Bridging the Treatment GapSidney C. Smith, Jr., MD

The leading cause of death and disability in the UnitedStates today is cardiovascular disease (CVD). The mainrisk factor, hypercholesterolemia, is grossly under-treated, although it is widely appreciated that loweringcholesterol levels is key to reducing the incidence ofCVD. Cholesterol-lowering therapy decreases total mor-tality, cardiovascular events, the need for revasculariza-tion procedures, and hospitalization costs. A 25–35%reduction of low-density lipoprotein (LDL) indicates sig-nificant benefits with regard to morbidity and mortality.Unfortunately, most patients who are candidates forcholesterol-lowering treatment do not receive it. Wideruse of lipid-lowering agents could, in fact, make a sig-nificant difference in patient outcomes. There is stronginterest on the part of consumers in over-the-counter(OTC) cholesterol-lowering products that may help them

reduce their risk of developing heart disease and livehealthier lives. Surveys estimate that half of all patientswith high cholesterol would like to have an OTC statinproduct made available. Increased availability of cho-lesterol-lowering therapies as well as changes in physi-cian prescribing practices could benefit a broad spec-trum of the population that is currently untreated orundertreated. Current prescribing practices and guide-lines have not resulted in widespread use of these ther-apies; therefore, outcomes for CVD prevention remainssuboptimal. The proposed advantages of making statinsavailable over-the-counter include their known efficacy,dose consistency, and proven safety profile. Q2000 byExcerpta Medica, Inc.

Am J Cardiol 2000;85:3E–7E

Cardiovascular disease (CVD) remains the leadingcause of death and disability in the United States

in both men and women.1 Mortality data show thatmore people in the United States die from CVD thanfrom any other illness. Nearly half a million men diefrom CVD each year and CVD is also the leadingcause of death in women. In fact, more women thanmen die from CVD.

The main culprit in the high CVD mortality rate iscoronary artery disease (CAD), the largest killer ofmen and women. The American Heart Association(AHA) estimates that nearly 14 million US citizenshave a history of myocardial infarction and/or angina,the classic CAD symptoms. Approximately 1 millionpeople have an acute myocardial infarction everyyear. In addition, by the time the average personreaches the age of 60, 1 in every 5 men and 1 in every17 women will develop CAD.2

THE CARDIOVASCULAR DISEASE/CORONARY ARTERY DISEASE (CVD/CAD) TREATMENT GAP

The most startling fact in this epidemic is that mostpatients who have hypercholesterolemia, the main riskfactor for CAD, and who are at risk for or have CAD,are undertreated or not treated and could clearly ben-efit from preventive strategies.

According to data from the National Health andNutrition Examination Surveys (NHANES), there are53.3 million adults with elevated cholesterol levelswarranting intervention.3 Of these, approximately 22million qualify for drug therapy based on current

management guidelines. However, only 5 million(roughly 20%) of these patients eligible for treatmentare currently receiving drug therapy.4

The NHANES III indicates that 97 million adultUS citizens have a total-cholesterol level.200 mg/dL. Of these, 38 million have a total cholesterol level.240 mg/dL4—levels that, according to the NationalCholesterol Education Program (NCEP) guidelines,require treatment and management by a physician.

With nearly 60% of CAD costs hospital related,and $50 billion per year spent on lost productivity,broadened primary-prevention initiatives appear to bethe solution to closing the treatment gap, therebycontrolling the CVD epidemic.

LOWERING SERUM CHOLESTEROLLEVELS: AN APPROACH TOCORONARY ARTERY DISEASE (CAD)MANAGEMENT

The healthcare community recognizes that reduc-ing cholesterol levels is the optimal therapeutic strat-egy for controlling CAD. Landmark clinical trial datahave demonstrated the importance of targeting low-density-lipoprotein (LDL) cholesterol levels whenconsidering drug intervention. It is, however, neces-sary to assess global risk of CAD to determine to whatdegree interventional therapies should be pursued. Asthe following section will demonstrate, cholesterol-lowering therapy is associated with significant bene-fits, including decreases in total mortality, cardiovas-cular events, the need for revascularization proce-dures, and hospitalization costs.

