Rationale and Public Health Implications of Changing CHD Risk...

ANRV305-PU28-17 ARI 6 March 2007 17:54

Rationale and Public HealthImplications of ChangingCHD Risk FactorDefinitionsRobert M. Kaplan and Michael OngDepartments of Health Services and Medicine, University of California, Los Angeles,California 90095-1772; email: [email protected], [email protected]

Annu. Rev. Public Health 2007. 28:321–44

The Annual Review of Public Health is onlineat http://publhealth.annualreviews.org

This article’s doi:10.1146/annurev.publhealth.28.021406.144141

Copyright c© 2007 by Annual Reviews.All rights reserved

0163-7525/07/0421-0321$20.00

First published online as a Review inAdvance on January 12, 2007

Key Words

risk factors, heart disease, prehypertension, impaired fastingglucose, JNC VII, ATP III

AbstractThe definition of disease is central to the practice of medicine andto public health policy. Practice guidelines set standards for diseaseidentification and treatment. Quality care is often defined as ad-herence to these guidelines. Over the past few years, the diagnosticthresholds for several common medical conditions have been low-ered, resulting in a substantial expansion in the market for healthcare. The most recent guidelines for high blood pressure, highcholesterol, and impaired fasting glucose each define a high percent-age of the adult population as in need of regular medical attention.Under the latest proposed thresholds, virtually the entire adult pop-ulation qualifies for a chronic condition diagnosis. We evaluate thehealth and financial outcomes associated with changes in diagnosticthresholds for the prevention of three risk factors for cardiovascu-lar disease and stroke: blood pressure, serum cholesterol, and fastingplasma glucose. Estimates of the numbers of people affected, the costimplications, and the overall public health consequences are offered.

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INTRODUCTION

In 1992 Rose published The Strategy of Preven-tive Medicine (71). Many consider the book tobe one of the most important statements aboutepidemiology and public health produced inthe twentieth century. Rose noted that thereis a systematic relationship between risk fac-tors for coronary heart disease (CHD) andpoor health outcomes. For example, the rela-tionship between systolic blood pressure andboth CHD and stroke moves systematicallyupward with systolic blood pressures above115 mm Hg (30, 38). Similarly, the Medi-cal Research Foundation/British Heart Foun-dation (MRC/BHF) heart protection studydemonstrated that lowering LDL cholesterolusing simvastatin (Zocor®) reduced the de-velopment of vascular disease independent ofthe initial levels of serum cholesterol (10).

Rose argued that only small portions ofcardiovascular events occur in those withrisk factor scores above typical therapeuticthresholds. For example, in comparison tothose with a systolic blood pressure less than120 mm Hg, only ∼24% of the excess deathsfrom stroke occur in patients with systolicblood pressures higher than 160 mm/Hg (59).The great majority of cases of CHD andstroke occur in patients with risk factor scoresbelow the therapeutic threshold. Accordingto Rose (70), too much attention has beendevoted to case identification and treatment,and not enough attention has been paid toshifting the entire distribution of blood pres-sure and cholesterol downward. A population-based intervention that shifts the distribu-tion of blood pressure toward the left willhave greater impact on population health thanwill targeted screening (59). This argumentforms the basis for population-based preven-tive medicine.

Rose argued that population-based pre-ventive measures must meet several criteria.First, they must be low cost. Second, theymust be minimally invasive. Any interventionapplied to an entire population must produceas little pain and discomfort as possible. Rose

urged the use of public health approaches tothe management of CHD risk factors. He didnot argue for changing the diagnostic thresh-old for treating disease, nor did he advo-cate for the use of high-cost pharmaceuticalproducts (71). Nevertheless, Rose’s argumentshave been used to justify more aggressivetreatment of CHD risk factors using expen-sive pharmaceutical interventions (5, 49). Inthe following section, we consider the ratio-nale for changing thresholds for the initiationof treatment.

CHANGING DISEASEDEFINITIONS

Over the past few years, the diagnostic thresh-olds for several common medical conditionshave been lowered, resulting in a substan-tial expansion in the market for health care(36, 53). For example, the most recent guide-lines for high cholesterol (32) and high bloodpressure (21) each define most of the olderadult population as in need of regular medi-cal attention. One analysis published in 1999suggested that three quarters of the adult pop-ulation now qualify for a chronic disease di-agnosis (73). In the past few years, proposalshave emerged to lower disease thresholds evenfurther. Under the latest proposed thresholds,virtually the entire adult population qualifiesfor a chronic condition diagnosis (42).

The purpose of this chapter is to eval-uate what is known about the health andfinancial outcomes associated with changesin diagnostic thresholds for the preventionof cardiovascular disease and stroke. Bene-fits include increased life expectancy and im-proved quality of life associated with earlydetection. They also include dollar savingsleading to other spending opportunities andimproved health outcome. Harms includeconsequences of treatment resulting from sideeffects and the potentially damaging effects oflabeling. Financial harms could include dol-lars spent, reducing opportunities to investin other programs that might have a greater

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potential to enhance public health. To evalu-ate these issues, we consider three case studies:blood pressure, serum cholesterol, and fastingplasma glucose.

EXAMPLE 1:PRE-HYPERTENSION

Hypertension is a major public health prob-lem. According to a variety of data sets, ∼24%of the adult population have prevalent hyper-tension under the current definition as systolicblood pressure (SBP) > 140 or diastolic bloodpressure (DBP) > 90 mm Hg (16). Using pop-ulation surveys, the proportion of the pop-ulation with hypertension has remained sta-ble over the past 40 years. Between 1970 and2000, the proportion of the population awarethat they had hypertension, treated for highblood pressure, and with blood pressure con-trolled systematically increased (89). Chang-ing the diagnostic threshold for hypertensionfrom 160/95 to 140/90 approximately dou-bled the number of cases (82).

The National Heart Lung and Blood Insti-tute (NHLBI) has administered the NationalHigh Blood Pressure Education Program(NHBPEP) for more than three decades. InMay 2003, the commission released its sev-enth national report, known as Joint NationalCommittee ( JNC) VII (21). Successive JNCreports have pushed for lower diagnosticthresholds for high blood pressure. JNC VIdefined high-normal blood pressure as SBP =130–139 mm Hg and DBP = 85–89 mm Hg.JNC VII goes a step further by defining a newcondition known as prehypertension. Indi-viduals in this category have a SBP of 120–139mm Hg or a DBP of 80–89 mm Hg (21).

On the surface, the rationale for creatingthe new category of prehypertension is com-pelling. Epidemiologic studies of adults be-tween the ages of 40 and 70 years suggest thateach increase in SBP of 20 mm Hg and eachincrease in DBP of 10 mm Hg results in a dou-bling of cardiovasular disease (CVD) risk, ex-cept for those with blood pressures lower than115/75 mm Hg (51). The report argued that

SBP: systolic bloodpressure

DBP: diastolicblood pressure

management of blood pressure using medica-tion results in 40% reduction in the incidenceof stroke, a 25% reduction in the incidenceof myocardial infarction (MI), and a 50% re-duction in the incidence of heart failure (64).However, large clinical trials have not shownbenefits for lowering high-normal to optimalblood pressure.

