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Management of elevated low density lipoprotein-cholesterol (LDL-C) in primary prevention of cardiovascular disease
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Management of elevated low density lipoprotein-cholesterol (LDL-C) in primary prevention of cardiovascular disease
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Literature review current through: Nov 2017. | This topic last updated: Nov 14, 2017.

INTRODUCTION — The management of the risk factors for atherosclerotic cardiovascular disease (CVD), of which elevated LDL-C level is one, is called primary prevention if this process is done in someone who has not previously experienced an atherosclerotic vascular event. The rationale for activities focused on LDL-C reduction is based upon epidemiologic data documenting a continuous, positive, graded relationship between LDL-C concentration and CVD events and mortality and evidence that lowering of LDL-C in patients across a broad range of LDL-C levels reduces CVD events in patients with and without CVD [1-4]. (See "Overview of established risk factors for cardiovascular disease".)

Patients without known CVD are generally at much lower baseline risk of cardiovascular events than patients with known CVD. As such, the treatment approach to lowering LDL-C will depend on a determination of global CVD risk, as the potential absolute risk reduction with treatment for hypercholesterolemia will usually be smaller than for patients with established CVD.

For the purpose of risk reduction in patients without manifest CVD, only LDL-C lowering, among all lipid components, has been shown to be of clinical benefit. (See "Hypertriglyceridemia", section on 'Summary and recommendations' and "HDL cholesterol: Clinical aspects of abnormal values", section on 'Summary and recommendations'.)

This topic reviews the evidence for treating patients with increased CVD risk due to elevated LDL-C but no known CVD or CVD equivalents. The management of patients with established disease is discussed separately. (See "Management of low density lipoprotein cholesterol (LDL-C) in secondary prevention of cardiovascular disease".)

RATIONALE FOR LDL-C LOWERING IN PRIMARY PREVENTION — The preponderance of evidence from randomized trials that have evaluated the impact of LDL-C lowering (or the surrogate of total cholesterol) have demonstrated a reduction in cardiovascular disease events, irrespective of the pre-therapy LDL-C level. Among these events, it is the risk of myocardial infarction that is reduced the most.

Three very early trials of lipid altering therapy evaluated clofibrate [5,6], cholestyramine [7], or gemfibrozil [8]. They found no difference in coronary mortality and an increase in noncardiovascular disease mortality (with the exception of cholestyramine). In contrast to the results seen with these early trials of non-statin lipid modifying agents, many large randomized trials of statin therapy have demonstrated reductions in myocardial infarction and all-cause mortality; no evidence of an increase in noncardiovascular mortality has been seen:

The West of Scotland Coronary Prevention Study (WOSCOPS) showed that cholesterol lowering with pravastatin (40 mg daily) for five years reduced both the number of nonfatal myocardial infarctions and coronary heart disease (CHD) mortality in middle-aged men with a serum LDL-C concentration above 155 mg/dL (4.0 mmol/L) (figure 1) [9]. LDL-C fell 26 percent from 192 to 142 mg/dL (5.0 to 3.7 mmol/L).There was a borderline (p = 0.051) 22 percent reduction in all-cause mortality. Extended follow-up of the trial examining outcomes 10, 15, and 20 years after the trial concluded found continued reductions in mortality in patients who had initially been assigned to receive pravastatin [10-13].  

The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) found that lovastatin (20 to 40 mg daily), which reduced the serum LDL-C concentration by 25 percent, reduced the incidence of a first major coronary event (unstable angina pectoris, fatal and nonfatal myocardial infarction, and sudden cardiac death) in low-risk men and women without clinical evidence of cardiovascular disease (CVD) and LDL-C levels near the average for the general population (150 mg/dL [3.9 mmol/L], range 130 to 190 mg/dL [3.4 to 4.9 mmol/L]) [14]. For every 1000 men and women treated with lovastatin for five years, 19 major coronary events, 12 myocardial infarctions, and 17 coronary revascularizations could be prevented. No effect was seen on all-cause mortality.  

