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`ATTACHMENT 1 (Part 6)
`
`(ATP-III)
`
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`Ex. 1013, p. 258 of 852
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`

`

`Vol 106, No 25, December 17/24, 2002
`ISSN 0009-7322
`http://circ.ahajou
`
`rnal 8.org
`
`.
`
`GD~
`
`....
`Amencan Heart .:
`Association-
`. '. .
`Fighting Heart Disease and Stroke
`
`•
`
`,D
`
`ecember 31, 2002
`
`JJ®Q!i UH~1
`-. .~',....',~.,:.,-
`
`»
`
`'--'
`
`'---,
`'),.
`,
`
`-..../
`
`/1
`-~
`
`.'
`
`r'
`
`.»
`
`Ir'
`;0
`
`J
`
`• Circulation Electronic Pages
`
`John M Miller, MD; Douglas P Zipes, MD .......... e203-e205
`
`Part!J Wang, MD; NA. Mark Estes III, MD
`
`e206-e208
`
`Cardiology Patient Page: Catheter Ablation of Arrhythmias *
`Cardiology Patient Page: Supraventricular Tachycardia *
`Image: Bronchogenic Cyst: Acute Presentation *
`Meeting Highlights of the ESC *
`
`R.FJ Browne, MD, et al.:
`
`e209-e21O
`
`Stephen B. Williams,MD; James J Ferguson, MD e2I1-e2I9
`Correspondences-
`e22D-e226
`
`Cardiovascular News *
`
`• Editorial
`Primary Prevention of Cardiovascular Disease
`Robert 0 Bono", MD......
`..
`• Special Report
`Detection, Evaluation, and Treatment of High Blood
`Cholesterol in Adults (Adult Treatment Panel III)
`Scott Grundy, MD, PhD, et al.,
`
`3140
`
`3143
`
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`

`

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`
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`Current Contents, EMBASElExcerpta
`
`if
`
`Ir rI!I
`
`Abstracts,
`
`CABS, CINAHL,
`
`Chemical Abstracts,
`
`Inc.
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`

`

`Detection
`
`Third Report of the
`National Cholesterol
`Education Program (NCEP)
`Expert Panel on
`
`Detection,
`Evaluation,
`and Treatment
`of High Blood
`Cholesterol
`in Adults
`(Adult Treatment
`Panel III)
`
`Evaluation
`
`Final Report
`
`Treatment
`
`National Cholesterol Education Program
`
`National Heart, Lung, and Blood Institute
`
`National
`
`Institutes of Health
`
`NIH Publication No. 02-5215
`September 2002
`
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`

`

`Detection
`···
`
`VI. Drug Therapy
`
`IEvalua~ion II
`
`·•···········•·····
`
`Treatment
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`