The rationale for the JNC VII definitionof prehypertension was that people with mod-erately high blood pressure are at increasedrisk for heart attack and stroke just as thosewith very high blood pressure are. The mostimportant piece of evidence supporting therationale came from the Prospective StudiesCollaborative. This group performed a meta-analysis of 61 studies involving more thanone million adults. The results of the meta-analysis are summarized in Figure 1. Thegraph shows the relationship between SBPand stroke and the relationship between DBPand stroke. The four lines on the left andright of the figure are for different age groups.There appears to be a linear relationship be-tween blood pressure and stroke. Concern-ing DBP, for example, the benefit one gainsfrom reducing blood pressure by 5 mm Hg isthe same for people whose initial values arevery high, for example, higher than 100 mmHg, and for those who are initially low, forinstance, 75 mm Hg.

Although the Prospective Studies Collab-orative suggests a linear relationship betweenblood pressure and stoke, it is important toexamine Figure 1 in more detail. Two fea-tures are important. First, values closer to nor-mal (i.e., DBP 70 mm Hg) are actually abovethe diagonal. The Prospective Collaborativeinvestigators simply decided to ignore thesepoints in their curve-fitting exercise. Themost important feature of Figure 1 is thatthe y-axis is a logarithmic rather than a linearscale. The relationship between blood pres-sure and stroke is approximately log-linearrather than linear. Each point on the y-axisis twice as large as the preceding point.

To gain a better understanding of the re-lationships, we redrew the SBP portion of

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Age at risk (years):

80 - 89

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Usual systolicblood pressure (mm Hg)

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Usual diastolicblood pressure (mm Hg)

Figure 1Blood pressure and the risk of stroke. From Reference 51. Reproduced by permission of the Lancet.

Figure 1. The revised graph is shown asFigure 2. The difference between the twographs is that our figure uses ordinary unitson the y-axis. The most striking feature in theredrawn graph is that the inflection point isat about 90 mm Hg, at which the probabil-ity of stroke rises more steeply. The relation-ships are quite similar for SBP (not shown).For the lower age groups, the relationshipbetween SBP and stroke is quite flat up to∼140 mm Hg. These results are consistentwith most articles previously published inthe literature. For example, Neaton & Went-worth (65) also found log-linear relationshipsbetween SBP/DBP and death from CHD us-ing data from 316,099 white male participantsin the Multiple Risk Factor Intervention Trial.The MRC trial in mild hypertension showedthreshold values for both coronary event andstroke at ∼150 mm Hg (61). This log-linear

relationship has been confirmed in a varietyof populations, including studies in Asia (50).In other words, the probability of stroke is notlinearly related to blood pressure. In fact, theprevious thresholds for initiation of treatmentat 140 mm Hg for SBP or 90 mm Hg for DBPappear to have a clear rationale.

We fit third-degree polynomials to thecurves and estimated the differences in ab-solute risk of stroke mortality in 5–10-yearintervals on the basis of these data. The fitsfor the polynomials were excellent (all aboveR2 = 0.99). These fit polynomials are shownin Figure 2. A 50- to 59-year-old who lowersDBP from 84 to 79 reduces his risk of strokefrom 0.0026 to 0.0021 (about 5 chances per10,000). However, a person the same age whoreduces DBP from 110 to 105 experiences arisk change from 0.0084 to 0.0066 (about 2chances per 1000). The benefit for those who

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y = 0.0007x3 - 0.1497x2 + 11.398x -

y = 0.0002x3 + 0.0022x2 - 2.9432x +

149.74

R2 = 0.9985

y = 0.0004x3 + 0.0171x2 - 9.0107x +

429.82

R2 = 0.9969

y = 0.0168x3 - 3.8842x2 + 299.86x -

7650.3

R2 = 0.9903

0

50

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70 75 80 85 90 95 100 105 110

50–59 years

60–69 years

70–79 years

80–89 years

Poly. (50–59years)




Figure 2Redraw of therelationship betweendiastolic bloodpressure andprobability of strokemortality usingnatural units on theY axis. For each agegroup the secondcurve was fit using athird-degreepolynomial.

start at high risk is much larger. The goal oftherapy is to normalize blood pressure. An80- to 89-year-old who reduces DBP from 85to 79 experiences a risk reduction for strokefrom 0.0091 to 0.0081. However, the 80- to89-year-old who normalizes DBP to 79 mmHg from a starting point of 110 experiencesa risk reduction from 0.0696 to 0.0081 (morethan eightfold). Benefits of therapy are muchstronger for those who begin at higher risk.

Another concern about the treatment ofpeople with mild-spectrum hypertension isthat few clinical trials have evaluated peoplewho have prehypertension but do not haveother risk factors. Table 1 summarizes a sam-pling of studies that have often been cited assupporting aggressive management of bloodpressure. The few studies that included partic-ipants with relatively normal blood pressurefocused on patients with other CHD risk fac-tors, including established coronary disease,diabetes mellitus, and renal disease. There arefew studies of people in the prehypertensiverange who do not exhibit other risk factors.The one exception is the Trial of Prevent-ing Hypertension (TROPHY) (40). In this

trial, 409 adults with SBP between 130 and139 mm Hg and DBP < 89 or DBP between85 and 89 mm Hg and SBP < 139 mm Hgwere randomly assigned to an angiotensin-receptor blocker (ARB) or to a placebo. Theplacebo group was significantly more likely toprogress to hypertension and to experience se-rious adverse events over the next four years.

HOW MANY PEOPLE WILL BEAFFECTED BY THE NEWGUIDELINES?

Using simulation techniques, we estimatedthe impact of lowering diagnostic thresholdsupon population health status. A variety ofassumptions were used to create these mod-els. First, the population distribution of bloodpressure was estimated using data from theThird National Health and Nutrition Exami-nation Survey (NHANES III). NHANES IIIwas conducted between 1999 and 2002 bythe National Center for Health Statistics ofthe Centers for Disease Control and Preven-tion (CDC). The purpose of the survey wasto evaluate the health and nutritional status of


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Table 1 Characteristics of participants in selected studies of hypertension treatment

Study Sample size Predominate risk factorBlood pressure at

baselineHypertension Detection andFollow-up Program (3)

10,940 Hypertensive, but not on medication All DBPs >90 and<104 mm Hg

Prospective Randomized Evaluationof the Prospective RansomizedEvaluation of the Vascular Effects ofNorvasc Trial (PRE-VENT)(17)

825 History of CV complications 129/79 mm Hg (34%measured while onmedication)

African American Study of KidneyDisease and Hypertension(AASK)(90)

1094 (all AfricanAmerican ages18–70

1094 hypertensive renal disease 150/95 mm Hg

Irbesartan Diabetic NephropathyTrial LIFE(52)

9193 Hypertensive patients with nephropathydue to type 2 diabetes

174/98 mm Hg

Appropriate Blood Pressure Controlin Diabetes Trial (ABCD)(26)

480 All subjects had diabetes mellitus 136/84 mm Hg

Diabetes, hypertension,microalbuminuria or proteinuria,cardiovascular events, and ramipril(DIABHYCAR)(55, 60)

4912 All subjects had diabetes mellitus 146/83 mm Hg

Hypertension in the Very ElderlyTrial (HYVET)(15)

1283 (all elderly) Previous hypertension 181/100

The Irbesartan Type II DiabeticNephropathy Trial (IDNT2)(68, 69)

1715 All subjects had diabetes mellitus andrenal disease

159/87

NIsoldipine in COronary arterydisease in LEuven (NICOLE)(24)

819 All subjects had established coronarydisease and underwent PTCA

129/78

Treatment of Mild HypertensionStudy (TOMHS) (54)

844 All subjects had mild hypertension,defined as DBP 90–99 mm Hg withoutmedication or 85–99 mm Hg if usingmedications

140/91

Trial of Preventing Hypertension(TROPHY)(40)

772 56% had total cholesterol values >200mg/dl, 38% had triglycerides 150 mg/dl

134/84

the civilian noninstitutionalized population ofthe United States. The study uses a nationalsample of ∼34,000 people 2 months of ageor older. In addition to household interviews,73% of the sample had blood drawn and un-derwent physical examination. Our analysisfocused on ∼20,000 men and women aged17 years or older for whom physical exami-nation data were available.

