NLA Recommendations for Patient-Centered Management of ... · replace, clinical judgment regarding...

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NLA Recommendations for Patient-Centered

Management of Dyslipidemia

Matthew K. Ito, Pharm.D., FCCP, FNLA, CLS

Immediate-Past President,

National Lipid Association

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Evolution of US Evidence-Based Treatment

RecommendationsLDL-C Goals Have Become More Intense Over Time

3

1988ATP I

1993ATP II

2001ATP III

2004ATP III

Update

2006AHA/ACC

2° Prevention2010ADA

2013ACC/AHA

2014NLA

Goal<130 mg/dL

Goal<100 mg/dL

Goal<100 mg/dL

Goal<100 mg/dL

Optional Goal

<70 mg/dL

Goal<100 mg/dL

Reasonable Goal

<70 mg/dL

Goal<100 mg/dL

Goal<70 mg/dL

Very-high risk High risk Overt CVD

Dual Goals<130 mg/dl (Non-HDL-C)

<100 mg/dL (LDL-C)

Very-high riskDual Goals

<100 mg/dl (Non-HDL-C)<70 mg/dL (LDL-C)

Definitions• ATP I defines as CHD or 2 other CHD risk factors1

• ATP II defines as evidence of CHD or other atherosclerotic disease2

• ATP III and 2004 update defines as CHD or CHD risk equivalent3,4

• AHA/ACC 2° Prevention defines as established coronary or other atherosclerotic disease5

• ADA defines as overt CHD6

• ACC/AHA defines as clinical ASCVD7

• NLA defines as diabetes mellitus with 0-1 other major ASCVD risk factors (no end-organ damage), chronic kidney disease Stage 3B or 42, or LDL-C ≥190 mg/dL (severe hypercholesterolemia phenotype)8,9

1. Arch Intern Med. 1988 Jan;148(1):36-69. 2. JAMA. 1993 Jun 16;269(23):3015-23. 3. JAMA. 2001 May 16;285(19):2486-97. 4.Circulation.2004;110:227-39. 5 JACC. 2006;47:2130-9. 6. Diabetes Care. 2010;33: S11-S61 7. JACC. 2014;63:2889-2934. 8. JCL. 2014;8(5):473–88. 9. JCL. 2015;9(2):129–169.

“No recommendations

are made for or against specific LDL-C or non–HDL-C goals”

Adherence to a fixed-

dose of statin at 4-12 weeks

In part a measure of

success

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Unintended ConsequenceNational Committee for Quality Assurance

4

Inability to ScreenRenders any guideline

useless!

Retiring the LDL-C Screening, LDL-C Control (<100 mg/dL), and BP Control (<140/80 mm Hg) indicators aligns with the latest ACC/AHA and JNC 8 recommendations.

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Recommendation Graded by:

Strength of Recommendations and Quality of Evidence

Jacobson TJ et al. JCL. 2015;9(2):129–169.

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Jacobson TJ et al. JCL. 2015;9(2):129–169.

Recommendation Graded by:

Strength of Recommendations and Quality of Evidence

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Guiding Principles/Conclusions

1. The key initiating process in atherosclerosis is the

subendothelial retention of Apo B-containing lipoproteins.

2. An elevated level of cholesterol carried by circulating Apo B-

containing lipoproteins (non-HDL-C and LDL-C, termed

atherogenic cholesterol) is a “root cause” of atherosclerosis,

the key underlying process contributing to most clinical

ASCVD events.

3. Reducing elevated levels of atherogenic cholesterol will lower

ASCVD risk in proportion to the extent that atherogenic

cholesterol is reduced (LOWER IS BETTER). This benefit is

presumed to result from atherogenic cholesterol lowering

through multiple modalities, including lifestyle and drug

therapies.

7Jacobson TJ et al. JCL.2014;8(5):473-488. Jacobson TJ et al. JCL. 2015;9(2):129–169.

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8Boekholdt et al. JACC 2014;64:485–94

Patients achieving an LDL-C <50 mg/dl had a statistically significantly lower risk for major cardiovascular events compared with patients achieving an LDL-C level between 75 and <100 mg/dl (adjusted HR: 0.81; 95% CI: 0.70 to 0.95).