ASCOT-LLA studied atorvastatin (10 mg) in hypertensive men and women with nonfasting serum cholesterol less 251 mg/dL (6.5 mmol/L) with at least three additional cardiac risk factors. There was a trend toward a reduction in all-cause mortality (hazard ratio [HR] 0.87, 95% CI 0.71-1.06) [15].

The JUPITER trial of rosuvastatin 20 mg daily in healthy adult men and women with aC-reactive protein ≥2 mg/L and LDL-C levels below 130 mg/dL (3.4 mmol/L) found a marked reduction in the primary end point of first major cardiovascular events and all-cause mortality (HRs 0.56 and 0.80, respectively) [16]. The absolute benefit for the primary end point was 0.59 events per 100 person-years and for all-cause mortality was 0.25 deaths per 100 person-years. In JUPITER, the final LDL-C was 55 mg/dL (1.4 mmol/L) in the rosuvastatin group and 110 mg/dL (2.8 mmol/L) in the placebo group. This trial was stopped early for benefit, which may exaggerate the true level of benefit, particularly for the primary end point [17].

Multiple meta-analyses of clinical trials of LDL-C lowering therapy in patients with and without manifest CVD have been performed [18-20]. They have all found strong evidence of reductions in CVD events and CVD mortality [21]. Other meta-analyses have also found a reduction in the risk of all-cause mortality. In terms of individual components, all have found important reductions in myocardial infarction and in CHD mortality; reductions in stroke are somewhat smaller in magnitude but also clinically important [21].

A 2016 meta-analysis evaluated outcomes in over 300,000 individuals at a broad range of risk in 49 trials. The mean baseline LDL-C was 122 mg/dL (3.16 mmol/L). The following were found [22]:

The relative risk for the end point of major vascular events (a composite of cardiovascular death, acute coronary syndrome, coronary revascularization, or stoke) per 38.7 mg/dL (1-mmol/L) reduction in LDL-C was 0.77 (95% CI 0.71-0.84) for statins and 0.75 (95% CI 0.66-0.86) for non-statin therapies.

Among primary prevention trials (n = 8), the post-treatment LDL-C was positively correlated with CVD events, meaning that lower post-treatment LDLs were correlated with lower event rates and higher post-treatment LDL levels were correlated with higher event rates.

The most complete meta-analyses of primary prevention trials found a reduction in all-cause mortality benefit (relative risk 0.91) [18,19]. This relative reduction translated to a small absolute reduction in deaths of 0.09 percent per year (1.33 versus 1.42 percent per year) [18].

Taken together, these trials demonstrate that lowering LDL-C with statin therapy for primary prevention is effective at reducing CVD events (mostly myocardial infarction) over a wide range of baseline LDL-C levels and lipid profiles, and produces a similar relative risk reduction to statin therapy in secondary prevention. (See "Management of low density lipoprotein cholesterol (LDL-C) in secondary prevention of cardiovascular disease".) The absolute magnitude of benefit is typically lower than in secondary prevention. In the individual patient, the decision to start LDL-C lowering therapy must balance a modest absolute benefit with the risks and burdens of long-term therapy.

LIFESTYLE MODIFICATION — It is reasonable to recommend that all patients, particularly those with high LDL-C, undergo lifestyle modifications such as weight loss in overweight patients, aerobic exercise, and eating diets lower in saturated fats (See "Healthy diet in adults".) The United Kingdom Lipid Clinics Programme study of 2508 subjects found that, with diet alone, 60 percent of subjects had a mean reduction in body weight of 1.8 percent, which was associated with 5 to 7 percent reductions in serum total and LDL-C [23]. In occasional patients with poor baseline diets, marked dietary change can lower LDL-C by as much as 30 percent [24]. (See "Lipid lowering with diet or dietary supplements".)

A study randomly assigned 180 postmenopausal women and 197 men with low levels of high-density lipoprotein cholesterol (HDL-C) and moderately-elevated levels of LDL-C to aerobic exercise, diet, diet plus exercise, or no treatment [25]. Although there were no significant changes in HDL-C in any group, there were significant reductions in LDL-C in both men and women (14.5 and 20 mg/dL [0.38 and 0.52 mmol/L], respectively) in the diet plus exercise group compared with control or diet alone and, in men, in the diet plus exercise group compared with exercise alone.