Figure 3 shows the distribution of SBP inthe U.S. population. This distribution is rela-tively normal. We estimated that ∼4% of thepopulation is in the highest risk category withSBP greater than 160 mm Hg. About 14% of

participants had SBPgreater than 140 mm Hg.However, using the new definition of prehy-pertension, nearly 60% qualify for a diagnosis.Furthermore, this number goes up systemat-ically with age. Using either current medi-cation user, SBP > 120 mm Hg, or DBP >

80 mm Hg, more than 90% of those olderthan 65 have hypertension or prehyperten-sion. These analyses are consistent with Wang& Wang (87) who independently reportedthat 58.2% of the total adult population is el-igible for a diagnosis of prehypertension orhypertension and 88.3% of those older than60 may fall into this category.

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0

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90 100 110 120 130 140 150 160 170 180 190 200 210

Figure 3Distribution of systolic blood pressure from NHANES III.

HOW MANY WILL PROGRESSTO CARDIOVASCULARDISEASE?

Progression from prehypertension to actualhypertension has been investigated in theFramingham cohort for different age groups(35–64 and 65–94) (83). After adjusting forsex, age, body-mass index, baseline examina-tions, and baseline SBP and DBP, individualswith SBP between 130 to 139 or DBP be-tween 85 to 89 progressed to hypertension af-ter 4 years in 37.3% of those aged 35 to 64 and49.5% of those aged 65 to 94. Individuals withSBP between 120 to 129 or SBP between 80to 84 progressed to hypertension after 4 yearsin 17.6% of those aged 35 to 64 and 25.5% ofthose aged 65 to 94. Of note, 20% to 30% ofindividuals with blood pressure in the prehy-pertension range spontaneously reduced theirblood pressure to normal.

It is interesting to consider the results ofthe TROPHY clinical trial in light of theseobservational data. In the TROPHY trial, therate of progression from prehypertension tohypertension was significantly higher in theplacebo group (63%) than would be expected

on the basis of observational data. The rateof progression in the treated group (53%)is closer to what observational studies wouldsuggest (40).

Hypertension leads to increased risk ofstroke and CHD. MacMahon and colleaguespooled the results from seven observationalstudies with stroke outcomes and nine obser-vational studies on CHD outcomes in hyper-tensive patients. The relative risk of strokebegan to increase systematically with DBP ex-ceeding 91 mm Hg. Those at 105 mm Hgwere nearly 3.5 times more likely to experi-ence stroke than were those at 90 mm Hg orlower. Similarly, the risks for CHD increasedto more than 2.0 for those with DBP of105 mm Hg or higher (58).

Whereas the Joint National Commissionon high blood pressure noted that aggressivetreatment of high blood pressure coincidedwith significant declines in stroke between1960 and 1990 (4), the evidence about the ef-fectiveness of aggressive management of highblood pressure is not so clear. For example,the decrease in strokes exceeds what would beexpected given studies on the effects of blood


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pressure control. One analysis pooled resultsfrom nine clinical trials and noted that a 5.6-mm-Hg decrease in DBP was associated witha 38% decrease in stroke. Between 1970 and1980 there was a ∼1 mm Hg/year decline inDBP, which should have resulted in an ∼18%decrease in stroke. However, the actual ob-served decline was 43% (48). The MinnesotaHeart Study showed significant annual de-clines in stroke over the course of time, but thedecline in stroke was uncorrelated with hy-pertension in their population (57). Ivanovicand colleagues (39) used insurance records tocompare policy holders who had equivalentblood pressure but were either treated or nottreated for hypertension. Those treated forhypertension were significantly more likely todie during the following 5.2 years (39). It re-mains unclear whether the decline in stroke isassociated with better control of blood pres-sure. Other public health measures may beresponsible for the decline. For example, thedecline in stroke coincides with the precip-itous decline in tobacco use in most U.S.states. Several studies have shown a decline instroke risk as a function of smoking cessation(45, 88).

In summary, changes in the diagnosticthreshold for high blood pressure have led tothe identification of at least 13 million newcases. The new category of prehypertensionin addition to hypertension will include upto 60% of the population and 90% of adults60 years of age or older. The consequencesof high blood pressure, including stroke andCHD, have been systematically declining, andthe changes in diagnostic thresholds have re-sulted in better population health. However,the observed decline in stroke and CHD hasbeen much more rapid than would be expectedfrom changes in blood pressure.

EXAMPLE 2: HIGH SERUMCHOLESTEROL

Following the Coronary Primary Preven-tion Trial (2) the national cholesterol ed-ucation program argued for the aggressive

management of elevated serum cholesterol.The arguments in favor of population-basedcholesterol lowering are multiple. Perhapsthe two most persuasive arguments comefrom the Multiple Risk Factor InterventionTrial (MRFIT) (79) and the British MedicalResearch Council/British Heart FoundationHeart Protection Study (10). The MRFITstudy demonstrated that the relationship be-tween total cholesterol and death from CHDwas systematic and independent of the origi-nal level. Reducing total cholesterol from 300to 280 mg/dl, for example, provided the samepercentage reduction in death from coronarydisease as would be afforded someone reduc-ing total cholesterol from 220 to 200 mg/dl(79). Ironically, the MRFIT study was an in-tervention trial that failed to demonstrate abenefit for intervening on risk factors (1).

The Coronary Primary Prevention Trial(CPPT) used cholestyramine to reduce ele-vated serum cholesterol for men at risk forcoronary disease. Over the next decade, asignificant controversy about the benefits ofcholesterol lowering ensued. Meta-analysisconsistently showed benefits for reduction indeaths from heart disease but no benefit fortotal mortality (62, 63). Furthermore, someinvestigators were concerned that reductionsin deaths from heart disease were compen-sated for by increases in deaths from othercauses (31).

