diet and lifestyle changes generally represent the initial approach toward lipid reduction, but these often produce small and inconsistent results. For patients who continue to have elevated cholesterol levels following diet and lifestyle modifications, drug therapy is recommended. Currently available lipid-lowering drugs include the “statin” hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (HMG-CoARIs), the bile acid sequestrants, nicotinic acid, the fibric acids (gemfibrozil, clofibrate) and probucol. The lipid-lowering market is one of the fastest growing in the nation, generating over $6 billion in sales and nearly 95 million prescriptions over the past year.

For initial cholesterol-lowering therapy, the National Cholesterol Education Program (NCEP) recommends bile acid sequestrant drugs used alone or in combination with other drugs, such as the statin HMG-CoARIs. The safety and efficacy of cholestyramine resin and colestipol hydrochloride, the most commonly prescribed bile acid sequestrants, have been demonstrated repeatedly. These bile acid sequestrants alone reduce LDL-C concentrations by 10% to 30%. Combination therapy of bile acid sequestrants with niacin or an HMG-CoARI produces even larger LDL-C reductions of up to 60%. Despite their proven efficacy and the lack of systemic effects resulting from nonabsorption from the gastrointestinal tract, the bile acid sequestrants currently available have a high drug discontinuation rate due, in large measure, to intolerable GI side effects. Constipation occurs in up to 39% of patients taking currently available bile acid sequestrants and in severe cases, this may result in fecal impaction. Other gastrointestinal side effects, such as bloating, flatulence, and cramping, also occur in a large percentage of patients who are treated with currently available bile acid sequestrants. Therefore, the development of effective cholesterol-lowering agents with greater tolerability than currently available bile acid sequestrants has been a priority of hypercholesterolemic drug research.

Colesevelam (WelChol/Sankyo) is a new, nonabsorbed polymer (water-absorbing hydrogel) that has been specifically designed to bind to bile acids in the GI tract. It is a poly-allylamine cross-linked with epichlorohydrin and alkylated with 1-bromodecane and brom hexyltrimethylammonium bromide. Colesevelam has a high affinity for both trihydroxy and dihydroxy bile acids in the intestine, leading to increased fecal bile acid excretion. Preliminary in vivo and in vitro studies suggest that colesevelam has superior bile acid binding efficacy compared to cholestyramine. Furthermore, its water-retaining characteristic creates a soft, gelatinous-like material that minimizes the potential for gastrointestinal irritation relative to other bile acid sequestrants.

Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) have traditionally been used to decrease serum cholesterol levels and to reduce morbidity and mortality associated with cardiovascular disease in patients with hyperlipidemia. Animal and human studies also suggest that HMG-coenzyme A reductase inhibitors may increase bone formation and bone mineral density. In humans, an increase in bone mineral density can decrease the risk of fractures, especially in patients with osteoporosis. Fracture risk is increased 1.5-2.5 times for every standard deviation below average peak bone mass.

Osteoporotic fractures are recognized as a common and important cause of disability and death; 1.5 million fractures are attributed to osteoporosis annually. Although several recently approved medications effectively prevent and treat osteoporosis, no currently approved drug stimulates bone formation by acting upon the bone-forming cells, known as osteoblasts. Recent animal studies suggested statins may have the potential to enhance osteoblastic activity, which allows for an increase in bone formation and bone mineral density.

Statins may affect bone formation by increasing the expression of protein 2, a protein in the bone that stimulates osteoblastic differentiation. The inhibitory effect of statins on mevalonate synthesis, a mechanism seen with many bisphosphonates, may also explain their positive effects on bone. Mevalonate, needed in the synthesis of cholesterol, is also a precursor to proteins involved in regulating osteoclast activity. Since statins inhibit mevalonate synthesis, osteoclast action is suppressed, resulting in decreased bone removal.

It is unknown whether the effect of statins on osteoblasts and osteoclasts is related to decreased fracture risk in humans. The following retrospective studies describe the association between statins and fracture risk in humans.