The clinical benefits from LDL-C reduction from lifestyle modification may be evident within 6 to 12 months [26,27]. The individual response to a cholesterol-lowering diet depends upon many factors; some of the response is genetically determined, and increased body mass index is associated with less response to dietary change [28]. Patients who are referred to a dietitian may have greater success in the short term with lowering LDL-C compared with patients who receive dietary counseling by clinicians, although long-term compliance with dietary therapy is inadequate for both groups [29,30].

Despite these benefits on LDL-C in primary prevention, there is limited evidence that lifestyle modifications improve cardiovascular outcomes. In the Multiple Risk Factor Intervention Trial (MRFIT) in 12,866 high-risk men, an intervention that included dietary advice to reduce cholesterol levels did not significantly reduce coronary heart disease mortality (1.8 versus 1.9 percent) or all-cause mortality (4.1 versus 4.0 percent) [31]. However, the differences in achieved total cholesterol levels between the groups (generally 5 to 10 mg/dL [0.13 to 0.26 mmol/L]) were probably too small to expect significant effects on mortality.

INDICATIONS — In order to determine which patients should make an attempt to lower their LDL-C, their risk for the development of cardiovascular disease (CVD) events needs to be assessed using risk evaluation tools that take into account more than the baseline LDL-C. Cardiovascular risk should be calculated using validated risk models/calculators. Patients and their providers can then decide whether a 20 to 30 percent relative risk reduction, which is a reasonable expectation for statin therapy, translates into an absolute risk reduction large enough to be worth the cost, burdens, and potential side effects of daily therapy. We recommend statin therapy to most patients with a 10-year risk of 7.5 to 10 percent or greater. This range is consistent with many guideline recommendations. (See 'Recommendations of others' below.)

Recommendations for the use of risk calculators are found elsewhere. (See "Cardiovascular disease risk assessment for primary prevention: Risk calculators".)

Although we recommend CVD risk calculation for most patients, we recommend therapy to lower LDL-C in a majority of individuals with an LDL-C >190 mg/dL, independent of their overall risk. For young women of childbearing age who wish to become pregnant, we carefully discuss the potential benefits and risks with the patient. Many of these individuals will have heterozygous familial hypercholesterolemia. (See "Familial hypercholesterolemia in adults: Treatment", section on 'Heterozygous individuals'.)

Lipid-lowering therapy with statins reduces relative cardiovascular risk by approximately 20 to 30 percent regardless of baseline LDL-C. (See 'Rationale for LDL-C lowering in primary prevention' above.) The absolute benefit of treatment will be proportional to the underlying absolute risk. It should be noted that statins have not been well-studied for such a benefit in patients with very low baseline LDL-C levels (eg, below 70 mg/dL [1.8 mmol/L]), but very few such patients would be expected to have a high enough absolute risk to justify statin therapy. Determining when the benefits of treatment outweigh its burdens (costs, adverse effects) requires determination of the patient's future CVD risk.

The following are two patient examples for which the decision to start statin therapy may differ despite both patients having the same baseline LDL-C:

A 45-year-old non-smoking normotensive woman with an LDL-C of 180 mg/dL and a high-density lipoprotein cholesterol (HDL-C) of 40 mg/dL (1.03 mmol/L) has a 10-year risk of a myocardial infarction of approximately 1 percent. This could likely be reduced by 0.2 to 0.3 percentage points if she were treated with a statin daily for 10 years.

A 60-year-old non-smoking normotensive man with an LDL-C of 180 mg/dL and an HDL-C of 40 mg/dL has a 10-year risk of a myocardial infarction of approximately 12 percent. Use of a statin would reduce this risk to 8 to 9 percent, a 3 to 4 percentage point reduction.