The introduction of the HMG-CoAreductase inhibitors or statin medicationshelped silence this controversy. Studies in-volving statins tended to show reductionsin both deaths from heart disease and to-tal mortality (19, 25). Nevertheless, somecontroversy remained. The MRC/BSF HeartProtection study was particularly importantbecause it was large (n = 20,536) and ran-domized (10). Perhaps the most interestingfinding was that simvastatin was given to awide range of individuals at risk for coro-nary disease. There was a benefit in termsof CHD mortality irrespective of the initialcholesterol concentrations. Consumption of40 mg of simvastatin daily was associated with

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the reductions in MI, stroke, and the num-ber of the revascularization procedures. Thestudy has been interpreted as suggesting theneed for greater use of statin drugs in the pop-ulation (10). However, whereas the relativerisk reduction afforded by the statins appearsfairly constant over all risk groups, the abso-lute risk reduction is much smaller in thoseat lower risk. Furthermore, some have ques-tioned the value of statins for low-risk women(86). Walsh & Pignone performed a meta-analysis of six trials of lipid lowering. The tri-als included 11,435 women without CVD. Inthese trials, lipid lowering did not reduce ei-ther CHD or total mortality. Among nearly2400 women randomly assigned to take statinsor placebos in secondary prevention trials,there were 102 deaths among women takingthe active drug and 103 deaths among womentaking the placebo (86). Thus, little evidenceindicates that statins reduce total mortalityin women. The rationale for statin therapyin older adults has also been challenged. Forexample, Packard and colleagues noted thatlow-density lipoprotein (LDL) cholesterol isa good predictor of neither outcome nor re-sponse to therapy in adults older than age 70.HDL cholesterol or the ratio of total to HDLmay offer more information (23, 66).

ATP III

The third report of the National CholesterolEducation Program (NCEP) expert panel ondetection, evaluation, and treatment of highcholesterol in adults (ATP III) (7) is the cur-rent standard for cholesterol screening andtreatment. ATP III is the third step in an evo-lutional process and follows two previous setsof guidelines. The first report (ATP I) out-lined the strategy for the prevention of heartdisease for adults with LDL >160mg/dl andfor those with high cholesterol (LDL 130–159mg/dl). The second report (ATP II) expandedATP I by discussing the intensive manage-ment of LDL cholesterol for people who hadestablished heart disease. ATP III, publishedin 2001, called for more intensive interven-

tion. Departing from previous recommenda-tions, ATP III identified LDL cholesterol lev-els between 130–159 mg/dl as borderline highand total cholesterol levels between 200 and239 mg/dl as borderline high for otherwiselow-risk individuals.

The ATP III argues that a linear relation-ship exists between the LDL cholesterol andthe chances of MI or death (see Figure 4). Theargument is that those who lower their LDLcholesterol from 170 to 160 gain about thesame amount as those who lower their LDLcholesterol from 110 to 100. However, they-axis on the graph is in logarithmic ratherthan regular units. As with blood pressure,the relationship between risk factor and out-come is not linear. It is log-linear. In addition,Figure 4 disguises some of the relationshipby excluding the small groups of the popu-lation with very low or very high LDL lev-els. Figure 5 redraws the relationship usingnatural units on the y-axis and the full range ofLDL values reported in the NHANES surveyalong the X-axis. Those who start with lowerlevels of LDL cholesterol gain significantlyless than those who start with high levels ofLDL cholesterol.

ATP III recommends lifestyle interven-tion for those with borderline high LDLor total cholesterol but also acknowledgesthat drug treatment may be appropriate for

Figure 4Figure 2 NCEP Revision July 2004.


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0

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LDL cholesterol (mg/dl)

Figure 5Relationship between LDL and CHD risk using natural unit.

those who fail lifestyle interventions. Direct-to-consumer advertising sponsored by thepharmaceutical industry suggests that mostpatients fail dietary interventions and that pa-tients should speak to their doctors about drugtherapy (see http://www.Lipitor.com).

The ATP III report discusses the cost-effectiveness of treatment, recognizing thatdrug therapy is expensive. However, it alsodismisses some cost concerns by suggestingthat drug prices are likely to decline in thefuture. ATP III suggests that the thresholdfor considering treatment is an LDL level of130 mg/dl. Following the publication ofthe Heart Protection study (22), the guide-lines were revised to lower the threshold to100 mg/dl (32, 34).


Using data from the National Health and Nu-trition Examination survey we reevaluated theproportion of the adult population affected

by the change in guidelines. The distribu-tion of LDL cholesterol in the U.S. popu-lation, and for the U.S. population age 60or older, is shown in Figure 6. The updatedATP III guidelines suggest that optimal levelsof LDL cholesterol are below 70 mg/dl (32).Considering the entire adult population in theUnited States, only ∼7% are at this level; 93%have levels that are higher. For adults olderthan age 60, 97% have LDL values higherthan 70 mg/dl. The first threshold for clin-ical concern is 100 mg/dl. According to theanalysis of the NHANES data, ∼73% of theadult population of the United States falls intothis category. According to our analysis of theNHANES data, 84% of adults older than age60 have LDL levels higher than 100, so 84 ineach 100 might need attention for cholesterolmanagement.

HOW MANY WILL PROGRESSTO CVD?

Pharmaceutical advertising suggests statintherapy for patients with mildly elevated LDL

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0

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12

0 50 100 150 200 250 300

% over 60All cases

LDL cholesterol (mg/dl)

Figure 6Distribution of LDL cholesterol for all participants and for those >60 years in NHANES.

cholesterol and without other risk factors.However, statins have not been studied inpopulations without risk factors. Table 2summarizes the entry criteria in several of themajor recent clinical trials. These are the exacttrials used as the rationale for the recent revi-sion of ATP III. The third column of the ta-ble shows that none of these trials used adultswho did not have heart disease or did not haveestablished risk factors. We remain uncertainabout the benefits for lowering cholesterol inadults with relatively normal levels of LDLcholesterol. These populations have not beenstudied in lipid-lowering trials.

EXAMPLE 3: IMPAIRED FASTINGGLUCOSE

Among the many adjustments in diseasethresholds are recent changes in the definitionof diabetes mellitus (DM) and impaired fast-ing glucose (IFG). The Expert Committee on

DM: diabetesmellitus

IFG: impairedfasting glucose

the Diagnosis and Classification of DiabetesMellitus recommended that the threshold fordiabetes be changed from a fasting plasmaglucose level of 140 mg/dl to 126 mg/dl (6).With a simple change in disease definition, theprevalence of diabetes increased 14%. Morerecently, the Expert Committee on the Diag-nosis and Classification of Diabetes Mellitusrecommended that the lower limit for IFGbe reduced from 110 mg/dl to 100 mg/dl (ordown to 5.6 mmol/l) (28).