BENEFITS OF LIPID-LOWERINGTHERAPIES

Several secondary-prevention trials have shownthat lowering LDL cholesterol levels can reduce car-diovascular events in patients after myocardial infarc-

From the Division of Cardiology, University of North Carolina Cardio-vascular Center, University of North Carolina at Chapel Hill, ChapelHill, North Carolina, USA.

Address for reprints: Sidney C. Smith, Jr., MD, Division of Cardi-ology, University of North Carolina at Chapel Hill, 348 Burnett Wo-mack Building, Chapel Hill, NC 27599-7075.

3E©2000 by Excerpta Medica, Inc. 0002-9149/00/$ – see front matterAll rights reserved. PII S0002-9149(00)00944-9

tion. This was first shown in the Scandinavian Sim-vastatin Survival Study (4S)5 study in a high-riskpopulation. The Cholesterol and Recurrent Events(CARE)6 trial and the Long-Term Intervention withPravastatin in Ischaemic Disease (LIPID)7 study fur-ther supported the benefits in patients with averagecholesterol levels (Figure 1). Interestingly, about onethird of the patients in LIPID had unstable angina andalso experienced a reduction in cardiovascular events.

Primary-prevention trials have also shown signifi-cant benefits both in a high-risk population in the Westof Scotland Coronary Prevention Study Group(WOSCOPS)8 and in a low-risk population in theAFCAPS/TexCAPS trial9 (Figure 1). More than 80%of the individuals in the AFCAPS/TexCAPS studywho did benefit from cholesterol-lowering therapieswould not have qualified for these therapies underexisting guidelines. The impressive results of theAFCAPS/TexCAPS study raise the important ques-tion of whether the NCEP treatment guidelines shouldbe broadened.

CONTINUUM OF CORONARYARTERY DISEASE (CAD) RISK INLIPID TRIALS

In the secondary and primary-prevention studiescited earlier (Figure 1), the LDL cholesterol levelsranged from a high of about 190 mg/dL in the 4S trialto only 150 mg/dL in the AFCAPS/TexCAPS study.Overall, the relative risk reductions were 25–35%,corresponding to LDL cholesterol reductions of 25–35%. Absolute risk reductions ranged from 8.5% inthe 4S trial among patients at higher risk due to highLDL cholesterol levels and a recent event, to approx-imately 2% in the lower-risk populations in the pri-mary-prevention trials.

Findings on statins show that a 25–35% reductionof LDL cholesterol levels convey significant benefitswith regard to cardiovascular morbidity and mortality.Further, a decrease in all-cause mortality has beenshown in the secondary-prevention trials. Importantly,the secondary-prevention trials showed that benefits oftreatment are not confined just to high-risk men. Ther-apeutic benefit was also observed in women, the el-derly, and patients with diabetes. Data from the pri-mary-prevention trials have demonstrated decreases incardiovascular events and in cardiovascular mortality,however the primary-prevention trials were not pow-ered to show reductions in total mortality.

LIPID-LOWERING THERAPIES: ANUNDER-APPRECIATED NECESSITY

Unfortunately, recent data reveal that most patientswho are candidates for treatment do not receive lipid-lowering therapies. In the largest study evaluatingimplementation of lipid-lowering therapy to date, Su-eta et al10 performed a retrospective chart audit on58,890 adult outpatients with established CAD or con-gestive heart failure. Patient data were gathered from140 medical practices in the United States, of which75% were cardiology practices. Among the 48,586patients with CAD, the majority (57%) did not have

LDL cholesterol levels documented in their charts,and only 11% were treated to their target LDL cho-lesterol goal (Figure 2). It was found that almost 90%of CAD patients were not being treated to goal withtherapies that could make a significant difference inoutcome. Based on this study, it is estimated that 90%of all patients in the United States are not being treatedoptimally with lipid-lowering therapies. Wider use oflipid-lowering agents could, in fact, make a significantdifference in patient outcomes.

The use of lipid-lowering therapies in individualswith documented CAD varied with age and gender inthe study by Sueta et al.10 The highest likelihood ofreceiving treatment was in the 50-year-old male,whose probability of being treated was about 50%. Inpatients older or younger than 50 years, the likelihoodof treatment declined. Only 30% of individuals.75years of age received any treatment at all. In theyounger age group, women were less likely to betreated than men.