Clinical Trials

The largest trial to date was conducted by van Staa et al. to evaluate the risk of fracture in patients using statin drugs.81,880 patients aged 50 years and older with documented fracture of the vertebrae, clavicle, humerus, radius/ulna, carpus, hip, ankle or foot from patient enrollment through July 1999 were compared with an age-, sex- and practice- matched control group of the same number of patients in the database who did not have a fracture. Information was extracted from the United Kingdom’s General Practice Research Database, a computerized medical record system that contains data from 683 general practices and encompasses 6.5% of the population of England and Wales. Prescription data were accessed to determine whether patients received any statin prescription. Current use was defined as a statin prescribed within 6 months of the fracture date; past users were defined as patients receiving one or more statin prescriptions previously but who had stopped more than 6 months from the index date. Non-statin lipid-lowering prescriptions were also evaluated.

Results were reported as odds ratios (OR), which in this case is the odds of having a fracture while on a statin versus the odds of fracture if the patient was not on a statin. If the odds ratio is less than one, there is a decreased risk of fracture associated with statin use. If the odds ratio is greater than one, the risk of fracture is higher with statin use. In current statin users, the trial showed an odds ratio of 1.01, with a possible range of 0.88-1.16. In the simplest terms, this suggests that the risk of having a fracture in a current statin user was 1.01 times that of a nonuser. This finding suggests that current statin use did not influence the risk of fracture. However, when the location of the fracture is considered, statin use decreased, increased, or had no effect when compared to patients who did not use statin drugs. For example, patients on statins had decreased risk of hip fracture (OR = 0.59) when compared with patients not on statins. Patients who developed forearm and vertebral fractures were at no additional or slightly higher risk of fracture in the current statin user group (OR = 1.01 and 1.15, respectively).

Statin dose and duration may also influence outcomes. Higher statin doses defined as 40 mg daily or more (standardized to simvastatin) were associated with a lower risk of fracture (OR = 0.85) compared to lower doses of 20-39.9 mg (OR = 1.07) and less than 20 mg daily (OR = 1.13). Interestingly, shorter duration of statin use appeared to be associated with odds ratios closer to one, compared to longer durations, which were greater than one. For example, statin use for 0-3 months had an OR of 0.71, compared to statin use for durations of 6-12 months (OR = 1.14) and more than 12 months (OR = 1.17). Fracture risk in patients receiving non-statin lipid-lowering agents was similar to statin users (OR = 1.02).

Overall, it appears from this study that statin use does not have a positive association in reducing fracture risk, with the possible exception of hip fractures. However, it is important to identify a few biases in the trial, summarized concisely in an editorial following its publication. The trial did not control for differences in body mass indexes between groups; increased BMI may decrease the risk of osteoporotic fractures. Differences in the amount of physical activity and calcium intake between groups may also influence the interpretation of the author’s findings.

In contrast to this trial, Meier et al. found that current statin users had almost half the risk of developing fracture when compared to non-statin users (OR = 0.55). Interestingly, despite the conflicting results, investigators also used the United Kingdom-based General Practice Research Database (but limited data extraction to 300 practices) over a period from the late 1980s to September 1998. They used a case-control study design to determine whether use of statins, fibrates, or other lipid-lowering drugs is associated with a decrease in bone fracture risk. Patients were excluded from the study only if they had osteoporosis, osteomalacia, cancer (other than non-melanoma skin cancer), alcoholism, or used bisphosphonates. A base population of 91,611 individuals was identified and separated into the following three groups: 1) patients, ages 50-89, who received at least one prescription for a statin, fibrate, or other lipid-lowering drug (n = 28,349); 2) patients with a diagnosis of hyperlipidemia without the use of lipid-lowering drugs (n = 13,271); and 3) a random sample of patients without hyper-lipidemia or use of any lipid-lowering agents (n = 50,000). Patients were followed until they developed a fracture, left the practice, or died. Fractures were identified using ICD-8 codes.

