Antonio M. Gotto

Over-The-Counter Statins Are Worth Considering in Primary Prevention of Cardiovascular Disease

Introduction

Much has already been written outlining the advantages and disadvantages of over-the-counter (OTC) access to low-dose therapy with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, or statin, for individuals at intermediate risk for coronary heart disease (CHD).1,2 After the United Kingdom’s approval in 2004 of an OTC, low-dose formulation of simvastatin, a pharmaceutical company in the United States reapplied to the US Food and Drug Administration (FDA) for a nonprescription preparation of lovastatin, which the FDA had first rejected in 2000.3 Previously, low-dose pravastatin also had failed to secure OTC approval. The sponsors of the application proposed that individuals who meet the following criteria may be those most likely to gain from access to OTC statin treatment: (1) those who qualify for primary prevention under the third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program,4 (2) those with multiple (2) risk factors and a 10-year CHD risk 20%, (3) those with no contraindications to statins, and (4) those with a favorable likelihood of experiencing benefit versus risk.

After reviewing the evidence to date, a joint session of the FDA’s Nonprescription Drugs Advisory and Endocrine and Metabolic Drugs Advisory committees again did not endorse the application.5 Despite these stumbling blocks, the appropriateness of OTC statins remains an important topic for the future of primary cardiovascular disease prevention. If further progress is to be made, advocates for OTC statins must address the concerns of the FDA panel and other critics.

Challenges of Primary Prevention of Coronary Heart Disease

As sampled across US birth cohorts from the National Health Examination Surveys (NHANES), total cholesterol levels have declined over the last few decades, likely because of the combined influence of aggressive preventive efforts and treatment effects.6 Although cholesterol awareness and control have improved, undertreatment remains a significant barrier to optimizing primary prevention. The Minnesota Heart Survey reports that >50% of the borderline-high-risk adults surveyed were not aware of their hypercholesterolemic status.7 Furthermore, only 10% of the participants in 2000 to 2002 were aware of their dyslipidemia and had it under control with treatment. It also is discouraging to note that 30% of the adults surveyed were aware of, but were not treating, their high cholesterol.

The third NHANES (NHANES III) identified 15.5% of US adults (23 million people) at moderate risk for CHD; ie, these adults have a 10% to 20% risk for a coronary event in the next 10 years according to the Framingham algorithm. By age and sex, 16% of 40- to 49-year-old men, 52% of 50- to 59-year-old men, and 81% of 60- to 69-year-old men fall into this moderate-risk category.8 Among women, the greatest percentage at moderate risk, 35%, occurs in those 70 to 79 years of age.

Although therapeutic lifestyle changes—including diet, weight management, and physical activity—are the "common-sense" cornerstones of managing these individuals, therapeutic lifestyle changes alone generally do not induce lipid changes that would achieve cholesterol goals. An analysis of data from the 1999 to 2000 NHANES from 1425 respondents at moderate risk for CHD (defined as those who have multiple risk factors and no CHD) estimated that the mean percent reduction in low-density lipoprotein cholesterol (LDL-C) required to achieve a goal of LDL-C <130 mg/dL (3.36 mmol/L) among those eligible for lipid-lowering drug therapy was 20.6%. Of these medium-risk US individuals, 16.6% would require a >30% reduction to reach the goal.9 The recent controversial findings of the Women’s Health Initiative, in which a low-fat dietary pattern was not associated with reduced cardiovascular risk, also suggest a need for treatment options beyond lifestyle monotherapy.10

What Is the Evidence of Benefit With Low-Dose Statin Therapy?

Some experts have questioned whether the proposed lovastatin dosage of 20 mg/d was potent enough to have clinical efficacy, but the FDA panel voted unanimously and with few qualifications that such a dosage likely would be effective.5 The key evidence of clinical benefit in support of the application was the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Participants in that trial were 6605 middle-aged men and women with no clinical evidence of atherosclerosis. They had average levels of LDL-C and below-average high-density lipoprotein cholesterol (HDL-C) compared with the overall NHANES III cohort.11 Treatment was lovastatin 20 to 40 mg/d versus placebo. The statin dosage was titrated at week 18 if an LDL-C target goal of 110 mg/dL (2.84 mmol/L) was not attained. At 1 year, lovastatin induced a 25% reduction in LDL-C compared with baseline. In the lovastatin group, 50% of the patients required titration, and the mean on-treatment LDL-C was 115 mg/dL (2.97 mmol/L). Of the group randomized to lovastatin, 81% reached the ATP III target goal of 130 mg/dL (3.36 mmol/L) compared with 12% of the placebo patients.