`3303
`
`is the primary target of
`Although LOL cholesterol
`therapy, other lipid risk factors besides elevated LOL
`affect CHO risk. Among these are low HOI. choles-
`terol, elevated triglyceride (especially VLOL remnants),
`and possibly small LOL particles. This "lipid triad"
`has been called atherogenic dyslipidemia. It commonly
`occurs as one component of the metabolic syndrome.
`Weight reduction and increased physical activity consti-
`tute first-line therapy for atherogenic dyslipidernia,
`and three classes of drugs-statins,
`nicotinic acid, and
`fibrates-favorably
`modify the lipid abnormalities
`of atherogenic dyslipidernia. Many persons with
`atherogenic dyslipidernia have high triglycerides
`(2:200 mg/dL). Such persons usually have an increase
`in atherogenic VLOL remnants, which can be estimated
`clinically by measuring VLOL cholesterol. In persons
`with high triglycerides,
`the combination of LOL
`cholesterol + VLOL cholesterol
`(non-HOI. cholesterol)
`represents atherogenic cholesterol. Non-HOL choles-
`terol thus represents a secondary target of therapy
`(after LOL cholesterol) when triglycerides are elevated.
`Statins alone will be sufficient to attain the non-
`HDL-cholesterol goal in some persons, but a combina-
`tion of statins and nicotinic acid (or fibrates) can
`be helpful in others.
`
`(
`
`The general strategy for initiation and progression
`of drug therapy is outlined in Figure VLl-l.
`Consideration of drug therapy often occurs simultane-
`ously with the decision to initiate TLC therapy for the
`metabolic syndrome (Figure V2-1). Thus weight reduc-
`tion and increased physical activity may begin at the
`same time as drug treatment.
`
`the response to therapy should
`After another 6 weeks,
`be assessed. If the LOL-cholesterol goal is still not
`achieved, further intensification of therapy should be
`considered, with re-evaluation in another 6 weeks.
`Once the LOL-cholesterol goal has been attained,
`attention turns to orher lipid risk factors when present.
`If triglycerides are high (2:200 mg/dL), the secondary
`target of treatment becomes non-HOI. cholesterol. If
`the LOL-cholesterol goal has been attained but not the
`non-HOL-cholesterol
`goal, there are two alternative
`approaches:
`(a) the dose of the LOL-lowering drug can
`
`Il VI. Drug Therapy
`
`Thresholds and goals for drug treatment
`
`a. Drug therapy to achieve treatment goals: overview
`
`in
`
`is the primary target of rreatment
`1.01. cholesterol
`clinical lipid m.magement. The use of therapeutic
`lifestyle changes (TIC),
`including LOL-Iowering
`dietary options (plant stanols/srerols and increased
`viscous fiber) will achieve the therapeutic goal in many
`persons. Nonetheless, a portion of the population
`whose short-term and/or long-term risk for CHO, will
`require LOL-Iowering drugs to reach the prescribed
`goal for 1.01. cholesterol. The availability of HMG
`CoA reductase inhibitors (statins) allows attainment
`of the 1.01. goal in most higher risk persons. Other
`agents-bile
`acid sequestrants, nicotinic acid, and some
`fibrates-also
`can moderately lower 1.01. levels.
`
`II, \
`
`1.
`
`,II
`
`f!I\
`
`If TLC alone fails to achieve the goal for 1.01. choles-
`terol, consideration can be given to adding drug
`therapy. In such cases, the third visit of dietary therapy
`[ (Figure V2-1) will be the visit to initiate drug treat-
`ment. When drugs are used, however, TLC also should
`I always be used concomitantly. Dietary therapy pro-
`, vides additional CHO risk reduction beyond drug
`I
`efficacy. Suggestions for combined use of TLC and
`, drug therapy are given in Table VI.l-l.
`
`The general scheme for initiation and progression of
`LOL-Iowering drug therapy is outlined in Figure VI.l-l.
`As with dietary therapy, the first priority of drug thera-
`py is to achieve the goal for LOL cholesterol. For this
`reason an LOL-Iowering drug should be started. The
`usual drug will be a statin, but alternatives are a bile
`acid sequestrant or nicotinic acid. The starting dose of
`statin will depend on the baseline LOL-cholesterol
`level. In persons with only moderate elevations of 1.01.
`cholesterol, the LOL-cholesterol goal will be achieved
`with low or standard doses, and higher doses will not
`be necessary. The response to drug therapy should be
`checked in about 6 weeks. If the treatment goal has
`if
`been achieved, the current dose can be maintained;
`not, LOL-Iowering therapy can be intensified, either by
`increasing the statin dose or by combining a statin with
`a bile acid sequestrant.
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`