During follow-up, 3,940 patients experienced a bone fracture (group 1: n = 705; group 2: n = 681; group 3: n = 2,554). Patients currently using statin drugs had a lower adjusted odds ratio (OR), adjusted for smoking, number of general practice visits, body mass index, and steroid or estrogen use (OR = 0.55), compared to patients currently using fibrate drugs (OR = 0.87), and patients using other lipid-lowering drugs (OR = 0.76). Statins decreased the risk of fracture to the femur (OR = 0.2), hand, wrist, or arm (OR = 0.58), vertebrae (OR = 0.14), and foot (OR = 0.58). Similar to the van Staa trial, the odds of developing a hip fracture on a statin were lower compared to patients not on a statin (OR = 0.12).

Exposures were further stratified into number of prescriptions obtained, and past versus current use. Fibrates were associated only with significantly decreased vertebrae fractures (OR = 0.21) and fractures in men (OR = 0.05). The findings suggest that statins decrease fracture risk even with short exposure (1-4 prescriptions of statin medication). The reduced fracture risk was observed at various skeletal sites. There was little evidence of a decrease in fracture risk for fibrates and other lipid-lowering agents.

The main source of potential bias in this study is associated with the use of estrogens and corticosteroids. It appears there was a greater number of case patients taking chronic corticosteroids (n = 36 or 0.9%) and a greater number of control patients taking estrogens (n = 111 or 0.5%) with an OR of 2.03 (CI 1.39-2.96; p < 0.001). Estrogens increase bone mineral density and decrease fracture risk compared to corticosteroids, which cause osteoporosis if used long-term. Furthermore, the inclusion/exclusion criteria of this study were loosely regimented. Many disease states and medications (e.g., osteopenia, Rickett’s, bisphosphonate use, calcium use) may change bone mineral density and integrity. Psychotropic/CNS medications that alter the CNS and may have predisposed patients to falls were not evaluated prior to study inclusion. A person’s lifestyle can also affect the results: patients leading a sedentary lifestyle may be at a greater risk of fracture compared to those who exercise frequently. It is also unknown how often the information in the GPRD is updated. If information is not updated on a prompt basis, data pertinent to the study may be omitted.

Wang et al. conducted a case-control analysis to determine whether the use of statin drugs is associated with a reduced hip fracture risk. Subjects were accessed using data extracted from New Jersey Pharmacy Assistance for the Aged and Disabled (PAAD), and New Jersey Medicaid from 1/1/93 to 6/30/95. Patients were included in the study if they were at least 65 years old, had at least one medical service during 1994, and filled at least one prescription for any medication through Medicaid or PAAD programs in each of four consecutive six-month periods beginning 1/1/93. Patients were excluded if they had a diagnosed hip fracture, evidence of hip fracture surgery prior to the index date, or were hospitalized in the month prior to the index date. A base population of 6,110 patients was identified and separated into the following four equal groups: 1) patients who used statin drugs 180 days prior to the index date (date of hip surgery due to a fracture); 2) patients who used statin drugs three years prior to the index date; 3) patients who used non-statin lipid-lowering agents 180 days prior to the index date; and 4) patients who used non-statin lipid-lowering agents three years prior to index date.

During follow-up, 1,222 patients underwent hip surgery to repair a fracture (4,888 were control patients). The results indicate that statin use within 180 days and three years prior to the index date are associated with an approximate 50% reduction in hip fracture risk (OR = 0.5 and OR = 0.57, respectively). Non-statin lipid-lowering agents used 180 days and three years prior to index date were associated with reductions in fracture risk (OR = 0.8 and OR = 0.87, respectively). Similar to previous studies discussed, it was calculated that recent statin use had a stronger association with reduced hip fractures compared to past statin use (OR = 0.2 vs. OR = 0.60). The study suggests that the use of statin drugs is associated with a 50% decrease in the risk of hip fractures after controlling for confounding variables, compared to the use of non-statin lipid-lowering agents.