The implementation of primary-prevention strate-gies is also low, as was demonstrated by Pearson etal11 in the recent Lipid Treatment Assessment Pro-gram (L-TAP) study involving 4,888 patients from 5regions in the United States. The study found that 82%of patients with known CAD were not treated to theirtarget LDL cholesterol goal of#100 mg/dL. Of thosewith $2 risk factors, 63% were not treated to thetarget goal of,130 mg/dL, and 32% of the patientswith ,2 risk factors did not achieve their target goalof ,160 mg/dL. Thus, there was a stepwise decreasein the application of important lipid-lowering thera-pies, with increasing severity of disease.

Data from the recent Heart and Estrogen/ProgestinReplacement Study (HERS) indicate that,15% ofwomen with known CAD are treated to the currentNCEP II LDL cholesterol goal of#100 mg/dL, and,40% are treated to the previous NCEP I goal of#130 mg/dL.12 It can thus be concluded that mostindividuals are not receiving adequate treatment over-all, and those few who are receiving treatment are notbeing treated to goal.

CURRENT SELF-MEDICATIONPRACTICES

The use of established medical therapies for CADdoes not seem to reflect accurately the concern of thegeneral public. Twenty-five percent of the adult pop-ulation in the United States, 57–65 million people, areconcerned about their cholesterol and would like to dosomething about it.13 Of those consumers who arevery or somewhat concerned about their cholesterol,49% use a nutraceutical product,14 such as vitamin E(17%), garlic (15%), niacin (8%), or other herbalpreparations. Despite very little evidence of productefficacy, over-the-counter (OTC) medications directedtoward prevention of CAD are the fastest growingsegment of health products, with the majority of dol-lars spent on garlic supplements. In addition, 23% ofindividuals use low-dose aspirin. The HOPE trialshowed little benefit of vitamin E,15 so aside fromniacin, the OTC solutions available to the consumer

4E THE AMERICAN JOURNAL OF CARDIOLOGYT VOL. 85 (12A) JUNE 22, 2000

are rather ineffective in lowering LDL cholesterol.Yet, consumers spend almost $12 billion per year onself-medication to prevent CAD (Figure 3).16

Another OTC product, red yeast rice from China, isbecoming increasingly popular as a result of claimsthat it promotes healthy cholesterol levels. Red yeastrice actually contains a low dose of lovastatin and isavailable to the general public without prescription.The public’s response to red yeast rice suggests that

OTC statins could be a useful therapeutic option. Thepotential advantages of OTC statins over neutraceuti-cals include consistent dose, extensive clinical trials,and established safety.

The medical community has been closely follow-ing this controversial debate. Some healthcare provid-ers believe that cholesterol-lowering drugs should al-ways be taken under a doctor’s supervision, whileothers profess lovastatin to be as safe as aspirin.

FIGURE 1. Continuum of risk in primary prevention trials. 4S 5 Scandinavian SimvastatinSurvival Study; AFCAPS/TexCAPS 5 Air Force/Texas Coronary Atherosclerosis PreventionStudy; CAD 5 coronary artery disease.

FIGURE 2. Percentage of coronary artery disease (CAD) patients on lipid-lowering drugtherapy.10 LDL-C 5 low-density lipoprotein cholesterol.

A SYMPOSIUM: EXPANDING THE IMPACT OF STATIN THERAPY 5E

HIGH CONSUMER INTEREST INOVER-THE-COUNTER (OTC)PRODUCTS

There is strong interest on the part of consumers inOTC products that may help them reduce their risk ofdeveloping heart disease and live healthier lives. Ofthose patients with high cholesterol, 50% in one sur-vey indicated that they would like to have an OTCstatin product made available.17 In the same survey,among those patients who are very or somewhat con-cerned about their cholesterol,.60% are interested inpurchasing an OTC statin and.80% of consumersindicated that they would consult with their physicianbefore using an OTC cholesterol reducer.