(8 statin trial; n=38,153)

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4. The intensity of risk-reduction therapy should generally be

adjusted to the patient’s absolute risk for an ASCVD event.

5. Atherosclerosis is a process that often begins early in life and

progresses for decades before resulting in a clinical ASCVD

event. Therefore, both intermediate-term and long-term/lifetime

risk should be considered when assessing the potential benefits

and hazards of risk-reduction therapies.

6. For patients in whom lipid-lowering drug therapy is indicated,

statin treatment is the primary modality for reducing ASCVD risk.


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7. Non-lipid ASCVD risk factors should also be managed

appropriately, particularly high blood pressure, cigarette smoking,

and diabetes mellitus.

8. The measurement and monitoring of atherogenic cholesterol

levels remain an important part of a comprehensive ASCVD

prevention strategy.


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Conceptual Framework for Formulation

of NLA Expert Panel Recommendations

• Various guidelines and recommendations have been issued in

the last few years that contain material differences (ie

targets).

• An NLA Expert Panel was formed to prepare a set of

consensus recommendations intended to inform, not

replace, clinical judgment regarding dyslipidemia

management.

• The NLA Expert Panel Recommendations for Patient-

Centered Management of Dyslipidemia were prepared after

a comment period to allow input and advice to be

obtained from other experts and organizations.

• A patient-centered approach dictates that clinical judgment take into

account the circumstances, objectives, and preferences of each

individual patient. Collaboration between the patient and the clinician. 11Jacobson TJ et al. JCL.2014;8(5):473-488.

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Conceptual Framework (continued)

• The NLA recognizes that dyslipidemia management has

made a major contribution to the progressive reduction in

ASCVD morbidity and mortality observed in the last

decade (plus).

– This reduction in risk occurred under the guidance provided by

previous documents (most notably the NCEP ATPIII).

• The NLA Expert Panel consensus view is that the evidence

accumulated since the 2004 update of the National

Cholesterol Education Program Adult Treatment Panel III

Guidelines warrants a modest refinement of previous lipid-

related risk management strategies.

12Jacobson TJ et al. JCL.2014;8(5):473-488.

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US age-standardized death rates

attributable to CVD, 2000 to 2010

Go A S et al. Circulation. 2014;129:e28-e292

Copyright © American Heart Association, Inc. All rights reserved.

Release of NCEPATP III Release of NCEP

ATP III Update

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Conceptual Framework (continued)

• The panel considered evidence from randomized

controlled trials (RCTs), including:– primary, subgroup and pooled analyses where available

– epidemiological studies

– metabolic studies

– mechanistic and genetic studies.

• The panel acknowledges that the primary results from RCTs

represent the strongest evidence from which to draw

conclusions about benefits and risks of treatment strategies.– However, the available RCT evidence has limitations, is often

incomplete, or is of uncertain relevance to patients with

characteristics that may differ in important ways from those who

participated in the RCTs.


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Importance of Lifestyle Therapies

• The NLA Expert Panel’s consensus view is that lifestyle

therapies are an important element of risk-reduction

therapies, whether or not drug therapy is used.

• The application of pharmacotherapy to dyslipidemia

management has been enormously successful, and may be

needed in those with sufficient risk.

– Large-scale RCTs, involving, in aggregate, hundreds of thousands of

participants, have shown that drug therapies (particularly statins) that

lower atherogenic cholesterol levels are effective for reducing ASCVD

morbidity and mortality.

• However, results from observational studies strongly suggest

that lifestyle habits have an important impact on atherogenic

cholesterol levels, as well as other related disturbances (i.e.,

obesity, hypertension, and insulin resistance).


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Usefulness of Treatment Goals

• Treatment goals are useful as means to ensure that the

aggressiveness of therapy to lower atherogenic

cholesterol is matched to absolute risk for an event.

• Facilitate effective communication between patients and

clinicians while maximizing long-term adherence to the

treatment plan.

• The strategy of treating patients to a specific level of

LDL-C or non-HDL-C has not been tested in any of the

large trials assessing ASCVD morbidity or mortality.

– However, results from RCTs (pharmacotherapy, diet, ileal bypass

surgery) have indicated that lower on-treatment levels have been

consistently associated with lower absolute risk for an ASCVD event.