`

`3304
`
`Circulation
`
`December
`
`17/24, 2002
`
`Table VI.1-1. Suggestions
`Drug Therapy
`
`for Combined Use of TlC and
`
`I
`
`o Intensive LDLlowering with TLC,including therapeutic dietary
`options (plant stanols/sterols and/or increased viscous fiber)
`- May obviate need for drug therapy
`- Can augment LDL-Ioweringdrug therapy
`
`.0
`
`i •..
`
`,
`
`- May allow for lower doses of drugs
`- .
`o Weight control plus increased physical activity
`- Reduces risk beyond LDL-cholesterollowering
`- Constitutes primary management of the metabolic syndrome
`- Raises HDL-cholesterollevels
`- Enhances reduction of non-HDLcholesterol
`" Initiating TLCbefore drug consideration
`- For most persons, a trial of dietary therapy of about
`3 months is advised before initiating drug therapy
`- Unsuccessful trials of dietary therapy without drugs should
`not be prolonged indefinitely if goals of therapy are not
`approached in a reasonable period; drug therapy should not
`be withheld if it is needed to reach targets in persons with a
`short-term and/or long-term CHD riskthat is high.
`'''Initiating drug ther~py simult~rieouslywith TLC '
`- For severe hypercholesterolemia in which dietary therapy
`alone cannot achieve LDLtargets
`
`- For those with CHDor CHD risk equivalents in whom dietary
`therapy alone will not achieve LDLtargets
`
`,
`
`/
`
`..
`
`Figure VI,1-1. Progression of Drug Therapy
`
`. .
`
`Il
`
`I
`
`e.
`
`I,.
`
`(
`
`'I'
`
`I
`!,
`!
`
`,
`
`(b)
`both LDL and VLDL, or
`to reduce
`be increased
`can be given to adding
`a triglyceride-low-
`consideration
`ering drug (fibrate
`or nicotinic
`acid)
`to LDL-lowering
`therapy, which will mainly
`lower VLDL (see Section
`VIT). The latter
`approach
`has the advantage
`of raising
`HDL cholesterol
`in addition
`to lowering
`non-HDL
`for
`cholesterol.
`Thereafter,
`persons
`can be monitored
`response
`to therapy
`every 4 or 6 months,
`or more often
`if considered
`necessary.
`
`avail-
`are currently
`agents
`Some cholesterol-lowering
`(e.g., nicotinic
`acid),
`and
`able over-the-counter
`(OTe)
`manufacturers
`of several
`classes of LDL-lowering
`drugs
`(e.g., statins,
`bile acid sequestrants)
`have applied
`to the
`Food and Drug Administration
`(FDA)
`to allow these
`agents
`to become OTC medications.
`At
`the time of
`publication
`of ATP III,
`the FDA has not granted
`per-
`mission
`for OTC status
`for sratins
`or bile acid seques-
`If an OTC cholesterol-lowering
`drug is or
`trants.
`becomes
`available,
`patients
`should
`continue
`to consult
`with their physicians
`about whether
`to initiate
`drug
`treatment,
`about
`setting
`goals of therapy,
`and about
`monitoring
`for
`therapeutic
`responses
`and side effects.
`
`b. Cholesterol management
`CHD risk equivalents
`
`in persons with CHD or
`
`in persons with
`to drug therapy
`approach
`The general
`in Figure
`CHD or CHD risk equivalents
`is shown
`IV.2-1. The LDL-cholesterol
`goal
`is <100 mg/dL. Most
`persons with CHD or CHD risk equivalents
`should
`be
`
`I
`
`Initiate
`LDL-Iowering
`drug therapy
`
`6 wks
`...................
`
`If LDLgoal
`not achieved,
`intensify
`LDl·lowering
`therapy
`
`6 wks
`.................
`
`e Start statin or bile
`acid sequestrant
`or nicotinic acid
`
`• Consider higher
`dose of statin or
`add bile acid
`sequestrant or
`nicotinic acid
`
`If LDLgoal
`not achieved,
`intensify
`drug therapy
`or refer to a
`lipid specialist
`
`•
`
`If LDLgoal
`achieved, treat
`other lipid risk
`factors
`
`Q-4-6 mos
`.
`...
`
`Monitor
`response and
`adherence
`to
`therapy
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`