Interestingly, prescription brand statin manufactur-ers have been supporting direct-to-consumer educa-tional advertising campaigns. Consumer advertising inthe cholesterol arena seems to spur consumers to seekout the professional advice of their doctor. In a surveyconducted from January to September 1998, duringwhich time there was no special advertising campaign,general office visits increased by 2%. However, in thewake of heavy direct-to-consumer advertisement forcholesterol awareness and prescription statin thera-pies, there was a 19% increase in visits to physicians’offices.18

CONCLUSIONThe available cholesterol-lowering therapies could

be more beneficial if they were better utilized. Ourcurrent guidelines and prescribing practice have notresulted in widespread use of these important preven-tive therapies. Many consumers are using readilyavailable OTC nutraceuticals for CAD preventionwithout substantiation of their benefits. There may beseveral advantages to making statins available OTC,

in light of their known efficacy, dose consistency, andproven safety profile confirmed in recent clinical tri-als. Issues that await further exploration include def-inition of appropriate dosage should statins be madeavailable OTC, mechanisms by which an educationalmessage about guidelines and cholesterol screeningcould be incorporated with OTC availability, and pro-grams to expand patient-physician activities in CADprevention.

1. 1999 Heart and Stroke Statistical Update. Dallas, TX: American Heart Asso-ciation.2. Kannel WB. Contributions of the Framingham Study to the conquest ofcoronary artery disease.Am J Cardiol1988;62:1109–1112.3. Johnson CL, Rifkind BM, Sempos CT, Carroll MD, Bachorik PS, Briefel RR,Gordon DJ, Burt VL, Brown CD, Lippel K, et al. Declining serum total choles-terol levels among US adults: the National Health and Nutrition ExaminationSurveys.JAMA 1993;269:3002–3008.4. Summary of the second report of the National Cholesterol Education Program(NCEP) Expert Panel on Detection, Evaluation, and Treatment of High BloodCholesterol in Adults (Adult Treatment Panel II).JAMA 1993;269:3015–3023.5. Randomised trial of cholesterol lowering in 4444 patients with coronary heartdisease: the Scandinavian Simvastatin Survival Study (4S).Lancet 1994;344:1383–1389.6. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG,Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effectof pravastatin on coronary events after myocardial infarction in patients withaverage cholesterol levels: Cholesterol and Recurrent Events Trial investigators.N Engl J Med1996;335:1001–1009.7. Prevention of cardiovascular events and death with pravastatin in patients withcoronary heart disease and a broad range of initial cholesterol levels: the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.N Engl J Med1998;339:1349–1357.8. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW,McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatinin men with hypercholesterolemia: West of Scotland Coronary Prevention StudyGroup.N Engl J Med1995;333:1301–1307.9. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA,

FIGURE 3. Annual dollar sales of heart-related supplements. ASA 5 acetylsalicylic acid (aspirin); CV 5 cardiovascular.

6E THE AMERICAN JOURNAL OF CARDIOLOGYT VOL. 85 (12A) JUNE 22, 2000

Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr. Primary prevention of acutecoronary events with lovastatin in men and women with average cholesterollevels: results of AFCAPS/TexCAPS (Air Force/Texas Coronary AtherosclerosisPrevention Study).JAMA 1998;279:1615–1622.10. Sueta CA, Chowdhury M, Boccuzzi SJ, Smith SC Jr, Alexander CM, LondheA, Lulla A, Simpson RJ Jr. Analysis of the degree of undertreatment of hyper-lipidemia and congestive heart failure secondary to coronary artery disease.Am JCardiol 1999;83:1303–1307.11. Pearson TA, Laurora I, Chu H, Kafonek S. The lipid treatment assessmentproject (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemicpatients receiving lipid-lowering therapy and achieving low-density lipoproteincholesterol goals.Arch Intern Med2000;160:459–467.12. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff

E. Randomized trial of estrogen plus progestin for secondary prevention ofcoronary heart disease in postmenopausal women: Heart and Estrogen/progestinReplacement Study (HERS) Research Group.JAMA 1998;280:605–613.13. Rosetta Marketing Group. April 1999.14. The 1998 Gallup Study of Attitudes Toward and Knowledge of Cholesteroland Saturated Fats. Multi-Sponsor Surveys, Inc.15. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementationand cardiovascular events in high-risk patients: the Heart Outcomes PreventionEvaluation Study Investigators.N Engl J Med2000;342:154–160.16. OTC Review. IMS HEALTH Self-Medication Headquarters. 1998.17. Data on File. 1999. Johnson & Johnson Merck Consumer Pharmaceuticals.18. Scott Levin’s Source Prescription Audit . “From the Heart: Why Patients SeeCardiologists”. December 6, 1999.

A SYMPOSIUM: EXPANDING THE IMPACT OF STATIN THERAPY 7E