– Generally align with results from observational studies suggesting a log-

linear relationship between levels of atherogenic cholesterol and

absolute ASCVD event risk.16

Jacobson TJ et al. JCL.2014;8(5):473-488. Jacobson TJ et al. JCL. 2015;9(2):129–169.

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Very Low LDL-C and Non-HDL-C in Statin

Trials and Major CVD Event Risk

0,44

0,510,56 0,58

0,64

0,71

1,00

0,570,60

0,640,69

0,75

0,89

1,00

<50, <75 50-74, 75-99 75-99, 100-124 100-124, 125-149 125-149, 150-174 150-174, 175-199 >=175, >=200

LDL-C Non-HDL-C

Boekholdt et al. JACC 2014;64:485-494

On Treatment LDL- C, Non-HDL-C mg/dL

HR 0.81

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Screening in Adults

• A fasting or non-fasting lipid profile should be measured at

least every 5 years, starting at age 20; ideally fasting to allow

assessment of LDL-C and triglyceride levels.

– If non-fasting, focus on non-HDL-C (total-C minus HDL-C) and HDL-C.

• Should be accompanied by an assessment of ASCVD risk

factors and risk stratification when indicated (covered later).

• If low risk, public health recommendations may be applied for

those with atherogenic cholesterol levels in the desirable range

(LDL-C <100 mg/dL, non-HDL-C <130 mg/dL)

– Re-screen in 5 years, or with changes in risk factors (including weight gain),

co-morbidities, new secondary causes of dyslipidemia, premature ASCVD

events in first degree relatives, or other changes, based on clinical judgment

• Otherwise, institute therapies and monitoring as outlined in the

subsequent slides.18Jacobson TJ et al. JCL.2014;8(5):473-488. Jacobson TJ et al. JCL. 2015;9(2):129–169.

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• Clinicians may consider measuring LDL particle concentration as an alternative to Apo B.

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Co-Primary TargetsRisk of Major Cardiovascular Events by Non-HDL-C and LDL-C

Categories

From Statin Trials (1994-2008)

21Boekholdt SM, et al. JAMA. 2012;307:1302-1309.

• When non-HDL-C and LDL-C are discordant, risk follows non-HDL-C more closely than LDL-C.

• Non-HDL-C can be determined in non-fasting state

N=38,153

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Targets of Therapy – Triglycerides

• An elevated triglyceride level is not a target of therapy per

se, except when very high (severe; ≥500 mg/dL ).

• When triglycerides are between 200-499 mg/dL, the targets

of therapy are non-HDL-C and LDL-C.

• When the triglyceride concentration is very high (≥500 mg/dL,

and especially if ≥1000 mg/dL), reducing the concentration to

<500 mg/dL to prevent pancreatitis becomes the primary goal

of therapy.


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HDL-C

• The level of HDL-C is an important risk indicator and used

in risk factor counting and quantitative risk assessment. Low

HDL-C is also a component of the metabolic syndrome.

• HDL-C is not recommended as a target of therapy per se,

but the level is often raised as a consequence of efforts to

reduce atherogenic cholesterol through lifestyle and drug

therapies.


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Criteria for Clinical Identification of Metabolic Syndrome (Any 3 or More of the Listed Components)

Measure Categorical Cut Points

1. Elevated waist circumference ≥40 inches (≥102 cm) in men

≥35 inches (≥88 cm) in women

2. Elevated triglycerides ≥150 mg/dL(drug treatment with a triglyceride-lowering

agent is an alternate indicator)

3. Reduced HDL-C <40 mg/dL in men

<50 mg/dL in women

4. Elevated blood pressure Systolic ≥130 and/or diastolic ≥85 mmHg(antihypertensive drug treatment in a patient with

a history of hypertension is an alternate indicator)

5. Elevated fasting glucose ≥100 mg/dL(drug treatment of elevated glucose is an

alternate indicator)

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Candidates for intensive lifestyle therapy


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Lifestyle Therapy

• Dietary therapy in accordance with the AHA

recommendations and ≥150 minutes per week of

moderate or higher intensity physical activity is

recommended

• Weight reduction should be recommended in those

who are overweight or obese

• The addition of viscous fiber and/or plant

sterol/stanols should be considered in those not

responding to dietary change

• Dietitian consultation is recommended, whenever

possible


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Secondary Causes of Dyslipidemia

• Screen for conditions and medications that produce

adverse changes in lipid levels and may be targets for

intervention.