`

`VI. Drug Therapy
`
`3305
`
`#1
`
`Table VI.1-2. Therapeutic Options for Clinical Management
`of Persons with On-Treatment LDL-CholesterolLevels of
`100-129 mg/dL
`"Increase intensityof TLCfor LDLloweringto achieveLDL-
`cholesterolgoal <100 mg/dL
`_ Reinforcereduction of saturated fats and cholesterol
`- Add other dietarytherapies
`~ Plantstanols/sterols
`>- Increase viscous fiber
`- Promoteweight loss in overweight/obesepersons
`#2 n IntensifyLDL-Ioweringdrug therapy to achieveLDL-
`cholesterolgoal <100 mg/dL
`-
`Increase dose of statin
`-Add a second LDL-Ioweringdrug (bileacid sequestrant
`or nicotinic acid)
`"Introduce lifestyletherapies for treatment of the
`metabolicsyndrome, if present
`- Promoteweight loss in overweighVobesepersons
`- Recommendincreased physicalactivity
`" Employdrug therapy for treatment of atherogenic
`dyslipidemia,ifpresent
`- Nicotinic acid
`- Fibricacids
`#5 " Intensifytreatment of nonlipidriskfactors
`- Hypertension
`- Hyperglycemia
`- Prothromboticstate (antiplateletdrugs/anticoagulants)
`
`#3
`
`#4
`
`loss
`turn to managing this condition through weight
`and increased physical activity; besides improvement
`of lipid and nonlipid risk factors of this syndrome,
`further LDL lowering often is obtained. Fourth,
`if
`the patient has atherogenic
`dyslipidemia, other drugs
`(nicotinic acid or fibric acids) can be added to the
`regimen, or LDL-Iowering
`therapy can be intensified.
`Nicotinic acid not only will improve atherogenic
`dys-
`lipidemia, but
`it also can lower LDL-cholesterollevels.
`If elevated triglycerides
`are present, addition of one of
`these drugs will assist
`in reaching the non-HDL-choles-
`terol goal. And fifth,
`treatment of nonlipid risk factors
`can be intensified. Finally, a combination
`of these
`options is advisable for some persons.
`
`3) Baseline LDL cholesterol 100-129 mgldL
`
`NHANES III data showed that more than 30 percent
`of people with CHD have baseline LDL-cholesterol
`levels in the 100-129 mg/dL range. In clinical practice,
`however, misclassification
`of LDL-cholesterollevels
`from single measurements
`in individuals will be high.
`Many persons will have true baseline LDL-cholesterol
`
`treated to achieve this goal. Special considerations
`for LDL-lowering therapy with drugs are given for
`the following subcategories of persons with CHD or
`CHD risk equivalents.
`
`1) Baseline LDL cholesterol :2130 mgldL
`
`Secondary prevention trials consistently show benefit
`from LDL-lowering drugs when baseline LDL choles-
`terol
`is 2130 rng/dl., Thus, most persons with baseline
`LDL cholesterol 2130 mg/dL should be started on
`LDL-lowering drugs simultaneously with TLC since
`many such persons cannot achieve the LDL-cholesterol
`goal of <100 mg/dL on dietary therapy alone.
`Nonetheless,
`the use of dietary therapy is essential
`because it provides benefits not available through
`drugs. In some persons,
`to achieve the LDL goal,
`relatively high doses of LDL-lowering drugs will be
`required. Statins typically are the drug of first choice.
`In persons whose baseline LDL cholesterol
`is very
`high, drugs in combination
`(e.g., statins + bile acid
`, sequestrants) will be necessary to reduce the LDL
`cholesterol
`to <100 mg/dL.
`
`2) On-treatment LDL cholesterol 100-129 mgldL
`
`If the LDL-cholesterollevel
`is reduced to <100 mg/dL,
`current drug therapy can be continued. However, even
`in controlled clinical
`trials,
`less than half of persons
`with CHD achieved an LD L-cholesterol goal of
`<100 mg/dL on standard doses of statins (i.e., simvas-
`tatin 20-40 mg/day in the 4S trial435 or pravastatin
`In the majority
`40 mg/day in CARE436 and LIPID206).
`of participants,
`on-treatment LDL cholesterol was in
`the range of 100-129 mg/dL. For such persons,
`several
`therapeutic options are available (Table VI.l-2).
`
`First, dietary options for LDL lowering can be intensi-
`fied. These include reinforcement
`of lifestyle therapies
`(reduced intakes of saturated fat and cholesterol and
`weight reduction);
`referral
`to a dietitian for medical
`nutrition therapy is advisable. These changes in eating
`habits, combined with other dietary therapies
`(plant
`stanols/sterols and increased viscous fiber), often will
`reduce LDL-cholesterollevels
`to near 100 mg/dL.
`Second, LDL-Iowering drug therapy can be intensified.
`The dose of statins can be increased, or a second LDL-
`lowering drug (bile acid sequestrant
`or nicotinic acid)
`can be combined with statin therapy. Third,
`if the
`patient has the metabolic syndrome,
`attention can
`
`I
`
`I\I
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`Ex. 1013, p. 273 of 852
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`