There are a few areas where bias could have been introduced into this study. The study only evaluated fractures of the hip in elderly patients. Most of the patients in this study were at least 75 years old. This may skew the results because these patients may have increased fracture risk due to their age. The use of corticosteroids could have also affected the results. Among the case patients, 4.5% (n = 55) used corticosteroids compared to 3.9% (n = 192) in the control group. Statistics, such as a modified Charlson Comorbidity Index Score, were used to adjust for estrogen, oral corticosteroid, thiazides, and psychoactive drug use, as well as congestive heart failure, ischemic heart disease, diabetes and cancer. Although the statistical adjustments can help eliminate confounding variables, each of these characteristics may still clinically influence study findings. Results did not indicate whether statistical significance was achieved between group comparisons.

Chan et al. evaluated the effects of statins on decreasing fracture risk in women 65 years and older. There were 3,675 women enrolled in the case-controlled analysis (n = 928 cases; 2,747 controls). Subjects were accessed using data derived from six health maintenance organizations from 10/94 to 9/97.

The base population was divided into two groups: those who used statins two years before the fracture date, and those who used other non-statin lipid-lowering drugs two years before the fracture date. The fracture date was the date of the first fracture code after 10/96. Women were excluded if they had a diagnostic code for major trauma, cancer of the breast, bone, colon or lung, multiple myeloma, metastatic cancer, pathological fractures between 10/94 and 9/97, or if they were taking hormone replacement therapy, bisphosphonates, calcitonin, anticonvulsants, or thyroid hormone.

During follow-up, 928 cases of fracture were reported. Of the cases, 262 had hip fracture, 196 had humerus fracture, 152 had fractures of the distal tibia, and 253 had wrist fractures. It is unknown whether any patients had more than one fracture. The general health status of the cases was generally poorer than the controls (the reason for this is unknown). The patients in the statin and non-statin groups were evaluated based on the number of prescriptions dispensed. Unlike previous trials, there appeared to be a positive correlation between the length of statin therapy and the reduction in fracture risk. In the statin group, patients receiving more than 13 prescriptions had the strongest association for decreasing fracture risk (OR = 0.5). Patients receiving 1-6 and 7-12 statin prescriptions also had an associated reduction in fractures (OR = 0.62 and OR = 0.81, respectively). In the non-statin group, no definitive associations can be determined due to wide confidence intervals noted with the data. The study suggests statins are protective against nonpathological fractures among older women. Similar to the previous trial, regular statin use was associated with a 50% decrease in fracture risk.

There are areas of bias in this study that could potentially affect the results. The study did not assess the differences in body weight index, lifestyle (e.g., smoking, exercise, diet), or corticosteroid use. These factors can affect the incidence of fractures among older women. Although the Mann Whitney U test was used to attempt to control confounding variables by comparing the chronic disease scores of cases and controls, many confounding variables were not accounted for. It is unknown how many case versus control patients were taking corticosteroids or other medications that may influence bone metabolism. It was stated that the general health of the case patients was poorer than that of the control patients (for unknown reasons). This suggests the case patients may have been at a greater risk of fracture due to their health status.

A recent abstract by Bauer et al. evaluated the effect of statin use on bone mineral density and the relative risk of hip fracture in a combined analysis of two large prospectively designed trials. The first trial, also known as the “Study of Osteoporotic Fractures” (SOF), enrolled 8,412 women ages 65 and older and followed them for a mean of 4.2 years. The second trial, also known as the “Fracture Intervention Trial” (FIT), enrolled 6,459 women aged 55-80 years old. Of these women, 314 and 284 women were statin users in the SOF and FIT trial respectively. A combined relative risk of hip fractures and non-spine fractures was reduced in the statin treated patients [RR = 0.3 (0.08-1.18) and 0.83 (0.61-1.15) respectively]. Similar to previous study results, no definitive associations were noted for patients receiving non-statin lipid-lowering agents. Because this trial is not yet published, additional details need to be determined before the results can be appropriately interpreted.

Conclusion

Each of the studies was similar with respect to study design, objectives and results. All limited in interpretation due to the retrospective study design and the potential for confounding variables. Some potential flaws include lack of compliance assessments; misdiagnosed injuries; severity of injuries; lifestyle of patients; baseline health of subjects; dosages of statin medications; severity of hyperlipidemia; risk factors for osteoporosis, calcium and vitamin D intake; and the fact that concomitant medications were not screened in detail. It is also unknown how often the databases were updated, and if results were properly added to the system.