After a median of 5.2 years, lovastatin therapy yielded a statistically significant 37% reduction in the rate of first acute major coronary events defined as fatal or nonfatal myocardial infarction, unstable angina, and sudden cardiac death (P<0.001). Significant reductions also were seen in a number of secondary end points, including the risk for revascularization and the risk for cardiovascular end points. Investigators detected no major difference in safety between statin and placebo, except for small, consistent increases in creatine kinase with lovastatin compared with placebo. The frequency of creatine kinase elevations >10 times the upper limit of normal was identical in the study groups.12 Therefore, AFCAPS/TexCAPS was the first major statin trial to confirm that primary prevention is effective and safe in a lower-risk cohort.

Despite these positive findings, some features of AFCAPS/TexCAPS make the analogy with a hypothetical OTC experience an imperfect one. The 5.6% 10-year CHD event rate in the placebo-treated group of the study is much lower than any treatment threshold currently recommended for lipid-lowering drugs in primary prevention.11 The cost-to-benefit ratio of treating such a low-risk cohort may be unfavorable. Furthermore, the use of drug titration in the study to achieve the goal does not mimic the fixed dosage proposed for the OTC scenario.

Indeed, only a few other studies have looked at the effects of lower-dose statin therapy on clinical end points, but none of these other trials studied lovastatin as the active intervention. In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), atorvastatin 10 mg/d reduced the risk for first CHD events compared with placebo in hypertensive patients with moderate CHD risk.13 The Japan Lipid Intervention Trial (J-LIT), a nationwide cohort study, analyzed the lipid effects and safety of an open-labeled, low dosage of simvastatin (5 to 10 mg/d) in 52 421 hypercholesterolemic patients. After 6 months of therapy, LDL-C was reduced by 26% and HDL-C was increased by 2.3% on average compared with baseline. There was a <1% incidence each of hepatic and musculoskeletal disorders, although there was a 3.3% overall incidence of adverse drug effects over 6 years of follow-up.14 In J-LIT, 47 294 patients would have qualified for primary prevention because they had no history of cardiovascular disease. In this subgroup, each 10-mg/dL decrease in LDL-C was associated with a 15.8% decrease in CHD risk, whereas each 10-mg/dL increase in HDL-C was associated with a 37.5% decrease in CHD risk.15 However, interpretation of the findings of J-LIT suffers because of its lack of a control group as a comparator.

The Management of Elevated Cholesterol in the Primary Prevention of Adult Japanese (MEGA) study was a randomized, primary-prevention, open-label, parallel-group trial of a low-fat/low-cholesterol diet versus diet plus pravastatin 10 to 20 mg/d in 8009 men and women 40 to 70 years of age who had total cholesterol of 220 to 270 mg/dL (5.69 to 6.98 mmol/L). Follow-up was planned for >5 years.16 The primary end point was a composite of major CHD events, comprising fatal or nonfatal myocardial infarction, sudden cardiac death, unstable angina, and coronary revascularizations. As announced at the American Heart Association Scientific Sessions in November 2005, a between-group LDL-C difference of 23 mg/dL was associated with a significant 33% reduction in this end point (P=0.010).17 There was no significant difference between groups in the development of adverse phenomena.

The real incidence of statin side effects may be higher in clinical situations in which patients are not selected or monitored as closely as they are in clinical trials,18 but the FDA panel agreed that the muscle and liver risks associated with lovastatin at the proposed OTC dosage were low.5 Nevertheless, rare cases of hepatocellular toxicity and jaundice necessitate careful monitoring of patients with significant liver disease, heavy alcohol consumption, or chronic hepatitis who are prescribed statins.19 Certain groups may be more prone for myopathy on statin treatment and would not be candidates for statin self-medication: frail elderly individuals, especially women; patients with diabetes complicated by chronic renal failure; individuals in the perioperative phase after surgery; those with liver disease; and those taking specific concomitant medications.18

Can Patients Self-Select for OTC Statin Treatment?