`

`I I
`
`\
`I
`I
`'
`
`5)
`
`Initiating cholesterol-lowering drugs in hospitalized
`patients
`
`Hospitalization for a coronary event or procedure
`provides a unique opportunity to initiate LDL-lowering
`therapy. Physicians should take advantage of this
`opportunity.
`In the past, this opportunity has often
`been lost due to confusion about the meaning of LDL-
`cholesterol levels obtained during hospitalization.
`Although it is true that LDL levels can change during
`an acute illness, this should not stand in the way of
`starting needed therapy. A few simple recommenda-
`tions can guide initiation of LDL-Iowering therapy
`during hospitalization. The guiding principle is that
`LDL cholesterol should be measured in all patients,
`preferably on admission, but in any case at some time
`during hospitalization, and can be used as a guide to
`start treatmentJ93 Thns, the first 24 hours of hospital
`admission should be considered a "window of oppor-
`tunity" during which a fasting lipoprotein profile
`should be obtained. Whereas as much as a 10 percent
`fall in LDL cholesterol may occur during this first day
`(due to heparinization,
`stress, diet, and other factors),
`a value quite close to the actual baseline for that
`individual will be obtained and will be crucial in the
`decision to initiate early cholesterol-lowering therapy.
`
`If this first 24-hour "window"
`is missed, a fasting
`lipoprotein profile should still be obtained during hos-
`pitalization since an elevated LDL cholesterol
`in that
`setting will identify persons with even higher baseline
`LDL cholesterol. The following summarizes the ATP III
`position on initiation of LDL-Iowering drugs during
`hospitalization of CHD-related events or procedures.
`
`First, persons hospitalized with a coronary event
`or procedure should be discharged on both dietary
`therapy and drug therapy if the LDL cholesterol
`is
`20130mgldL.
`
`Second, if the LDL is 100-129 mg/dL during hospital-
`ization, clinical judgment should be used in deciding
`whether to initiate drug treatment at discharge. The
`initial LDL-cholesterollevel obtained in the hospital
`may be the lowest value seen for this patient. LDL-
`cholesterol levels are decreased beginning in the first
`24--48 hours after an event and may remain low
`for many weeks. Later, if necessary, therapy can be
`adjusted according to the LDL response.
`
`3306
`
`Circulation December 17/24, 2002
`
`levels 2:130 mgldL. Baseline levels of LDL cholesterol
`are labile from one measurement
`to another. Regardless
`of apparent baseline level, the LDL-cholesterol goal for
`all CHD patients and CHD risk equivalents is <100
`mgldL. The various options outlined in Table VI.1-2
`can be applied to this category. Many persons with
`baseline LDL-cholesterollevels
`between 100 and 129
`mgldL will be able to attain LDL cholesterol <100
`mgldL through TLC especially if it includes plant
`stanols/sterols and increased viscous fiber. Others will
`require cholesterol-lowering drugs to reach this target.
`Clinical judgment
`is required as to when to initiate a
`cholesterol-lowering drug. If the LDL cholesterol falls
`near 100 mgldL on dietary therapy alone, the physician
`has the option to forego a cholesterol-lowering drug
`for the present. This is particularly so if other lipid or
`nonlipid risk factors seem to need greater attention.
`
`Once adeqnate LDL-Iowering therapy has been
`attained, other lipid risk factors deserve attention.
`For example, if the patient has an elevated triglyceride
`or low-HDL cholesterol, a different lipid-lowering drug
`can be considered (e.g., nicotinic acid or fibric acid).
`The positive results of the VA-HIT trial showing the
`efficacy of gemfibrozil therapy alone in CHD patients
`have led some authorities to favor fibrates over statins
`in low-LDL patients with CHD.48 Overall, however,
`for monotherapy, clinical trials with statins have been
`more robust in their favorable ontcomes than have
`fibrates. In addition, combined drug therapy (low-dose
`statin + fibrate [or nicotinic acid]) remains an option
`in such persons, provided that precautions are taken to
`prevent and monitor for side effects of lipid-lowering
`drugs used in combination.
`
`4) Baseline LDL cholesterol <100 mg/dL
`
`Some patients with CHD or CHD risk equivalent will
`have a baseline LDL cholesterol <100 mg/dL. These
`patients are already at their LDL-cholesterol goal. For
`them, further LDL lowering is not reqnired. Attention
`shifts to other lipid or nonlipid risk factors. If triglyc-
`erides are elevated (20200mgldL), the non-HDL choles-
`terol remains a secondary target of therapy. Alternative
`therapies to reduce VLDL-cholesterollevels
`to attain
`the non-HDL-cholesterol
`goal are statins or triglyc-
`eride-lowering drugs (nicotinic acid or fibrate).
`Furthermore, nonlipid risk factors may be largely
`responsible for the patient's CHD and thus may
`deserve intensive modification.
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1013, p. 274 of 852
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`