Based on the available data, there may be an association between regular use of statin drugs and a decreased bone fracture risk, particularly in the hip. However, it is still not clear what fracture locations may be most affected, if there are any dose/product/duration differences, and whether gender response plays a role in bone response to statins. Since osteoporosis in men is pathophysiologically linked to osteoblast reduction, it is speculative that men may be more responsive than women, since women have increased bone resorption after menopause. Despite the promising results revealed in these studies, prospective controlled clinical trials need to be performed to definitively correlate statin-associated reductions in fracture risk. Although statins remain a valuable tool in decreasing morbidity and mortality associated with cardiovascular disease in patients at risk, statin therapy cannot be recommended solely for the prevention of fracture risk at this time.

Past research has shown that people with type 2 diabetes have at least twice the risk of developing coronary heart disease as those without diabetes. And once diabetics develop heart disease, their prognosis is worse than non-diabetics. Therefore, doing what it takes to avoid heart disease is important. This includes not only keeping the blood sugar within normal limits, but maintaining healthy cholesterol levels as well.

Ideally, a low-fat diet alone will lower cholesterol, but when this fails, patients should take cholesterol-lowering medication, according to a study at the University of Texas Health Sciences Center in San Antonio.

The study examined data gathered by a Scandanavian trial that investigated the ability of simvastatin (Zocor) to lower cholesterol and prevent heart attacks in diabetics.

The study involved three groups of patients: 483 people with type 2 diabetes; 678 people with elevated blood sugars but not full-blown diabetes; and 3,237 people with normal blood sugars. All of the patients, however, had elevated cholesterol levels (from 212 milligrams to 309 milligrams), and they all received either 20 milligrams of simvastatin daily or placebo.

If patients taking simvastatin did not achieve lower cholesterols, the dose was increased to 40 milligrams.

In patients with high cholesterol, diabetes and heart disease, the simvastatin reduced their risk of heart attacks, death from heart disease and cardiac arrest by 42 percent when compared to the placebo group. They also reduced the risk of undergoing vascular procedures, such as bypass by 48 percent.

In patients with high cholesterol, heart disease, and an elevated blood sugar without diabetes, simvastatin lowered the risk of major coronary events (such as heart attacks) by 38 percent.

The study also demonstrated that simvastatin reduced the risk of death from heart disease by more than half in people with high cholesterol and heart disease who were considered to be at risk for developing diabetes.

Atorvastatin (Lipitor) is a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor or “statin.” HMG-CoA reductase is the enzyme responsible for converting HMG-CoA to mevalonate; this occurs at an early and rate-limiting step in the biosynthesis of cholesterol (see figure).

Mechanism of action of Lipitor (atorvastatin)

Although a number of “statins” are now available, atorvastatin is the only drug in this class indicated as an adjunct to diet in the reduction of elevated total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo-B), and triglyceride (TG) levels in patients with primary hypercholesterolemia and mixed dyslipidemia. It is the first drug of its class specifically indicated for lowering both low-density lipoprotein cholesterol and triglyceride levels. It is also the only statin indicated for the reduction of total cholesterol and low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia, a rare, serious, life-threatening, autosomal dominant, inherited disorder of lipid metabolism.

Clinical Tips

In head-to-head clinical trials when starting doses were compared, atorvastatin was superior to lovastatin, pravastatin, and simvastatin in reducing elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides. In two placebo-controlled, dose-response studies in hypercholesterolemic patients, once-daily administration of atorvastatin significantly reduced low-density lipoprotein cholesterol by 39% to 60% across the dose range of 10 mg to 80 mg. In addition, atorvastatin reduced triglyceride levels by 19% to 37% across the dose range. In a large clinical study, the number of patients meeting the National Cholesterol Education Program – Adult Treatment Panel II target levels, while taking daily 10-mg doses of Lipitor, was assessed. After 16 weeks, 93% of patients with fewer than two risk factors for coronary heart disease and a baseline low-density lipoprotein cholesterol of 190 mg/dL or lower reached a target of 160 mg/dL or lower, and 19% of those with coronary heart disease and an low-density lipoprotein cholesterol of 130 mg/dL or more reached a target of 100 mg/dL low-density lipoprotein cholesterol or lower.