Specific populations

Young patients — There are few data on the safety of statins over decades of therapy. It is also uncertain whether long-term treatment leads to better outcomes compared with postponing treatment until the patient's cardiovascular risk rises to an absolute level at which treatment becomes warranted. Notably, statins are contraindicated in pregnant women. (See "Statins: Actions, side effects, and administration", section on 'Risks in pregnancy and breastfeeding'.)

Because the short-term benefits of therapy may be both small and delayed in young patients, even a low rate of harmful side effects could outweigh potential benefits in such a low-risk group. If statin therapy is being contemplated for primary prevention in adults in their 20s and 30s, clinicians should carefully discuss the lack of good evidence on long-term safety prior to initiating therapy.

Older patients — As few elderly patients were enrolled in randomized trials of statins, outcomes with therapy in this age group have not been well studied. The decision to lower LDL-C in adults 75 years of age and older should be individualized and should occur after a full discussion of the potential benefits and costs. Shared decision making is important in this setting. Some lipid experts do not initiate statin therapy in individuals older than 85 years.

We believe that the risk of myocardial infarction and stroke will be significantly lowered by statin therapy in elderly patients. The higher the risk of a CVD event, the more inclined we are to recommend statin therapy in the elderly.

Since the rate of death from other all causes increases with aging, it is difficult to demonstrate a benefit from statin therapy on mortality. The overall benefit from statin therapy in individuals with significant noncardiovascular disease that it may shorten lifespan within the next 10 years is likely small.

Patients should consider the financial cost of statin therapy as well as the potential burdens of requiring multiple medications.

INITIAL DRUG THERAPY — Several randomized trials have examined the effects of lipid-lowering pharmacologic therapy on cardiovascular disease (CVD) events. Most trials have compared a fixed dose of a single pharmacologic agent with placebo, with both groups receiving basic, limited lifestyle counseling. No trials that have evaluated effects on CVD events have tested any medication in combination with statins or treatment to specific LDL-C goals.

As discussed below, when a pharmacologic agent is indicated for treatment in primary prevention, a statin is the preferred medication. If a statin is not tolerated or a particular LDL-C goal is not achieved on a statin alone, we suggest not administering or adding a non-statin lipid-lowering medication in most patients.

Nonstatin therapy — In early trials of lipid lowering therapy in primary prevention with medications other than statins, several trials found a disturbing increase in noncardiovascular mortality [5-8]. (See 'Rationale for LDL-C lowering in primary prevention' above.) In primary prevention, where the absolute benefit of any therapy may be quite small, well-designed trials demonstrating greater benefit than harm are generally needed before a non-statin agent can be recommended.

Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors have not been adequately evaluated in primary prevention in patients without familial hypercholesterolemia. (See "Familial hypercholesterolemia in adults: Treatment", section on 'Goal of therapy'.) Their effects in secondary prevention suggest that they could be expected to reduce cardiovascular outcomes to a similar degree, as is seen with statin therapy. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use".) However, their cost, the requirement for injections, and the lack of long-term safety data would make them an option only in the highest-risk primary prevention patients who are unable to tolerate statin therapy.

USE OF STATINS

Intensity — Moderate-intensity statin therapy includes daily treatment with:

Lovastatin 40 mg

Pravastatin 40 mg

Simvastatin 40 mg

Atorvastatin 10 to 20 mg

Rosuvastatin 5 to 10 mg

High-intensity statin therapy includes daily treatment with:

Atorvastatin 40 to 80 mg

Rosuvastatin 20 to 40 mg

Dose — If a decision is made to treat with statins to achieve the 20 to 30 percent reduction in coronary heart disease events seen in most clinical trials, it may make sense to treat with the doses shown to be of benefit in clinical trials.

Statin doses that have been used in clinical trials of primary prevention include low-to-moderate-intensity (pravastatin 40 mg, lovastatin 20 to 40 mg, atorvastatin 10 mg) and high-intensity (rosuvastatin 20 mg) therapy. No trials have directly compared the effects of low-to-moderate- with high-intensity statin therapy for primary prevention.