Perhaps the greatest concern expressed by the FDA panel was whether patients would be able to select themselves correctly for OTC statin without physician supervision.2,5 An early evaluation of a proposed self-management system, the Consumer Use Study of Over-the-the Counter Lovastatin (CUSTOM) was an open-label, uncontrolled, multicenter study that examined the behavior of potential OTC purchasers in 14 storefront sites intended to simulate a "real-world" pharmacy setting.20 The materials developed for the self-management system focused on describing primary prevention of CHD in the intermediate-risk population and encouraged participants to discuss their concerns about cholesterol, including OTC statin treatment, with their physicians.

Nurse-practitioners, in the role of the "pharmacists," were not permitted to volunteer any information that might influence the participant’s ability to self-select, but they could answer questions and perform an eligibility assessment interview at the participant’s request. Respondents were then categorized as "purchasers, users," "purchasers, nonusers," or "nonpurchasers," depending on their behavior.

Although most nonpurchasers correctly followed the label (ie, they did not qualify for the OTC statin and therefore did not buy it), only 10% of the users met all label criteria for use.20 Most users met many, but not all, of the criteria mainly because they either were slightly outside the age range or lipid values or had no risk factors for CHD, as specified in the label. The FDA panel thought that because the preponderance of users did not match the label criteria, the general public would not be able to follow the label exactly.5 Although this strict interpretation of the proposed label is reasonable, coronary risk is continuous. There is no confirmed cholesterol threshold below which there is no further benefit of treatment. Some allowance for personal judgment would be desirable in these borderline individuals.

A small survey of 3 pharmacies in Bristol (UK) that involved 102 men and women (mean age 57 years) who were not taking statins provides another perspective.21 Using a questionnaire, the investigators determined that 45% of respondents were willing to purchase simvastatin, but 94% of those willing to buy would do so only after consulting their general practitioner. The potential for misuse was evident in that high-risk respondents were as likely as low-risk respondents to consider buying OTC simvastatin. This small, informal study suggests a greater need for patient education to understand the place of OTC statins in preventive care and that physician guidance still would be necessary to individuals who chose this approach.

Discussion

Before the United Kingdom’s decision to deregulate simvastatin, drugs that have moved to OTC have been intended for acute symptom control (eg, the allergy medication loratidine and the heartburn medication omeprazole) rather than treatment of chronic conditions like hypercholesterolemia or hypertension.22 The United Kingdom has indicated that it is considering a list of >100 individual drugs that also may move to OTC.23 However, the release of OTC simvastatin in the United Kingdom met its share of controversy. Critics have questioned the clinical efficacy of the dosage approved, and consumer groups have challenged the marketing of the product.24 Nevertheless, there are several potential advantages of being able to get a statin without a prescription: improved and broader access to treatment, increased education about risk factor modification, greater patient autonomy in making decisions about treatment, and healthcare savings resulting from reduced coronary events.25 The FDA panel concurred that the OTC dosage of lovastatin suggested by the sponsor was likely to produce a significant benefit, that the risks for side effects with OTC lovastatin were low, and that safety monitoring with regular liver function tests and creatine kinase measurements would not be necessary.5

However, the challenges conferred by nonprescription status are equally great. Hypothetically, misuse may occur by high-risk patients who wish to circumvent a doctor’s care or by low-risk patients who undertake a course of treatment that has an unfavorable cost-benefit ratio.25 The FDA panel emphasized the need for a clear label, for an unambiguous definition of the target population for OTC statins, and for patient educational materials that would minimize the risk for mistreatment. More likely, patients may avoid OTC statins because they are reluctant to bear the cost of buying their own OTC drugs, especially when the drug is for the treatment of a chronic condition with no visible indicators. In the United Kingdom, the sales of OTC simvastatin have not been vigorous.26

An important criticism of a single-dose OTC statin is that it may delay the introduction of drug titration or combination therapy to patients who need it. Those at intermediate risk for near-term CHD have an LDL-C goal of <130 mg/dL (3.36 mmol/L), but recently, the ATP III also has allowed an optional goal of <100 mg/dL (2.59 mmol/L).27 The introduction of a more aggressive goal that is based on clinical judgment further necessitates the physician’s participation in treatment decisions for intermediate-risk patients and thus complicates the case for self-medication.