The rationale for the recommendation wasthe panel’s belief that metabolic and clinicalcomplications of hyperglycemia rise sharplyfor those above the 100 mg/dl level. However,the committee noted that very little evidenceindicated that cardiovascular risk factors andall-cause mortality increase with IFG. Theyalso noted that some studies did not supportlowering the threshold (8, 35). As part of theirdiscussion, the group noted that lowering thethreshold to 100 mg/dl would significantly


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Table 2 Entry criteria in trials used as the basis for the ATP-III revised guidelines

Study Population Entry criteriaHeart Protection Study(10) 20,536 adults, ages 40–80 in

United KingdomCoronary disease, other occlusiveartery disease, or diabetes

Prospective Study of Pravastatin in theElderly at Risk (PROSPER)(76)

5804 adults, ages, 70–82 History of heart disease or CVD riskfactors

Antihypertensive and Lipid-LoweringTreatment to Prevent Heart Attack(ALLHAT)(9)

10,355 adults 55 years or older LDL levels between 120 and189 mg/dl and triglycerides<350 mg/dl

Anglo-Scandinavian Cardiac OutcomesTrial-Lipid Lowing Arm(ASCOT-LLA)(74)

19,342 patients ages 40–79 years All had hypertension and at least 3other CHD risk factors

Pravastatin or Atorvastatin Evaluation andInfection-Thrombolysis in MyocardialInfarction 22 (PROVE IT)(18)

4162 patients from Australia, Canada,France, Germany, Italy, Spain, theUnited Kingdom, or the United States

All participants had been hospitalizedfor acute coronary syndrome within10 days prior to randomization

increase the number of patients with a diag-nostic label. The committee felt this was desir-able because it would bring medical attentionto more individuals. The committee arguedthat population studies from Mauritius (75)and from the Pima Indians (27) supported thelower threshold. The only American popula-tion considered was the San Antonio HeartStudy population, which had a high ad-mix ofNative Americans (56). In making their rec-ommendation, the committee acknowledgedthat risks associated with IFG were not con-sistently documented and that the few stud-ies identifying the risks tended to use pop-ulations that were not representative of thegeneral U.S. population.


Our preliminary analysis suggests that 37% ofthe U.S. population 50 years of age or olderwould have IFG or DM under the new defi-nition. Using data from the National Healthand Nutrition and Examination Survey, it ap-pears that ∼9 million adults in America wouldqualify for a diagnosis of IFG or diabetesif the definition was fasting plasma glucose(FPG) >110 <126. Lowering the threshold to100 mg/dl would increase the number of in-

dividuals deemed eligible for treatment by 24million people to about 33 million cases ofIFG. This represents a 166% increase in thenumber of people eligible for a diagnosis.

DOES IFG INCREASE THE RISKOF DIABETES OR DIABETICCOMPLICATIONS?

The American Diabetes Association (ADA)suggests that impaired fasting glucose or “pre-diabetes” is the pathway to full diabetes.Furthermore, they urge the general popu-lation to be tested because elevated bloodglucose may result in diabetic complications.The recommendation was based on the as-sumption that those with IFG are at risk fortransition to DM and the complications ofimpaired glucose metabolism. But what dowe know about the long-term consequencesof minor elevations in blood glucose? Withcolleagues at the University of California,San Diego, we evaluated the benefit of thenew definition of IFG. In 1972–1974, 82%of an upper-middle-class white community(Rancho Bernardo, California) were screenedfor heart disease risk factors as part of theLipid Research Clinic Prevalence Program.The average age at baseline was 49.9 years. Afollow-up visit of this cohort was conducted20 years later and included ∼75% of the

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surviving Rancho Bernardo cohort (n =1781). Among these, 1494 subjects had validplasma glucose values for both visits (n =1494).

FPG levels were measured at both visitsand four categories of fasting plasma glucosewere created: nonimpaired (lower than 100mg/dl), low IFG (100–110 mg/dl), IFG (111–126 mg/dl), and diabetes mellitus (greaterthan 126 mg/dl and/or diagnosed or takingdiabetic medications). Each participant wasplaced in one of the four categories at the base-line (1972–1974) and the follow-up (1992–1996) visits. Diabetic complications were alsomeasured at the second visit. These includedkidney function and eye problems. A self-report questionnaire was used to ask questionsrelating to neuropathy including three cate-gories: (a) numbness or tingling, (b) loss ofsensation in both hands or feet, and (c) de-creased ability to feel temperature by touch-ing. For this analysis, a participant was scoredas having neuropathy if he or she reportedany one of the three symptoms. The ques-tionnaire was also used to determine self-reported use of prescription medications fordiabetes and whether a health professionalhad told the respondent that he or she haddiabetes.

About 83% of those FPG values lower than100 mg/dl at baseline maintained FPG valueslower than 100 mg/dl over the next 20 yearsand less than 3% progressed to diabetes. Forthose with baseline FPG values between 100and 110, transition to diabetes was similar(4%). Chances of conversion to diabetes sig-nificantly increased for those in the 111–126range (7%) in comparison with the nonim-paired (<100 mg/dl) (3%) but not the lowIFG (100–110 mg/dl) groups (4%). Twentyyears later, little evidence indicated that thosewith FPG levels between 100 and 110 were atelevated risk for diabetic complications, in-cluding elevated urinary albumin/creatinineratios, retinopathy, and neuropathy (RM Ka-plan, D Morton, DL Wingard, E Barrett-Connor, submitted manuscript). Several otherstudies are consistent with our analysis. A 6.8-

year follow-up of 2763 women with estab-lished heart disease did not find a relation-ship between the new definition of IFG (100–110 mg/dl) and incident events of CHD,stroke, TIA, or CHF (41).

From a public health perspective, costmust also be considered. The committee sug-gested, “We do not yet know the total benefitor the total cost to an individual who is des-ignated at risk for diabetes by either test, byany criterion. The higher the ratio of bene-fit to cost, the lower the optimum cut pointthat should be selected.” The committee feltthat there was a cost advantage to loweringthe threshold because complications of di-abetes could be prevented. They cited theDiabetes Prevention Program (DPP) as ev-idence (46). However, lowering the thresh-old will mean that many people will be sub-jected to treatment even though they have avery low probability of complications. Fur-thermore, the DPP did not study isolatedIFG; participants had to have IFG and im-paired glucose tolerance.

Multiple studies have shown that lifestylemodifications or pharmacotherapy can de-lay or prevent the progression from impairedglucose control (as measured either by im-paired glucose tolerance or IFG) (14, 20, 46,67, 81). Only one study, the Diabetes Pre-vention Program (DPP) (46), has comparedlifestyle modifications and pharmacotherapytogether.

The DPP study enrolled individuals witha FPG of 95 to 125 mg/dl and an oral glu-cose tolerance test of 140 to 199 mg/dl,which was considered elevated but did notmeet the threshold for diabetes by the 1997ADA guidelines. The DPP study had threearms that enrolled ∼1000 patients each:placebo, lifestyle intervention, and pharma-cotherapy intervention (metformin), in whichthe lifestyle intervention combined a healthylow-calorie, low-fat diet with a physical ac-tivity regimen of moderate intensity, such asbrisk walking, for at least 150 min per week.The placebo rate of progression to diabetes inthe DPP study was 11 per 100 person-years,


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and both the lifestyle and pharmacotherapyintervention (metformin) reduced progres-sion to diabetes compared with placebo by58% and 31%, respectively.

The DPP also included a cost/utility anal-ysis. Quality of life was measured using theQuality of Well-Being Scale (QWB) (44). Themeasure was chosen because it can be used toestimate quality-adjusted life years (QALYs)(43). Over the course of three years, thoserandomly assigned to the lifestyle interven-tion accrued 0.050 more QALYs than didthose assigned a regular dose of metformin.Among the three interventions, the lifestyleapproach was the most expensive (total cost$27,065 in 2000 U.S. dollars). Metformin wasless expensive ($25,937), whereas the placebowas the least expensive option ($23,525). Al-though both interventions offer significantbenefits over placebo or doing nothing, thecost/QALY for the lifestyle invention was sig-nificantly lower than for metformin. In otherwords, even though the lifestyle interventionwas more expensive, it offers significantly bet-ter value for money.