When the decision is made to treat, we suggest starting treatment with a moderate dose of a statin, such as 20 mg of atorvastatin (or 40 mg of lovastatin, pravastatin, or simvastatin, or 5 to 10 mg of rosuvastatin). Long-term compliance is likely increased if the patient does not have a side effect on first use of the drug.

Side effects and intolerance — Statin side effects and intolerance, which vary somewhat among the statins, are discussed in detail separately. (See "Statins: Actions, side effects, and administration".)

GOAL SETTING — For patients in whom a decision is made to lower LDL-C with drug therapy, the optimal target LDL-C is not well studied. Most trials have evaluated a single dosage level of statin therapy or a limited strategy of titration rather than treatment to a given LDL goal level. In addition, the two other drug therapies that might be considered for additional LDL-C lowering, ezetimibe and proprotein convertase subtilisin kexin 9 (PCSK9) antibodies, have not been well studied in patients without cardiovascular disease (CVD; excluding individuals with familial hypercholesterolemia).

Given these considerations, we do not think that it is necessary to set a specific LDL-C goal for these patients. We attempt to treat them with moderate-intensity statin therapy. For patients at high risk, we increase to high-intensity statin therapy. (See 'Intensity' above.)

Failure to achieve goal LDL-C — We do not suggest targeting a goal LDL-C level when treating with a statin for primary prevention. (See 'Goal setting' above.) Thus, in patients who do not achieve a particular LDL-C goal on statin therapy alone, we suggest not adding a non-statin lipid-lowering medication for primary prevention. That is, the patient should be maintained on statin therapy as his/her only lipid-lowering medication. Until there is better long-term evidence of the safety of PCSK9 inhibitors, we would not add these agents on to statin therapy in primary prevention.

Some patients do not achieve appropriate LDL-C reduction due to non-adherence. It is important to ask about adherence at follow-up visits. Measuring LDL-C response may be helpful in determining whether patients are adherent to treatment. When determining adherence is desired, LDL-C can reasonably be measured six weeks after initiating statin therapy and every 6 to 12 months thereafter, or as the clinical situation dictates.

The LDL-C does not require fasting in most cases. However, in patients who have had prior significant elevation(s) of nonfasting triglyceride, a fasting LDL-C (calculated from the lipid profile) should be obtained. This will help to avoid miscalculation of the LDL-C. An alternative approach is to obtain a direct measurement of LDL-C. This approach can be chosen as long as the direct method is always used to assess LDL-C; switching between the calculated and direct measurements is not recommended. (See "Measurement of blood lipids and lipoproteins", section on 'Fasting versus non-fasting tests'.)

In patients who do not tolerate statins, we suggest not administering a non-statin lipid-lowering medication for primary prevention, unless the patient has LDL-C levels substantially higher than 190 mg/dL. That is, no lipid-lowering therapy should be administered in patients who are intolerant of statins unless their LDL-C is very high. Potential interventions include lifestyle modification and, in higher-risk patients, antiplatelet therapy. (See 'Lifestyle modification' above and "Aspirin in the primary prevention of cardiovascular disease and cancer".)

In the highest-risk patients (10-year risk of events of approximately 20 percent or more), if statin myopathy has been carefully assessed (algorithm 1) and statin therapy is not possible, treatment with a PCSK9 inhibitor or ezetimibe is an option [32]. We recognize that PCSK9 antibodies are not approved for use in patients without established CVD in many geographies. (See 'Nonstatin therapy' above.) As additional information becomes available on the long-term safety of these agents, more patients may become eligible for such treatment.

RECOMMENDATIONS OF OTHERS — Most societal guidelines recommend evaluating future cardiovascular disease (CVD) risk using a risk calculator and treating those patients at higher levels of risk. For patients with modestly elevated risk, shared decision making about treatment is warranted.

The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline on the treatment of blood cholesterol makes the following recommendations for adults ages 40 to 75 without CVD and LDL-C between 70 mg/dL (1.81 mmol/L) and 189 mg/dL (4.90 mmol/L) [33]:

Treat those with an estimated 10-year CVD risk ≥7.5 percent with moderate-to-high intensity statin therapy.