`

`drugs at the
`Initiation of both TLC and LDL-lowering
`time of hospital discharge has several advantages. First,
`at this time persons are particularly motivated to
`undertake
`and adhere to risk-lowering
`interventions.
`Second, failure to initiate indicated therapy early is one
`of the causes of a large "treatment
`gap" as outpatient
`follow up is often less consistent and more fragmented.
`Finally, new and ongoing studies suggest a very early
`benefit of LDL-cholesterol-Iowering
`therapy.4?1.?94-?9?
`Recent support
`for this approach comes from the
`Myocardial
`Ischemia Reduction with Aggressive
`Cholesterol Lowering (MIRACL) Trial of over 3,000
`persons hospitalized with non-Q myocardial
`infarction
`or unstable angina, with a mean hospital LDL-choles-
`terol
`level of 124 mg/dL. Statin treatment,
`initiated in
`the hospital, was safe and resulted in a 16 percent
`rela-
`
`I tive risk reduction in subsequent coronary events at
`I Sweden showed an adjusted 25 percent
`I patients
`
`16 weeks.469 Finally, a large observational
`srudy from
`reduction in
`total mortality at one year for myocardial
`infarction
`started on statins in-hospital.f?t
`
`These latter trials,469.471while suggesting benefit
`from starting LDL-Iowering therapy at time of acute
`coronary syndrome, do not preclude the need for
`further
`research on efficacy of drug therapy started
`at this time.
`
`6) Special considerations for drug therapy in
`CHD patients
`
`In most persons with CHD, goals for LDL-lowering
`therapy can be achieved with lifestyle therapies and
`drug monotherapy. The benefits of intensive LDL
`reduction with the use of drugs apparently extend to
`those with advanced age and poor cardiac prognosis;
`nonetheless, some persons with severe co-existing
`medical conditions
`that severely impair quality of life
`or life expectancy will not benefit.
`
`is common in
`A low HDL cholesterol «40 mg/dl.)
`patients with CHD. A low HDL level can be secondary
`to other modifiable risk factors such as cigarette smoking,
`obesity, or physical
`inactivity. Beta-blockers
`can
`also lower HDL-cholesterollevels
`in CHD patients,
`hut have been shown to be efficacious for reducing
`subsequent CHD events after myocardial
`infarction.
`Therefore,
`their benefit
`in CHD patients outweighs
`the drawback of HDL lowering. Secondary prevention
`trials show that statin therapy significantly reduces risk
`
`(
`
`VI. Drug Therapy
`
`3307
`
`for major coronary events even in patients with low
`HDL cholesterol;
`therefore
`in these patients, LDL
`remains the primary target of therapy. The VA-HIT
`srudy48 suggests that fibrate therapy also may be bene-
`ficial for patients with low HDL levels in whom LDL-
`cholesterol
`levels are near optimal.
`
`c. General principles of primary prevention with drug
`therapy
`
`to individuals without
`Primary prevention pertains
`clinically evident CI-ID. For those with CHD risk
`equivalents, primary and secondary prevention merge.
`The guidelines
`for consideration
`of drug therapy and
`target goals for primary prevention are shown in
`Table VI.1-3.
`
`d. Drug considerations
`risk factors
`
`for persons with multiple (2+)
`
`1) 1a-year risk >20 percent
`
`Persons with multiple (2+) risk factors whose 10-year
`risk for hard CHD is >20 percent are included in the
`category of CHD risk equivalent. As discussed in sec-
`tion VI.1.b,
`they are managed similarly to other CI-ID
`risk equivalents
`that
`include non-coronary
`forms of
`clinical atherosclerotic