– Discontinuing, reducing the dosage, or switching to an alternative

medication;

– Managing the condition (e.g., treating hypothyroidism, diabetes

mellitus, obesity).

26Jacobson TJ et al. JCL.2014;8(5):473-488.Jacobson TJ et al. JCL.2014;8(5):473-488. Jacobson TJ et al. JCL. 2015;9(2):129–169.

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Step 1: Identify Patients with Very-High

Risk Conditions• ASCVD

– Documented CHD

– Thrombotic stroke or TIA

– Atherosclerotic PAD

• Ankle-brachial index <0.9

– Renal atherosclerosis

– Atherosclerotic aortic

aneurysm

– Carotid plaque ≥50%

stenosis

• DM ± end organ (following

slides) involvement or ≥2

additional major ASCVD

risk factors (following

slides)

Non-HDL-C ≥100 mg/dL

LDL-C ≥70 mg/dL

Non-HDL-C <100mg/dLLDL-C <70 mg/dLOptional apo B <80 mg/dL

Goals

NOTE: Consider moderate or high-intensity statin therapy, regardless of non-HDL-C or LDL-C

Threshold tobegin treatment at


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End-Organ Involvement in Type 2 DM

• Urinary albumin/creatinine ratio >30 mg/g

• Chronic kidney disease (<60 eGFR)

• Diabetic retinopathy


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Major Risk Factors for ASCVD

1. Age

Male ≥45 years

Female ≥55 years

2. Family history of early CHD

<55 years of age in a male first-degree relative, or

<65 years of age in a female first-degree relative

3. Current cigarette smoking

4. High blood pressure (≥140/≥90 mm Hg, or on blood

pressure medication)

5. Low HDL-C

Male <40 mg/dL

Female <50 mg/dL


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Step 2: Identify Patients with High-Risk

Conditions

• DM with 0-1 additional ASCVD risk factor and no

end-organ involvement

• Chronic kidney disease stage 3B (30-44 eGFR) or

4 (15-29 eGFR)

• LDL-C ≥190 mg/dL (severe hypercholesterolemia

phenotype)

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Non-HDL-C ≥130 mg/dLLDL-C ≥ 100 mg/dL

Non-HDL-C <130 mg/dLLDL-C <100 mg/dLOptional apo B <90 mg/dL

Goals

Jacobson TJ et al. JCL.2014;8(5):473-488.



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Step 3: Count Major Risk Factors for

ASCVD1. Age

Male ≥45 years

Female ≥55 years

2. Family history of early CHD

<55 years of age in a male first-degree relative, or

<65 years of age in a female first-degree relative

3. Current cigarette smoking

4. High blood pressure (≥140/≥90 mm Hg, or on blood pressure medication)

5. Low HDL-C

Male <40 mg/dL

Female <50 mg/dL

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a. If 0–1 and no other major indicators of higher risk, assign to low-risk

category. Consider assigning to a higher risk category based on other

known risk indicators (Table 11 on following slides), when present.

b. If >3 major ASCVD risk factors are present, assign to high-risk

category (Previous slide).


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Low-Risk Patients

• 0-1 ASCVD risk factor

• No characteristics of very-high or high-risk

groups

• No evidence of high-risk indicators (Table 11)


Non-HDL-C ≥190 mg/dLLDL-C ≥160 mg/dL

Goals


Jacobson TJ et al. JCL.2014;8(5):473-488.Jacobson TJ et al. JCL.2014;8(5):473-488. Jacobson TJ et al. JCL. 2015;9(2):129–169.

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• If 2 major ASCVD risk factors, risk assessment refinement

can be employed.

A. If quantitative risk scoring (following slides) reaches the

high-risk threshold, assign to high-risk category.

B. Consider assigning to high-risk category if other risk

indicators are present based on additional testing (Table 11).

– If, based on above steps, no indication is present to assign to

high-risk, assign to moderate-risk category.

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Step 3: Count Major Risk Factors for

ASCVD (Continued)

Jacobson TJ et al. JCL.2014;8(5):473-488.Jacobson TJ et al. JCL.2014;8(5):473-488. Jacobson TJ et al. JCL. 2015;9(2):129–169.