In conclusion, we find little evidence thatFPG levels between 100 and 110 mg/dl arestrong predictors of transition to diabetes orthe development of diabetic complications.These data contrast the recommendation ofthe expert committee on the diagnosis andclassification of DM. The expert commit-tee recognized that the selection of diseasethresholds is arbitrary. We believe that theselection of disease thresholds requires con-tinuing thought and evaluation. Furthermore,given the benefits of diet and exercise for thosewith prediabetes, we see little justification foruse of medication by those in the 100–110mg/dl range.

HOW MANY PEOPLE HAVE ATLEAST ONE OF THE THREELOW THRESHOLDCONDITIONS?

Using data from the NHANES III weestimated the percentage of the adult pop-

ulation meeting the criteria for IFG, pre-hypertension, or modestly elevated LDLcholesterol (greater than 100 mg/dl). Thispreliminary analysis concentrated on the 62million Americans 50 years of age or older.The results are summarized in Figure 7. Ourpreliminary estimates suggest that 37% ofthe population ages 50 or older have fast-ing glucose levels greater than 100 mg/dl.Furthermore, nearly 60% of the popula-tion has SBP greater than 120 mm Hg. ForLDL cholesterol, nearly three quarters of thepopulation (73%) have levels greater than100 mg/dl.

Figure 7 also shows the percent of thepopulation with any one of these three condi-tions. According to this preliminary analysis,97% of American adults ages 50 or older haveone of the three conditions. The expandedmarkets for health care will include virtuallythe entire population of adults older than age50. These changes in diagnostic thresholds arelikely to have profound impacts on the costsof health care, and their effects on popula-tion health have not been comprehensivelyevaluated.

Because the effect of risk factors is multi-plicative, some in the field may be concernedthat people with multiple borderline riskfactors may be at greater risk than those withonly one concern. An analysis conducted byVasan and colleagues (84) suggests that evenwhen accounting for multiple preconditions,treating them will have only modest effects onmorbidity and mortality. The analysis consid-ered three preconditions (prehypertension,borderline high LDL cholesterol, and IFG)plus borderline low HDL cholesterol andprevious smoking. Using this information,the investigators calculated the proportion of10-year CHD event rates, defined as eithermyocardial infarction or coronary death fromthese five risk factors using weights fromthe Framingham Heart Study. The eventrates were then applied to the NHANESIII non-Hispanic white cohort between theages of 35 and 74 without a previous vascularevent and extrapolated to the U.S. population

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on the basis of the 2000 census. The analysissuggested that of these, only 8% of CHDevents will occur in individuals with any com-bination of these borderline conditions butwithout any of the five actual conditions. Thisnumber would be even lower if restricted toprehypertension, borderline high LDLcholesterol, and IFG; the two other riskfactors have high prevalence rates, withborderline low HDL cholesterol seen in 50%of men and 53% of women in NHANES-III,and former smoking seen in 42% of men and30% of women in NHANES-III.

CONSEQUENCES

The greatly expanded market for health careassociated with these definition changes mayhave important public health consequences.In this section, we consider some of theseissues.

Labeling

Labeling adults with a “disease” is not with-out consequence. In a classic study Haynesand colleagues (37) screened for hypertensionin an industrial setting. Hypertension is usu-ally considered to be a silent disease. Thosewho were labeled as hypertensive had an in-crease in absenteeism from work of more than5 days per year. This amounted to nearlyan 80% increase in days missed from work.The authors suggested that simply becomingaware that a person had a diagnosis was a ma-jor factor in absenteeism. Days missed fromwork was attributed to the labeling becausethe increases in absenteeism were observedfor those who were previously unaware oftheir condition and happened independentlyof whether the person started hypertensivetherapy (72). However, a variety of concernsabout the Haynes study have been noted. Forexample, absenteeism may have increased be-cause people were diagnosed at work and mayhave attributed their high blood pressure towork-related stress. More recent reviews havedownplayed the effect of labeling. Evidenceon the psychological consequences of label-

ing is less of a concern. A review of 10 co-hort studies examined the adverse effects ofscreening for hypertension and subsequentlylabeling a person as hypertensive, and it foundfair-quality evidence suggesting that screen-ing and labeling adults with hypertension pro-duce no adverse effects on psychological well-being (77).

Increased Health Care Utilization

Current recommendations suggest that thesenew definition changes will lead to increasedhealth care utilization. The U.S. PreventiveServices Task Force (USPSTF) makes rec-ommendations regarding screening visit fre-quencies. The USPSTF has yet to update itsrecommendations for people with high bloodpressure, high cholesterol, and IFG since thechange in these definitions. In the past, theUSPSTF recommendations for high bloodpressure and high cholesterol screening havemirrored prior iterations of the JNC and ATP.The USPSTF has previously stated there wasinsufficient evidence to screen for diabetes(USPSTF 2003).

JNC VII recommends that individualswith prehypertension have their blood pres-sure screened yearly for progression to hy-pertension and recommends individuals with“normal” blood pressures be screened everytwo years. ATP III recommends reevaluatingindividuals with borderline high cholesterollevels (LDL 130–159) after one year and rec-ommends individuals with “normal” choles-terol levels be screened every five years. TheADA recommends screening individuals overthe age of 45 with a FPG every three years andmore frequently for those with IFG (or im-paired glucose tolerance). Adherence to theserecommendations for visit frequency will addsignificant burdens to scheduling resourcesif carried through given the huge numbersof people who would meet these definitionchanges. Assuming a cost of $50 for a physi-cian visit, these recommendations would addmore than a billion dollars to current healthcare expenditures.


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Medication Prescriptions

The recommended treatment for prehyper-tension, borderline high cholesterol, and IFGis lifestyle and dietary changes. However, pre-scription medication therapy will undoubt-edly also occur. Compliance rates with recom-mendations for lifestyle and dietary changesare likely to be lower than those seen in clini-cal trials (70%) (13). Individuals who are non-adherent may be placed on medication ther-apy despite lack of current recommendationsfor such a strategy. In addition, individualsprescribed medication may be less motivatedto change their lifestyles. We also estimatedthe costs of these prescriptions. The costs arebased on actual wholesale prices (AWP). AWPare often high estimates of costs because manypatients get prescriptions through the bulkpurchasing discounts of their insurers. We ex-amined the AWP available from the 2004 RedBook for all medications and selected the low-est price for medications purchased in quan-tities of 100.