It is reasonable to offer treatment with moderate-intensity statin therapy to those with an estimated 10-year CVD risk between 5.0 and 7.5 percent.

For adults with an LDL-C ≥190 mg/dL (4.92 mmol/L), the ACC/AHA recommends treatment with high-intensity statin therapy and consideration of use of non-statin drugs to further reduce the LDL-C. Many of these patients will have heterozygous familial hypercholesterolemia. (See "Familial hypercholesterolemia in adults: Treatment", section on 'Initial drug therapy'.)

The United States Preventive Services Task Force recommends treatment of adults 40 to 75 with 10-year ASCVD risk greater than 10 percent and at least one CVD risk factor [21].

Guidelines for lipid management for primary prevention of CVD from the United Kingdom's National Institute for Health and Clinical Excellence (NICE) state that patients with a 10-year risk of CVD of 10 percent or more should be offered statin therapy [34].

The 2016 European Society of Cardiology/European Atherosclerosis Society guidelines for the management of dyslipidemias recommends using the SCORE system to assess the 10-year risk for fatal CVD (there is a conversion factor to obtain the risk of fatal plus nonfatal hard CVD events) [35]. For individuals with a <5 percent 10-year risk, lipid lowering therapy is generally not indicated. An LDL-C goal of 100 mg/dL (2.6 mmol/L) is suggested.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lipid disorders in adults" and "Society guideline links: Primary prevention of coronary heart disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: High cholesterol treatment options (Beyond the Basics)")

Basics topics (see "Patient education: High cholesterol (The Basics)" and "Patient education: Can foods or supplements lower cholesterol? (The Basics)" and "Patient education: High triglycerides (The Basics)")

SUMMARY AND RECOMMENDATIONS

We suggest that all patients with an elevated LDL-C be counseled to exercise, eat a prudent diet, and lose weight as appropriate (Grade 2C). (See 'Lifestyle modification' above.)

We calculate a baseline risk for cardiovascular disease (CVD) events in all patients with an off-treatment LDL-C above 100 mg/dL whose demographics permit a calculation. (See 'Indications' above.)

In patients for whom a 20 to 30 percent reduction in events translates into an absolute reduction in events that would be worth the costs and burdens of daily statin therapy, we recommend statin therapy (Grade 1A). For example, such patients might include those with a 10 percent or greater 10-year risk. (See 'Rationale for LDL-C lowering in primary prevention' above and "Cardiovascular disease risk assessment for primary prevention: Our approach" and 'Indications' above.)

In primary prevention, when the decision is made to treat, we suggest treatment with a moderate dose of a statin such as atorvastatin 20 mg (or 40 mg of lovastatin, pravastatin, or simvastatin; or 5 to 10 mg of rosuvastatin), rather than starting at a higher dose (Grade 2C). (See 'Dose' above.)

Measuring LDL-C response at six weeks after initiating therapy and every 12 months thereafter may be helpful in assessing adherence to medication and diet. Occasionally, an LDL-C might drift upward in an adherent patient, such as a woman at menopause. In this situation, statin dose might be increased in an individual taking a moderate dose of a statin. (See 'Side effects and intolerance' above.)

For most primary prevention patients who do not tolerate statins, we suggest not administering a non-statin lipid-lowering medication (Grade 2C). Potential interventions include lifestyle modification and, in higher-risk patients, antiplatelet therapy.

However, in patients with very high LDL-C levels and high CVD risk, we believe it is reasonable to consider a non-statin drug. (See 'Side effects and intolerance' above.)

In primary prevention patients who do not achieve a particular LDL-C level on statin therapy alone, we suggest not adding a non-statin lipid-lowering medication (Grade 2C). That is, the patient should be maintained on statin therapy as their only lipid-lowering medication. (See 'Failure to achieve goal LDL-C' above.)

ACKNOWLEDGMENT — Michael Pignone, MD, MPH, was recently a member of the United States Preventive Services Task Force. The expressed opinions herein are those of Dr. Pignone and do not necessarily represent those of the United States Preventive Services Task Force.

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