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Quantitative Risk Scoring Calculators

Thresholds for “High-Risk”

• ATP III Framingham risk calculator: ≥10% 10-

year risk for a hard CHD event (myocardial

infarction or CHD death);

• Pooled Cohort Equations (ACC/AHA): ≥ 15%

10-year risk for a hard ASCVD event (myocardial

infarction, stroke, or death from CHD or stroke);

and

• Framingham long-term (30-year to age 80) risk

calculator: ≥ 45% risk for CVD (myocardial

infarction, CHD death, or stroke).


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Moderate-Risk Patients

• 2 major ASCVD risk factors

• No characteristics of very-high or high risk

groups

• No evidence of high-risk quantitative risk

scoring (Previous slide). or key high-risk

indicators (Table 11).


Non-HDL-C ≥160 mg/dLLDL-C ≥130 mg/dL

GoalsThreshold tobegin treatment at


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Drug Therapy: Key Considerations

• Provider-patient discussion of risk-benefit ratio and

respect for patient preferences are keys to

enhancing adherence.

• Moderate or high-intensity statin is the preferred first

step except when TG ≥500 mg/dL, when therapy

directed at hypertriglyceridemia is the first priority.

• For statin-intolerant patients consider switching

statins; alternate-day or lower-dose statins; lower

dose statin-non-statin regimens; non-statin

monotherapy or combination therapy


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Drug Therapy –Key Considerations

(continued)

• Combination therapy with a statin plus a second (or

third) agent may be considered for patients who have not

reached their treatment goals for atherogenic cholesterol

levels, particularly in those at high and very high risk.

Generally, the maximally tolerated statin dose should be

used before add-on therapy is considered.


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Drug Therapy: Triglycerides

• For TG ≥1000 mg/dL, consider fibrate, high-

dose long chain Ω-3 fatty acids and niacin; for

500-999 mg/dL and no history of pancreatitis,

consider statins or any of the above

• For TG 200-499 mg/dL, targets of therapy are

non-HDL-C and LDL-C, generally using statins


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Severe Hypercholesterolemia Phenotype

• Usually due to FH and associated with early

ASCVD

• Cascade screening is recommended

• Goals of treatment in absence of a very-high-risk

condition are non-HDL-C <130 mg/dL and

LDL-C <100 mg/dL, or reduction of

atherogenic cholesterol of ≥50% from

baseline if goals cannot be achieved

• Consider lower goals in those with multiple or

poorly controlled other major ASCVD risk

factors43Jacobson TJ et al. JCL.2014;8(5):473-488. Jacobson TJ et al. JCL. 2015;9(2):129–169.

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NLA Treatment Recommendations:

Summary

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• A “root cause” of atherosclerotic cardiovascular disease

is cholesterol-containing particles attaching to the walls

of arteries. Thus our focus should remain on treatment of

the “root cause” and in general, the lower the

cholesterol, the better.

• A healthy lifestyle that incorporates diet, weight

management and exercise should be the first approach

to lowering cholesterol levels that are too high.

• Control and reduction of LDL-C is important, but an even

better overall marker of risk is “non-HDL-C”.


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• Patients at very high risk, such as those who have already had a

cardiac event, should try to achieve non-HDL-C <100 mg/dL (LDL-

C <70mg/dL), while those at lower risk levels should try to

achieve levels below 130 mg/dL (LDL-C <100mg/dL).

• Since the co-primary target is non-HDL-C, drug therapies

specifically aimed at lowering TG levels may not be necessary

unless TG > 500 mg/dL.

• Efforts to specifically raise HDL levels have been shown to be both

less important and less achievable.

• Use of more potent statin drugs, at moderate to high doses if

necessary, should be the first approach to reach cholesterol

goals if lifestyle changes have not been adequate.

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Summary (cont)


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• Use of other medications or therapies, such

as fibrates, cholesterol absorption inhibitors,

niacin or omega-3 fatty acids can be considered

if cholesterol and triglyceride goals are not

reached with statins alone.

• Non-lipid risk factors should also be managed,

such as high blood pressure, cigarette smoking

and diabetes.

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Summary (cont)


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