The FDA committees also cited limitations in the current infrastructure of US pharmacies as a factor in its decision. In the United Kingdom, simvastatin is sold "behind the counter," which requires the patient to engage in dialogue and risk assessment with the pharmacist before being allowed access to the drug. Behind-the-counter services are not common in US pharmacies, but support is growing for pharmacists to play an intermediary role in screening patients and to control access to some medications.28 However, involving the pharmacist more deeply in clinical decision making in favor of an OTC would require that remuneration structures account for the increased time commitment, additional training, and loss of prescription drug revenues.22

In addition, some members of the panel thought that the availability of a nonprescription statin would have a negative effect on efforts to promote preventive lifestyle measures such as diet and exercise.5 An OTC version of the antiobesity medication orlistat 60 mg, which the same joint panel recently endorsed, raises the same concern.29 The sponsors of both OTC lovastatin and orlistat, however, intend to include extensive educational and support materials about lifestyle modification as a critical complement to drug therapy as part of their respective OTC programs. It is important to observe that although orlistat has been shown to reduce the risk for developing diabetes,30 it is unclear whether the weight loss it produces will translate in the long term into reductions in other obesity-related risks such as CHD; statins, on the other hand, have clinical event reduction indications. The OTC dosage of orlistat was associated with only a modest 5- to 10-lb weight loss with an 50% frequency of mild to severe gastrointestinal side effects.31 Despite these issues, the panel acknowledged the potential public health benefit and voted 11 to 3 in favor of the application.

Although there is almost total consensus that statins are cardioprotective drugs with few adverse side effects, obstacles remain for the approval of OTC statins, largely questions related to how best to implement an OTC program. In its 20-to-3 vote against the application, members of the FDA’s advisory committee who opposed the application shared similar concerns (Table).5 Whether statins will ever make the leap from prescription to OTC remains to be seen. Nevertheless, the discussion is worthwhile in the face of the continuing epidemic of CHD morbidity and mortality in the United States. At present, proponents require a major feat to break the stalemate over OTC statins in the United States. A change in the law that facilitates behind-the-counter pharmacy services, a more convincing use study that addresses the concerns raised by CUSTOM, or data that demonstrate the public health benefit of OTC statin access could provide that impetus. Discovering whether an OTC statin would be a viable option for patients who need treatment will help shape future efforts in cardiovascular prevention.

Major Concerns About the Approval of OTC Statins in the United States

References

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2) Gotto AM Jr. Over-the-counter statins and cardiovascular disease prevention: perspectives, challenges, and opportunities. Clin Pharmacol Ther. 2005; 78: 213–217.

3) Reuters News Service. Merck heart drug set to go over counter in Britain. May 10, 2004.

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5) Joint Meeting of the Nonprescription Drugs Advisory Committee and the Endocrinologic & Metabolic Drugs Advisory Committee January 13–14, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/minutes/2005–4086M1.htm. Accessed May 16, 2005.

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Response to Gotto
Philip J. Barter, MBBS, PhD, FRACP; Kerry-Anne Rye, PhD
In his support of over-the-counter statins, Dr Gotto clearly highlights a number of potential benefits of this approach. However, he also notes that a number of challenges must be addressed before such a strategy is adopted. He points out that the cost-to-benefit ratio of treating low-risk people is still not known and may well be high. He is also concerned that a very low rate of adverse effects observed in people taking low-dose statins in clinical trials may not reflect the situation in the general population in which the usual clinical trial exclusion criteria tend not to apply. We agree with Dr Gotto’s concern about potential problems in people taking statins without physician supervision. There is no doubt that, if made available over the counter, these agents will be used by many people in whom simple lifestyle measures would have been sufficient to achieve recommended low-density lipoprotein cholesterol goals. There also is a real danger that, in the absence of physician supervision, many high-risk people will not have their statin dose titrated to levels necessary to achieve the low-density lipoprotein cholesterol targets shown in trials to minimize risk. For these and the other reasons stated in our case against the use of over-the-counter statins, we urge extreme caution and call for much more information before this strategy is adopted. In the meantime, we strongly agree with Dr Gotto’s conclusion that it is important to continue discussions on this issue (and on any other potential preventive measures) when confronted with an escalating worldwide epidemic of cardiovascular disease.