The TROPHY study has demonstratedthat antihypertensives can be used as pharma-cotherapy in prehypertensive individuals (40),which may lead to prescriptions of the studymedication, candesartan, in prehypertensiveindividuals. Most prehypertensive individualswho are started on medication therapy will usemonotherapy (i.e., one medication) and willlikely have utilization patterns similar to hy-pertensive patients using monotherapy. Datafrom the 1999–2002 NHANES show thatamong hypertensive patients using monother-apy, more than 50% of patients use a calcium-channel blocker (CCB) or an angiotensin-converting enzyme (ACE) inhibitor, and onlyone of ten uses diuretics, which are the recom-mended vehicle by JNC VII guidelines for un-complicated hypertension monotherapy (33).Angiotensin receptor blockers, like candesar-tan, are used as monotherapy by less than 4%of hypertensive patients and are the furthestaway from patent expiration. For prehyper-tension, the least expensive medication is hy-drochlorothiazide. The one-year cost of thismedication is $9 (hydrochlorothiazide 25 mg

tablets, assuming doses of 12.5 mg per day).However, the one-year cost of candesartan,one of the most expensive antihypertensives,is $541. Systematic clinical trials have failed toshow that newer high-cost antihypertensivesare more effective than older, cheaper prod-ucts (78). Recently, a review suggested thatthe more expensive ARBs are not as effectiveas cheaper ACE inhibitors in preventing car-diovascular and all-cause deaths (80).

Prescriptions of lipid-lowering medica-tions to low-risk individuals are highly preva-lent. A medical record review of all outpatientsaffiliated with the Brigham and Women’sHospital who were using statins for pri-mary prevention of coronary artery disease onJanuary 1, 1996, showed that 32.6% wereindividuals with fewer than two risk factorsthat did not meet National Cholesterol Ed-ucation Program (NCEP) criteria for statinuse (i.e., LDL cholesterol > 190 mg/dl) (12).This group consisted of 47.5% of all indi-viduals using statins for primary preventionof coronary artery disease. Even after exclud-ing those who did not receive any LDL test-ing, 25.9% of statin users had fewer thantwo risk factors and documented LDLs below190 mg/dl. As this data predates the dec-laration of LDL cholesterol levels of 130–159 mg/dl as borderline-high, we expect thatsuch prescribing has increased since ATPIII. The most common cholesterol medica-tions prescribed are HMG-CoA reductase in-hibitors, commonly known as statins. Cur-rently, some statins but not all have lost patentprotection. The most inexpensive one-yearcost of a generic statin prescription is $491(lovastatin 10 mg tablets), whereas the mostexpensive one-year cost of a statin still underpatent protection is $793 (atorvastatin 10 mgtablets).

Public health approaches such as lifestylemodification are typically preferred overpharmaceutical interventions. Despite the su-periority of the lifestyle intervention, therehas been concern that physicians will prefermetformin over lifestyle intervention for pre-venting progression to diabetes. This concern

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is grounded in part by the difficulty of get-ting patients to adhere to lifestyle interven-tions and the ease of prescribing comparedwith teaching the lifestyle intervention. At theclosure of the DPP study, the adherence rateto the lifestyle intervention (58%) was lowerthan to the metformin or placebo interven-tion (72% and 77%, respectively). Metforminmakes up only about one third of all antidi-abetic prescriptions (91), but it is commonlyused as oral monotherapy for people with dia-betes. This recommendation, combined withthe findings from the DPP study, suggests thatthose with prediabetes using pharmacother-apy would likely use metformin. The medi-cation regimen from the Diabetes PreventionProgram trial was metformin 850 mg tabletstwice a day. The one-year cost of this regimenis $460.

Wald & Law (85) argued that CVD couldbe lowered by 88% if the entire popula-tion took a “polypill” composed of atorvas-tatin (10 mg), three blood pressure medica-tions, folic acid (.8 mg), and aspirin (75 mg).The recommendations were based on a meta-analysis of 15 trials of low-dose aspirin andother published meta-analyses of trials andcohort studies. Although the polypill is aninteresting idea, it has also encountered sig-nificant criticism. A multidisciplinary publichealth research working group considered thestrengths and concerns of combination phar-macotherapy proposals (11). Most important,they noted that no clinical trial has shown thebenefit of the pill. Furthermore, the groupraised questions about possible side effectsand problems with patient adherence. An-other concern is that a footnote to the polypillpaper notes that the authors have filed for apatent on the combined pill. At this point, itseems a bold step to advocate a policy for theentire public without direct evidence for ef-fectiveness of this combined agent.

Although most of the current medicationsthat would be used in these preconditions areor will be generic in a few years, the costs ofmedication treatment may be on the low endof these estimates. However, pharmaceutical

companies will likely develop new treatmentstargeting those with preconditions, given thehuge potential markets. As a result, medi-cation costs will likely be higher than theseestimates. The reader should note that wehave reported only the one-year costs. In mostcases, patients will be asked to comply withthese or similar medications continually forthe remaining years of their lives. The yearlycost of a statin medication for a person witha 25-year current life expectancy should bemultiplied by 20.

Likelihood of Benefit/Chancesof Side Effects

No treatment is without side effects. Becauseside effects occur, patients must decide if theyare willing to expose themselves to these risks.Glasziou & Irwig (29) have analyzed thisproblem and concluded that the benefits oftreatment go disproportionately to patientsat the greatest risk. Similarly, the lower therisk of the disease is, the lower the benefit oftreatment is. Figure 8 provides a pictorial ex-planation of their ideas. In this case, imag-ine the risk is blood pressure and the out-come is stroke. As blood pressure increases,the chances of stroke also increase. Everyoneexposed to the treatment experiences theseconsequences, and they are independent ofthe level of risk. However, not all people re-spond to treatment the same way. Some arevery responsive to treatment (high respon-ders) and others are less responsive (low re-sponders). Similarly, some people are moresensitive to the medication and are highly vul-nerable to side effects. Others may have lowvulnerability. The treatment threshold shouldbe higher for those who are more vulnerableto side effects.

WHAT IS UNKNOWN

Geoffrey Rose convincingly argued the ra-tionale for public health approaches to com-mon medical problems. Given the normaldistribution of most CHD risk factors, thetraditional medical approach has been to seek


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0.10

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arm

Figure 8The solid line in panel A shows the relationship between the benefits of treatment and the risks of theillness. The dashed line shows the chances of harm due to side effects of treatment. The point where thelines intersect is the treatment threshold, or the point at which treatment should be considered. Panels B,C, and D outline other situations. Panel B shows that the treatment threshold should be lower for highresponders than for low responders. The different horizontal dashed lines in Panel C indicate patientswho are sensitive to medication and highly vulnerable to side effects. Panel D shows treatment thresholdsfor different combinations or response to treatment and vulnerability to side effects (from Reference 47,reproduced with permission of Blackwell Publishing).

out and treat those in the upper tail of thecurve. Rose suggested that more public healthbenefit could result from focus on the entiredistribution and greater attention to those to-ward the center. Attacking the entire distribu-tion might produce more public health bene-fit than would concentration on clinical casesat the extremes. Recent changes in treatmentguidelines place a much greater portion of thepopulation in categories for concern. How-ever, the new guidelines emphasize medicalapproaches to these problems. Rose proposedpublic health rather than clinical solutions tothis problem. New guidelines appear to medi-calize ordinary variation in CHD risk factors.We clearly need efforts to apply and evalu-ate public health approaches before exposinga large portion of the population to clinicalmeasures.

Perhaps the major discrepency in the cur-rent literature is that we do not know thebenefits of treatment for people not previ-ously believed to be at risk. Tables 1 and 2suggest that we have very little evidence onthe health benefits and consequences of phar-macological treatment for people not at risk.Furthermore, we have not formally evaluatedpublic approaches or compared the relativevalue of population versus clinical approaches.Furthermore, we need more evidence on thecosts, risks, and benefits of the expanded def-initions of disease.