`disease and diabetes. The LDL
`cholesterol goal
`in these patients is <100 mg/dL, and
`when LDL cholesterol
`is ;:,130 mg/dL, an LDl.elower-
`ing drug can be started together with theraputic
`is
`lifestyle changes. When baseline LDL cholesterol
`100-129 mg/dL, TLC is indicated and concomitant
`use of drugs is optional. Drug options
`include statins,
`bile acid sequestrants,
`fibrates, and nicotinic acid.
`
`2)
`
`lO-year risk 10-20 percent
`
`goal is <130 mg/dL. TLC
`Here the LDL-cholesterol
`first. If this goal is not achieved
`should be introduced
`after 3 months of TLC, drug therapy should be consid-
`ered. A low dose of drug may suffice if TLC drops the
`to near 130 mg/dL. If not, a higher
`LDL cholesterol
`dose can be used. At the same time,
`if the metabolic
`syndrome is present, weight
`reduction and physical
`can
`activity should be emphasized. Later, consideration
`be given to modifying other
`lipid risk factors with nico-
`tinic acid or fibrares if they have not been adequately
`controlled by TLC.
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1013, p. 275 of 852
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`3308
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`Circulation December 17/24, 2002
`
`Table VI.1-3. Drug Therapy Consideration and Goals of Therapy for Primary Prevention
`-=======:::J
`1:=====:;:=. ='=_=C~==7=::'c
`LDL cholesterol
`Primary Goal of Therapy
`Level at Which to Consider
`Drug Therapy
`
`10-Year Risk for CHD
`
`I \
`
`I
`
`>20% (includes all CHD Risk
`Equivalents*)
`
`10-20%
`<10%
`<10%
`
`...
`
`> 100 rnq/dl,"
`
`2130 mgidL*
`
`,
`
`...
`
`2160 mg/dL
`
`2190 mg/dL¥
`
`.
`
`..
`
`<100 mg/dL
`
`<130 mg/dL
`
`<130 mgidL
`
`<160 mg/dL
`
`Risk Category
`Multiple (2+)risk factors
`
`0-1 risk factor
`
`Most patients with CHD risk equivalents have multiple risk factors and a 1a-veer risk >20 percent. They include patients with non-coronary forms of clinical atherosclerosis,
`diabetes, and multiple (2+) risk teeters with a 10-year risk >20 percent by Framingham scoring.
`is 100-129 mgldL, TLC should be
`t When LDLcholesterol is ;:::130mg/dL, a cholesterol-lowering drug can be started concomitantly with TLC. If baseline LDL cholesterol
`started immediately. Concomitant use of drugs is optional; several options for drug therapy are available (e.g.. statlns. bile acid sequestrants, fibrates. nicotinic acid).
`:l: When LDLcholesterol is in the range of 130-159 mgfdL, drug therapy can be used if necessaryto reach the tpt-cholesterol goal of <130 mgfdL, after an adequate
`trial of TLC.
`¥ When LDLcholesterol is in the range of 160-189 mgfdL. use of cholesterol-lowering drugs is optional. depending on response to TL( diet.
`
`3) 10-year risk <10 percent
`
`The LOL-cholesterol goal for multiple risk factors and
`10-year risk -c l O percent also is <130 mg/dL. However,
`LOL-Iowering drugs are not to be considered unless
`LOL cholesterol
`remains ~160 mgldL on TLC. When
`10-year risk is <10 percent, cost-effectiveness of drug
`therapy begins to erode, especially when the LOL-cho-
`lesterollevel
`remains in the range of 130 to 159 mgldL
`and other risk factors are appropriately
`controlled. On
`the other hand, when LOL-cholesterol
`concentrations
`~160 mgldL occur with multiple (2+) risk factors,
`long-
`term (>10-year)
`risk for CHO is relatively high. Thus,
`drug therapy deserves consideration. Of course, costs
`and side effects of drugs must also be taken into
`account when contemplating
`lifetime drug t