The most frequent treatment-related adverse events are constipation, flatulence, dyspepsia, and abdominal pain. Fewer than 2% of patients treated with Lipitor in controlled studies discontinued treatment because of drug-related adverse events. Elevations of serum transaminases occurred in fewer than 1% of patients, but it is recommended that liver function tests be performed before the start of treatment, after 6 and 12 weeks, and periodically thereafter. As with other statins, the risk of myopathy is increased when the drug is taken with cyclosporine, fibric acid derivatives, niacin, erythromycin, or azole antifungals. Patients should be advised to report unexplained muscle pain, tenderness, or weakness, especially if accompanied by malaise or fever.

Talk to your pharmacist!

Cholesterol and its Role in the Body

Cholesterol is a type of fat, which we need in our diet to help us build cells in our body and make hormones, which act as chemical messengers.

The body also uses cholesterol to make Vitamin D, needed to help us absorb calcium from the food we eat.

There are two main sources of cholesterol:

1. The food we eat

2. Our liver

High Cholesterol

If you have too much cholesterol in your blood stream, you are at risk for getting heart disease and stroke. In some people, it may be difficult to lower cholesterol levels through diet and lifestyle changes alone. In such cases, medications may be required to reduce cholesterol.

Cholesterol Medications

Your doctor will help you decide what medication will work best for you. Once you have chosen a medication, you usually need to continue taking it for the rest of your life.

There are several different groups of cholesterol medications available.

1) Bile Acid Resins

This family of medications includes cholestyramine resin (Questran®), and colestipol (Colestid®). Questran® is available as a powder, and Colestid® as tablets or a powder. The powder is dissolved in water or juice and is usually taken four times daily.

These medications work by stopping cholesterol from leaving your stomach and going into your blood.

The most common side effects of these medications are stomach upset, a feeling of fullness, constipation, and nausea. These side effects may disappear in time, after your body adjusts to these medications.

2) Niacin

Niacin is one of the B vitamins. It can lower cholesterol when taken in appropriate doses. Niacin works by decreasing the amount of cholesterol made by the liver.

Flushing (face turning red), headaches, or itchy skin are the most common side effects. Ask your pharmacist how to manage some of these side effects.

3) The Statins

This group of medications includes fluvastatin (Lescol®), lovastatin (Mevacor®), pravastatin (Pravachol®), simvastatin (Zocor®) and atorvastatin (Lipitor®).

Normally, these kinds of medications are taken once or twice daily. The most common, once daily dose, should always be taken with your evening meal.

The statin medications work by lowering the amount of cholesterol made by the liver.

Very few people experience side effects from these medications. However, some patients may suffer from headaches or stomach upset. Your doctor will also do blood tests and remind you of yearly eye exams when you are taking these medications.

4) Fibric Acid Derivatives

This family of medications includes gemfibrozil (Lopid®) and fenofibrate (Lipidil®). These medications are usually taken once or twice daily.

Fibric Acid Derivatives help the body get rid of extra cholesterol.

These medications normally have few side effects, but may cause stomach upset in some patients.

Combination Drug Therapy

Your doctor may prescribe one or a combination of two medications to reduce your cholesterol to a required level. If you are prescribed combination therapy, your pharmacist will help you decide when to take the two different medications. This will ensure they work better together.

General Advice

It is important that you talk to your pharmacist to learn more about your medication. Your pharmacist will also tell you if it’s safe to take other medications.

Even if you think that your cholesterol has been lowered enough, you should never stop taking your medication without consulting your doctor or pharmacist. Stopping a cholesterol medication can cause your cholesterol levels to climb up again which may be hazardous to your health!