SUMMARY

This chapter has explored the implications ofchanging the definitions of CHD risk factors.JNC VII created a new category known as

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prehypertension. Individuals previously cat-egorized as normal now qualify for thisdiagnosis. ATP III lowered the threshold forconcern about serum cholesterol. An ADAcommittee lowered the threshold for IFGfrom 110 mg/dl to 100 mg/dl. Analysis of theNational Health and Nutrition Examinationsurvey shows that these definition changesproduce profound effects on the number ofpeople who could be labeled as having theserisk factors. Considering blood pressure, forexample, the number of people affected wouldgo from ∼14% to ∼40% of the adult popula-tion, a 185% increase. Considering the threerisk factors, more than 97% of the adult popu-lation would need to be under medical surveil-lance.

We do not know how many people wouldseek or gain treatment for these new diagnosesor whether the treatment would be effective.Clinical trials have not evaluated pharmaceu-tical interventions for people who were previ-

ously thought to have normal blood pressure,cholesterol, or glucose. Using observationaldata, it appears that the benefit of treatmentwill be quite small. However, the costs of thetreatment are likely to be substantial. Newpharmacological approaches to the treatmentof high blood pressure are very expensive andcan cost several dollars per day. For a 50-year-old diagnosed with prehypertension, a drugcost could be $500 or more per year, and thiscost would be repeated each year for the re-mainder of the lifespan. In addition, monitor-ing costs would be substantial because peopletaking medications need to visit their physi-cians more often. The cost would be high andthe benefits would be uncertain. The value oftreatment for low-threshold illness must beassessed in systematic empirical studies andclinical trials. Considerably more research isneeded to estimate the costs and public healthimplications of these changes in diagnosticthresholds.

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AR305-FM ARI 26 February 2007 18:0

Annual Review ofPublic Health

Volume 28, 2007Contents

Symposium: Public Health Preparedness

Introduction: Preparedness as Part of Public HealthNicole Lurie � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �xiii

Assessing Public Health Emergency Preparedness: Concepts, Tools,and ChallengesChristopher Nelson, Nicole Lurie, and Jeffrey Wasserman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �1

Quality Improvement in Public Health Emergency PreparednessMichael Seid, Debra Lotstein, Valerie L. Williams, Christopher Nelson,

Kristin J. Leuschner, Allison Diamant, Stefanie Stern, Jeffrey Wasserman,and Nicole Lurie � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 19

Risk Communication for Public Health EmergenciesDeborah C. Glik � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 33

First Responders: Mental Health Consequences of Natural andHuman-Made Disasters for Public Health and PublicSafety WorkersDavid M. Benedek, Carol Fullerton, and Robert J. Ursano � � � � � � � � � � � � � � � � � � � � � � � � � � � � 55

Epidemiology and Biostatistics

Network Analysis in Public Health: History, Methods, and ApplicationsDouglas A. Luke and Jenine K. Harris � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 69

Methods for Improving Regression Analysis for Skewed Continuous orCounted ResponsesAbdelmonem A. Afifi, Jenny B. Kotlerman, Susan L. Ettner,

and Marie Cowan � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 95

New Challenges for Telephone Survey Research in the Twenty-FirstCenturyAngela M. Kempf and Patrick L. Remington � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �113

Seasonality of Infectious DiseasesDavid N. Fisman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �127

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Health Impact Assessment: A Tool to Help Policy Makers UnderstandHealth Beyond Health CareBrian L. Cole and Jonathan E. Fielding � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �393

Social Environment and Behavior

Physical Activity and Weight Management Across the LifespanJennifer H. Goldberg and Abby C. King � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �145

The Hitchhiker’s Guide to Tobacco Control: A Global Assessment ofHarms, Remedies, and ControversiesRonald M. Davis, Melanie Wakefield, Amanda Amos,

and Prakash C. Gupta � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �171

Youth Violence Prevention Comes of Age: Research, Training, andFuture DirectionsKara Williams, Lourdes Rivera, Robert Neighbours, and Vivian Reznik � � � � � � � � � � � � �195

Church-Based Health Promotion Interventions: Evidence and LessonsLearnedMarci Kramish Campbell, Marlyn Allicock Hudson, Ken Resnicow,

Natasha Blakeney, Amy Paxton, and Monica Baskin � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �213

Risk Communication for Public Health EmergenciesDeborah C. Glik � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 33

Environmental and Occupational Health

The Epidemiology of Autism Spectrum DisordersCraig J. Newschaffer, Lisa A. Croen, Julie Daniels, Ellen Giarelli,

Judith K. Grether, Susan E. Levy, David S. Mandell, Lisa A. Miller,Jennifer Pinto-Martin, Judy Reaven, Ann M. Reynolds, Catherine E. Rice,Diana Schendel, and Gayle C. Windham � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �235

Beryllium: A Modern Industrial HazardKathleen Kreiss, Gregory A. Day, and Christine R. Schuler � � � � � � � � � � � � � � � � � � � � � � � � � � �259

Adverse Late Effects of Childhood Cancer and Its Treatment onHealth and PerformanceKirsten K. Ness and James G. Gurney � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �279

First Responders: Mental Health Consequences of Natural andHuman-Made Disasters for Public Health and Public Safety WorkersDavid M. Benedek, Carol Fullerton, and Robert J. Ursano � � � � � � � � � � � � � � � � � � � � � � � � � � � � 55

Health Services

Managed Behavioral Health Care Carve-Outs: Past Performance andFuture ProspectsRichard G. Frank and Rachel L. Garfield � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �303

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Rationale and Public Health Implications of Changing CHD RiskFactor DefinitionsRobert M. Kaplan and Michael Ong � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �321

Delivery of Health Services to Migrant and Seasonal FarmworkersThomas A. Arcury and Sara A. Quandt � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �345

Public Health Practice

Lessons from Cost-Effectiveness Research for United States PublicHealth PolicyScott D. Grosse, Steven M. Teutsch, and Anne C. Haddix � � � � � � � � � � � � � � � � � � � � � � � � � � � � �365

Health Impact Assessment: A Tool to Help Policy Makers UnderstandHealth Beyond Health CareBrian L. Cole and Jonathan E. Fielding � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �393

How Can We Increase Translation of Research into Practice? Types ofEvidence NeededRussell E. Glasgow and Karen M. Emmons � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �413

Community Factors in the Development of Antibiotic ResistanceElaine Larson � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �435

Assessing Public Health Emergency Preparedness: Concepts, Tools,and ChallengesChristopher Nelson, Nicole Lurie, and Jeffrey Wasserman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �1

Quality Improvement in Public Health Emergency PreparednessMichael Seid, Debra Lotstein, Valerie L. Williams, Christopher Nelson,

Kristin J. Leuschner, Allison Diamant, Stefanie Stern, Jeffrey Wasserman,and Nicole Lurie � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 19

Indexes

Cumulative Index of Contributing Authors, Volumes 19–28 � � � � � � � � � � � � � � � � � � � � � � � �449

Cumulative Index of Chapter Titles, Volumes 19–28 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �454

Errata

An online log of corrections to Annual Review of Public Health chapters (if any, 1997to the present) may be found at http://publhealth.annualreviews.org/

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